cv cardiovascular physiology concepts klabunde

LEARNING OBJECTIVESTHE NEED FOR A CIRCULATORY SYSTEMTHE ARRANGEMENT OF THE

CARDIOVASCULAR SYSTEMTHE FUNCTIONS OF THE HEART AND

BLOOD VESSELSHeartVascular SystemInterdependence of Circulatory and

Organ Function

THE REGULATION OF CARDIAC ANDVASCULAR FUNCTION

THE CONTENT OF THE FOLLOWINGCHAPTERS

SUMMARY OF IMPORTANT CONCEPTSREVIEW QUESTIONS

c h a p t e r

1Introduction to the CardiovascularSystem

LEARNING OBJECTIVES

Understanding the concepts presented in this chapter will enable the student to:1. Explain why large organisms require a circulatory system, while single-cell and small multi-

cellular organisms do not.2. Describe the series and parallel arrangement of the cardiac chambers, pulmonary circula-

tion, and major organs of the systemic circulation.3. Describe the pathways for the flow of blood through the heart chambers and large vessels

associated with the heart.4. Describe, in general terms, the primary functions of the heart and vasculature.5. Explain how the autonomic nerves and kidneys serve as a negative feedback system for

the control of arterial blood pressure.

1

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THE NEED FOR A CIRCULATORYSYSTEM

All living cells require metabolic substrates(e.g., oxygen, amino acids, glucose) and amechanism by which they can remove by-products of metabolism (e.g., carbon dioxide,lactic acid). Single-cell organisms exchangethese substances directly with their environ-ment through diffusion and cellular transportsystems. In contrast, most cells of large organ-isms have limited or no exchange capacitywith their environment because their cells arenot in contact with the outside environment.Nevertheless, exchange with the outside envi-ronment must occur for the cells to function.To accomplish this necessary exchange, largeorganisms have a sophisticated system ofblood vessels that transports metabolic sub-stances between cells and blood, and betweenblood and environment. The smallest of theseblood vessels, capillaries, are in close proxim-ity to all cells in the body, thereby permittingexchange to occur. For example, each cell inskeletal muscle is surrounded by two or morecapillaries. This arrangement of capillariesaround cells ensures that exchange can occurbetween blood and surrounding cells.

Exchange between blood and the outsideenvironment occurs in several different or-gans: lungs, gastrointestinal tract, kidneys andskin. As blood passes through the lungs, oxy-gen and carbon dioxide are exchanged be-tween the blood in the pulmonary capillariesand the gases found within the lung alveoli.Oxygen-enriched blood is then transported tothe organs where the oxygen diffuses from theblood into the surrounding cells. At the sametime, carbon dioxide, a metabolic waste prod-uct, diffuses from the tissue cells into theblood and is transported to the lungs, whereexchange occurs between blood and alveolargases.

Blood passing through the intestine picksup glucose, amino acids, fatty acids, and otheringested substances that have been trans-ported from the intestinal lumen into theblood in the intestinal wall by the cells liningthe intestine. The blood then delivers thesesubstances to organs such as the liver for ad-ditional metabolic processing and to cells

throughout the body as an energy source.Some of the waste products of these cells aretaken up by the blood and transported toother organs for metabolic processing and fi-nal elimination through either the gastroin-testinal tract or the kidneys.

Cells require a proper balance of water andelectrolytes (e.g., sodium, potassium, and cal-cium) to function. The circulation transportsingested water and electrolytes from the in-testine to cells throughout the body, includingthose of the kidneys, where excessive amountsof water and electrolytes can be eliminated inthe urine.

The skin also serves as a site for exchangeof water and electrolytes (through sweating),and for exchange of heat, which is a major by-product of cellular metabolism that must beremoved from the body. Increasing blood flowthrough the skin enhances heat loss from thebody, while decreasing blood flow diminishesheat loss.

In summary, the ultimate purpose for thecardiovascular system is to facilitate exchangeof gases, fluid, electrolytes, large moleculesand heat between cells and the outside envi-ronment. The heart and vasculature ensurethat adequate blood flow is delivered to or-gans so that this exchange can take place.

THE ARRANGEMENT OF THECARDIOVASCULAR SYSTEM

The cardiovascular system has two primarycomponents: the heart and blood vessels. Athird component, the lymphatic system, doesnot contain blood, but nonetheless serves animportant exchange function in conjunctionwith blood vessels.

The heart can be viewed functionally as twopumps with the pulmonary and systemic circu-lations situated between the two pumps (Fig.1-1). The pulmonary circulation is the bloodflow within the lungs that is involved in the ex-change of gases between the blood and alveoli.The systemic circulation is comprised of allthe blood vessels within and outside of organsexcluding the lungs. The right side of the heartcomprises the right atrium and the right ventri-cle. The right atrium receives venous bloodfrom the systemic circulation and the right

2 CHAPTER 1

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ventricle pumps it into the pulmonary circula-tion where oxygen and carbon dioxide are ex-changed between the blood and alveolar gases.The left side of the heart comprises the leftatrium and the left ventricle. The blood leavingthe lungs enters the left atrium by way of thepulmonary veins. Blood then flows from theleft atrium into the left ventricle. The left ven-tricle ejects the blood into the aorta, whichthen distributes the blood to all the organs viathe arterial system. Within the organs, the vas-culature branches into smaller and smaller ves-sels, eventually forming capillaries, which arethe primary site of exchange. Blood flow fromthe capillaries enters veins, which return bloodflow to the right atrium via large systemic veins(the superior and inferior vena cava).

As blood flows through organs, some of thefluid, along with electrolytes and smallamounts of protein, leaves the circulation andenters the tissue interstitium (a processtermed fluid filtration). The lymphatic ves-sels, which are closely associated with smallblood vessels within the tissue, collect the ex-cess fluid that filters from the vasculature andtransport it back into the venous circulation byway of lymphatic ducts that empty into largeveins (subclavian veins) above the right atrium.

It is important to note the overall arrange-ment of the cardiovascular system. First, theright and left sides of the heart, which are sep-arated by the pulmonary and systemic circula-

tions, are in series with each other (see Fig. 1-1). Therefore, all of the blood that is pumpedfrom the right ventricle enters into the pul-monary circulation and then into the left side ofthe heart from where it is pumped into the sys-temic circulation before returning to the heart.This in-series relationship of the two sides ofthe heart and the pulmonary and systemic cir-culations requires that the output (volume ofblood ejected per unit time) of each side of theheart closely matches the output of the other sothat there are no major blood volume shifts be-tween the pulmonary and systemic circulations.Second, most of the major organ systems of thebody receive their blood from the aorta, andthe blood leaving these organs enters into thevenous system (superior and inferior vena cava)that returns the blood to the heart. Therefore,the circulations of most major organ systemsare in parallel as shown in Figure 1-2. Onemajor exception is the liver, which receives alarge fraction of its blood supply from the ve-nous circulation of the intestinal tract thatdrains into the hepatic portal system to supplythe liver. The liver also receives blood from theaorta via the hepatic artery. Therefore, most ofthe liver circulation is in series with the intesti-nal circulation, while some of the liver circula-tion is in parallel with the intestinal circulation.

This parallel arrangement has significanthemodynamic implications as described inChapter 5. Briefly, the parallel arrangement of

INTRODUCTION TO THE CARDIOVASCULAR SYSTEM 3

RA

LA

RV LV

AoPA

PulmonaryCirculation

Systemic Circulation

FIGURE 1-1 Overview of the cardiovascular system. The right side of the heart, pulmonary circulation, left side of theheart, and systemic circulation are arranged in series. RA, right atrium; RV, right ventricle; PA, pulmonary artery; Ao,aorta; LA, left atrium; LV, left ventricle.

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major vascular beds prevents blood flowchanges in one organ from significantly affect-ing blood flow in other organs. In contrast,when vascular beds are in series, blood flowchanges in one vascular bed significantly altersblood flow to the other vascular bed.

THE FUNCTIONS OF THE HEARTAND BLOOD VESSELS

Heart

The heart sometimes is thought of as an organthat pumps blood through the organs of thebody. While this is true, it is more accurate to

view the heart as a pump that receives bloodfrom venous blood vessels at a low pressure,imparts energy to the blood (raises it to ahigher pressure) by contracting around theblood within the cardiac chambers, and thenejects the blood into the arterial blood vessels.

It is important to understand that organblood flow is not driven by the output of theheart per se, but rather by the pressure gen-erated within the arterial system as the heartpumps blood into the vasculature, whichserves as a resistance network. Organ bloodflow is determined by the arterial pressure mi-nus the venous pressure, divided by the vascu-lar resistance of the organ (see Chapters 5 and7). Pressures in the cardiovascular system areexpressed in millimeters of mercury (mm Hg)above atmospheric pressure. One millimeterof mercury is the pressure exerted by a 1-mmvertical column of mercury (1 mm Hg is theequivalent of 1.36 cm H2O hydrostatic pres-sure). Vascular resistance is determined by thesize of blood vessels, the arrangement of thevascular network, and the viscosity of theblood flowing within the vasculature.

The right atrium receives systemic venousblood (venous return) at very low pressures(near 0 mm Hg) (Fig. 1-3). This venous returnthen passes through the right atrium and fillsthe right ventricle; atrial contraction also con-tributes to the ventricular filling. Right ven-tricular contraction ejects blood from theright ventricle into the pulmonary artery. Thisgenerates a maximal pressure (systolic pres-sure) that ranges from 20 to 30 mm Hg withinthe pulmonary artery. As the blood passesthrough the pulmonary circulation, the bloodpressure falls to about 10 mm Hg. The leftatrium receives the pulmonary venous blood,which then flows passively into the left ventri-cle; atrial contraction provides a small amountof additional filling of the left ventricle. As theleft ventricle contracts and ejects blood intothe systemic arterial system, a relatively highpressure is generated (100–140 mm Hg maxi-mal or systolic pressure). Therefore, the leftventricle is a high-pressure pump, in contrastto the right ventricle, which is a low-pressurepump. Details of the pumping action of theheart are found in Chapter 4.

4 CHAPTER 1

Arms

Kidneys

Legs

GILiver

AortaSVC

IVC

Lungs

Head

FIGURE 1-2 Parallel arrangement of organs within thebody. One major exception is the hepatic (liver) circula-tion, which is both in series with the gastrointestinal cir-culation (GI) by the hepatic portal circulation and in par-allel by the hepatic artery, which supplies part of thehepatic circulation. SVC, superior vena cava; IVC, infe-rior vena cava.

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The pumping activity of the heart is usuallyexpressed in terms of its cardiac output, whichis the amount of blood ejected with each con-traction (i.e., stroke volume) multiplied by theheart rate. Any factor that alters heart rate orstroke volume will alter the cardiac output.The heart rate is determined by groups ofcells within the heart that act as electricalpacemakers, and their activity is increased ordecreased by autonomic nerves and hormones(see Chapter 2). The action potentials gener-ated by these pacemaker cells are conductedthroughout the heart and trigger contractionof cardiac myocytes (see Chapter 3). This re-sults in ventricular contraction and ejection ofblood. The force of ventricular contraction,and therefore stroke volume, is regulated bymechanisms intrinsic to the heart, by auto-nomic nerves and hormones (see Chapters 3,4, and 6).

In recent years, we have learned that theheart has other important functions besidespumping blood. The heart synthesizes several

hormones. One of these hormones, atrial na-triuretic peptide, plays an important role inthe regulation of blood volume and bloodpressure (see Chapter 6). Receptors associ-ated with the heart also play a role in regulat-ing the release of antidiuretic hormone fromthe posterior pituitary, which regulates waterloss by the kidneys.

Vascular System

Blood vessels constrict and dilate to regulatearterial blood pressure, alter blood flowwithin organs, regulate capillary blood pres-sure, and distribute blood volume within thebody. Changes in vascular diameters arebrought about by activation of vascularsmooth muscle within the vascular wall by au-tonomic nerves, metabolic and biochemicalsignals from outside of the blood vessel, andvasoactive substances released by cells thatline the blood vessels (i.e., the vascular en-dothelium; see Chapters 3, 5, and 6).

Blood vessels have another function be-sides distribution of blood flow and exchange.The endothelial lining of blood vessels pro-duces several substances (e.g., nitric oxide[NO], endothelin-1 [ET-1], and prostacyclin[PGI2]) that modulate cardiac and vascularfunction, hemostasis (blood clotting), and in-flammatory responses (see Chapter 3).

Interdependence of Circulatory and Organ Function

Cardiovascular function is closely linked tothe function of other organs. For example, thebrain not only receives blood flow to supportits metabolism, but it also acts as a controlcenter for regulating cardiovascular function.A second example of the interdependence be-tween organ function and the circulation isthe kidney. The kidneys excrete varyingamounts of sodium, water, and other mole-cules to maintain fluid and electrolyte homeo-stasis. Blood passing through the kidneys is filtered and the kidneys then modify the com-position of the filtrate to form urine. Reducedblood flow to the kidneys can have detrimen-tal effects on kidney function and therefore on


FIGURE 1-3 Blood flow within the heart. Venous bloodreturns to the right atrium (RA) via the superior (SVC)and inferior vena cava (IVC). Blood passes from the RAinto the right ventricle (RV), which ejects the blood intothe pulmonary artery (PA). After passing through thelungs, the blood flows into the left atrium (LA) and thenfills the left ventricle (LV), which ejects the blood intothe aorta (A) for distribution to the different organs ofthe body.

RV

LV

LARA

A

IVC

SVCLungs

PA

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fluid and electrolyte balance in the body.Furthermore, renal dysfunction can lead tolarge increases in blood volume, which canprecipitate cardiovascular changes that some-times lead to hypertension or exacerbate heartfailure. In summary, organ function is depen-dent on the circulation of blood, and cardio-vascular function is dependent on the func-tion of organs.

THE REGULATION OF CARDIAC AND VASCULAR FUNCTION

The cardiovascular system must be able toadapt to changing conditions and demands ofthe body. For example, when a person exer-cises, increased metabolic activity of contract-ing skeletal muscle requires large increases innutrient supply (particularly oxygen) and en-hanced removal of metabolic by-products(e.g., carbon dioxide, lactic acid). To meet thisdemand, blood vessels within the exercisingmuscle dilate to increase blood flow; however,blood flow can only be increased if the arterialpressure is maintained. Arterial pressure ismaintained by increasing cardiac output andby constricting blood vessels in other organsof the body (see Chapter 9). If these changeswere not to occur, arterial blood pressurewould fall precipitously during exercise,thereby limiting organ perfusion and exercisecapacity. Therefore, a coordinated cardiovas-cular response is required to permit increasedmuscle blood flow while a person exercises.Another example of adaptation occurs when aperson stands up. Gravitational forces causeblood to pool in the legs when a person as-sumes an upright body posture (see Chapter5). In the absence of regulatory mechanisms,this pooling will lead to a fall in cardiac outputand arterial pressure, which can cause a per-son to faint because of reduced blood flow tothe brain. To prevent this from happening, co-ordinated reflex responses increase heart rateand constrict blood vessels to maintain a nor-mal arterial blood pressure when a personstands.

It is important to control arterial bloodpressure because it provides the driving forcefor organ perfusion. As described in Chapter

6, neural and hormonal (neurohumoral)mechanisms regulating cardiovascular func-tion are under the control of pressure sensorslocated in arteries and veins (i.e., barorecep-tors). These baroreceptors, through theirafferent neural connections to the brain, provide the central nervous system with in-formation regarding the status of blood pres-sure in the body. A decrease in arterial pres-sure from its normal operating point elicits a rapid baroreceptor reflex that stimulates the heart to increase cardiac output and constricts blood vessels to restore arterialpressure (a negative feedback controlmechanism) (Fig. 1-4). These cardiovascularadjustments occur through rapid changes inautonomic nerve activity (particularlythrough sympathetic nerves) to the heart andvasculature.

In addition to altering autonomic nerve ac-tivity, a fall in arterial pressure stimulates therelease of hormones that help to restore ar-terial pressure by acting on the heart andblood vessels; they also increase arterial pres-sure by increasing blood volume through theiractions on renal function. In contrast to therapidly acting autonomic mechanisms, hor-monal mechanisms acting on the kidneys re-quire hours or days to achieve their full effect

6 CHAPTER 1

↓AP

CardiacStimulation

VascularConstriction

↑Blood Volume

(+)

ANS Kidneys

Fast

Slow

FIGURE 1-4 Feedback control of arterial pressure (AP) bythe autonomic nervous system (ANS) and kidneys. Asudden fall in AP elicits a rapid baroreceptor reflex thatactivates the ANS to stimulate the heart (increasing car-diac output) and constrict blood vessels to restore AP.The kidneys respond to decreased AP by retaining Na�

and water to increase blood volume, which helps to re-store AP. The (�) indicates the restoration of arterialpressure following the initial fall in pressure (i.e., a neg-ative feedback response).

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on blood volume. Hormonal mechanisms in-clude secretion of catecholamines (chiefly ep-inephrine) by the adrenal glands, release ofrenin by the kidneys, which triggers the for-mation of angiotensin II and aldosterone, andrelease of antidiuretic hormone (vasopressin)by the posterior pituitary. Hormones such asangiotensin II, aldosterone, and vasopressinare particularly important because they act onthe kidneys to increase blood volume, whichincreases cardiac output and arterial pressure.In summary, baroreceptor reflexes are rapid,short-acting mechanisms in contrast to hor-mones that are slow, long-acting mechanismsthat the body uses for achieving blood pres-sure control.

Autonomic nerves and hormones affect the heart and vasculature by acting throughreceptor-coupled, signal transduction mecha-nisms (see Chapter 3). For example, sympa-thetic autonomic nerves innervating the heartand blood vessels release a neurotransmitter(norepinephrine) that binds to specific recep-tors located on the cell membrane of the car-diac myocyte or vascular smooth muscle cell.This causes the activation of biochemicalpathways within the cell that increases theforce of contraction of cardiac myocytes andvascular smooth muscle cells. Hormones suchas angiotensin II and vasopressin also bind tospecific cell receptors, which activate intracel-lular mechanisms to produce contraction ofvascular smooth muscle cells.

In summary, arterial pressure is monitoredby the body and ordinarily is maintainedwithin narrow limits by negative feedbackmechanisms that adjust cardiac function, sys-temic vascular resistance and blood volume.This control is accomplished by changes in au-tonomic nerve activity to the heart and vascu-lature, as well as by changes in circulating hor-mones that influence cardiac, vascular andrenal function.

THE CONTENT OF THE FOLLOWINGCHAPTERS

This textbook emphasizes our current knowl-edge of cellular physiology as well as the clas-sical biophysical concepts that have been used

for decades to describe cardiac and vascularfunction. Chapter 2 describes the electricalactivity within the heart, both at the cellularand whole organ level. Chapter 3 builds afoundation of cellular physiology by empha-sizing intracellular mechanisms that regulatecardiac and vascular smooth muscle contrac-tion. These cellular concepts are reinforcedrepeatedly in subsequent chapters. Chapter 4examines cardiac mechanical function.Chapter 5 summarizes concepts of vascularfunction and the biophysics of blood flow inthe context of regulation of arterial and ve-nous blood pressures. Neurohumoral mecha-nisms regulating cardiac and vascular functionare described in Chapter 6. Chapter 7 de-scribes the flow of blood within different or-gans, with an emphasis on local regulatorymechanisms. Chapter 8 addresses the primaryfunction of the cardiovascular system, that is,the exchange of nutrients, gases, and fluid be-tween the blood and tissues. Finally, Chapter9 integrates concepts described in earlierchapters by examining how the cardiovascularsystem responds to altered demands and dis-ease states.

SUMMARY OF IMPORTANTCONCEPTS

• Large organisms require a circulatory sys-tem so that metabolic substrates and by-products of cellular metabolism can be ef-ficiently exchanged between cells and theoutside environment, as well as transportedto distant sites within the body.

• The cardiovascular system is comprisedprimarily of the heart and blood vessels.Blood returning to the heart via the ve-nous circulation flows into the rightatrium and then into the right ventricle.Contraction of the right ventricle pumpsthe blood into the pulmonary circulationwhere oxygen and carbon dioxide are ex-changed with the gases found within thelung alveoli. Oxygenated blood from thelungs enters into the left atrium, then intothe left ventricle, which pumps the bloodinto the aorta for distribution to variousorgans via large distributing arteries.


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Smaller blood vessels within the organs(primarily capillaries) serve as the primarysite of nutrient exchange. Blood leaves theorgans and returns to the heart via the ve-nous circulation.

• The venous circulation, the right atriumand ventricle, the pulmonary circulationand the left atrium have relatively lowblood pressures. Contraction of the leftventricle and ejection of blood into theaorta generate relatively high blood pres-sures within the left ventricle and arterialsystem.

• Most major organ systems are in parallelwith each other so that blood flow in oneorgan has relatively little influence onblood flow in another organ. In contrast,the pulmonary and systemic circulationsare in series; therefore, altering blood flowand blood volume in one of these circula-tions alters the flow and volume in theother.

• Blood flow within organs is determined pri-marily by the arterial pressure (generatedby the pumping action of the heart againsta systemic vascular resistance), and bychanges in the diameters of blood vesselswithin the organs brought about by con-traction or relaxation of smooth musclewithin the walls of the blood vessels.

• Autonomic nerves and circulating hor-mones regulate cardiac, vascular and renalfunction to ensure that arterial pressure isadequate for organ perfusion.

• Baroreceptors continuously monitor arte-rial pressure and adjust the activity of auto-nomic nerves to maintain arterial pressurewithin narrow limits.

Review Questions

Please refer to the appendix for the answersto the review questions.For each question, choose the one best answer:1. The cardiovascular system

a. Aids in the transfer of heat energyfrom organs deep within the body tothe outside environment.

b. Is comprised of pulmonary and sys-temic circulations that are in parallelwith each other.

c. Transports carbon dioxide from thelungs to tissues within organs.

d. Transports oxygen from individualcells to the lungs.

2. Which of the following statements con-cerning the heart is true?

a. The right ventricle receives bloodfrom the pulmonary veins.

b. The right ventricle generates higherpressures than the left ventricle dur-ing contraction.

c. The right and left ventricles are inparallel.

d. Cardiac output is the product ofventricular stroke volume and heartrate.

3. Arterial pressure decreases whena. A person stands up.b. Blood volume increases.c. Cardiac output increases.d. Plasma concentrations of an-

giotensin II and aldosterone are ele-vated.

8 CHAPTER 1

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CD-ROM CONTENTSLEARNING OBJECTIVESINTRODUCTIONCELL MEMBRANE POTENTIALS

Resting Membrane PotentialsMaintenance of Ionic GradientsIon ChannelsAction PotentialsAbnormal Action Potentials

CONDUCTION OF ACTION POTENTIALSWITHIN THE HEART

Electrical Conduction within theHeart

Regulation of Conduction VelocityAbnormal Conduction

THE ELECTROCARDIOGRAM (ECG)ECG TracingInterpretation of Normal and

Abnormal Cardiac Rhythms from theECG

Volume Conductor Principles and ECGRules of Interpretation

ECG Leads: Placement of RecordingElectrodes

ELECTROPHYSIOLOGICAL CHANGES DURINGCARDIAC ISCHEMIA

SUMMARY OF IMPORTANT CONCEPTSREVIEW QUESTIONSSUGGESTED READINGS

c h a p t e r

2Electrical Activity of the Heart

Ion Permeability and ConductanceReentry Mechanisms

CD CONTENTS

LEARNING OBJECTIVES

Understanding the concepts presented in this chapter will enable the student to:1. Define and discuss the following terms as they relate to the heart:

a. resting membrane potentialb. depolarization and repolarizationc. threshold potentiald. action potentiale. pacemaker potentialf. automaticityg. effective refractory periodh. arrhythmias

2. Calculate the Nernst equilibrium potential for sodium, potassium, and calcium ions giventheir intracellular and extracellular concentrations.

3. Describe how changing the concentrations of sodium, potassium, and calcium ions insideand outside the cell affect the resting membrane potential in cardiac cells.

4. Explain why the resting potential is near the equilibrium potential for potassium and thepeak of an action potential approaches the equilibrium potential for sodium.

5. Describe how the sarcolemmal Na�/K�-adenosine triphosphatase (ATPase) affects the gen-eration and maintenance of cardiac membrane potentials.

6. Describe the mechanisms that maintain calcium gradients across the cardiac cell mem-brane.

7. Describe how activation and inactivation gates regulate sodium movement through fastsodium channels.

9

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INTRODUCTION

The primary function of cardiac myocytes is tocontract. Electrical changes within the myo-cytes initiate this contraction. This chapter examines (1) the electrical activity of individ-ual myocytes, including resting membrane po-tentials and action potentials; (2) the way ac-tion potentials are conducted throughout theheart to initiate coordinated contraction of theentire heart; and (3) the way electrical activity

of the heart is measured using the electrocar-diogram (ECG).

CELL MEMBRANE POTENTIALS

Resting Membrane Potentials

Cardiac cells, like all living cells in the body,have an electrical potential across the cellmembrane. This potential can be measuredby inserting a microelectrode into the cell and

10 CHAPTER 2

8. Contrast cardiac action potentials with those found in nerve and skeletal muscle cells.9. Contrast the shape, phases, and ionic currents of nonpacemaker and pacemaker (e.g.,

sinoatrial [SA] node) action potentials.10. Describe the ionic currents responsible for phase 4, spontaneous depolarization in SA

nodal pacemaker cells.11. Describe how autonomic nerves, circulating catecholamines, extracellular potassium con-

centrations, thyroid hormone, and hypoxia alter pacemaker activity.12. Describe how the effective refractory period serves as a protective mechanism in the

heart.13. Describe the role of afterdepolarizations in the generation of tachycardias.14. Describe the normal pathways for action potential conduction within the heart.15. Describe the effects of autonomic nerves, circulating catecholamines, cellular hypoxia,

and sodium-channel-blocking drugs on conduction velocity within the heart.16. Describe what each of the following electrocardiogram (ECG) components represents:

a. P waveb. P-R intervalc. QRS complexd. ST segmente. Q-T interval

17. Recognize the following from an ECG rhythm strip:a. normal sinus rhythmb. sinus bradycardia and tachycardiac. atrial flutter and fibrillationd. atrioventricular (AV) nodal blocks: first, second and third degreee. premature ventricular complexf. ventricular tachycardia and fibrillation

18. Describe the location for placement of electrodes for each of the following leads: I, II, III,aVR, aVL, and aVF, and precordial V1-V6.

19. Draw the axial reference system and show the position (in degrees) for the positiveelectrode for each of the six limb leads.

20. List the rules for determining the direction of a vector of depolarization and repolariza-tion relative to a given ECG lead.

21. Describe, in terms of vectors, how the QRS complex is generated and why the QRS ap-pears differently when recorded by different electrode leads.

22. Estimate the mean electrical axis for ventricular depolarization from the six limb leads.23. Describe some changes that can occur in the ECG during cardiac ischemia or hypoxia.

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measuring the electrical potential in millivolts(mV) inside the cell relative to the outside ofthe cell. By convention, the outside of the cellis considered 0 mV. If measurements aretaken with a resting ventricular myocyte, amembrane potential of about –90 mV will berecorded. This resting membrane poten-tial (Em) is determined by the concentrationsof positively and negatively charged ionsacross the cell membrane, the relative perme-ability of the cell membrane to these ions, andthe ionic pumps that transport ions across thecell membrane.

Equilibrium PotentialsOf the many different ions present inside andoutside of cells, the concentrations of Na�,K�, Cl�, and Ca�� are most important in de-termining the membrane potential across thecell membrane. Table 2-1 shows typical con-centrations of these ions. Of the four ions, K�

is the most important in determining the rest-ing membrane potential. In a cardiac cell, theconcentration of K� is high inside and lowoutside the cell. Therefore, a chemical gra-dient (concentration difference) exists for K�

to diffuse out of the cell (Fig. 2-1). The oppo-site situation is found for Na�; its chemicalgradient favors an inward diffusion. The con-centration differences across the cell mem-brane for these and other ions are determinedby the activity of energy-dependent ionicpumps and the presence of impermeable,negatively charged proteins within the cellthat affect the passive distribution of cationsand anions.

To understand how concentration gradi-ents of ions across a cell membrane affectmembrane potential, consider a cell in whichK� is the only ion across the membrane otherthan the large negatively charged proteins onthe inside of the cell. In this cell, K� diffusesdown its chemical gradient and out of the cellbecause its concentration is much higher in-side than outside the cell (see Fig. 2-1). As K�

diffuses out of the cell, it leaves behind nega-tively charged proteins, thereby creating aseparation of charge and a potential differ-ence across the membrane (leaving it negativeinside the cell). The membrane potential thatis necessary to oppose the movement of K�

ELECTRICAL ACTIVITY OF THE HEART 11

K+

(4 mM)

Myocyte

K+

(150 mM)

Na+

(20 mM)

Na+

(145 mM)

FIGURE 2-1 Concentrations of Na� and K� inside andoutside a cardiac myocyte.

TABLE 2-1 ION CONCENTRATIONS1 INSIDE AND OUTSIDE OF RESTINGMYOCYTES

ION INSIDE (mM) OUTSIDE (mM)

Na� 20 145

K� 150 4

Ca�� 0.0001 2.5

Cl- 25 140

1 These concentrations are approximations and are used to illustrate the concepts of chemical gradients and mem-brane potential. In reality, the free (unbound or ionized) ion concentration and the chemical activity of the ionshould be used when evaluating electrochemical gradients.

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down its concentration gradient is termed theequilibrium potential for K� (EK; Nernstpotential). The Nernst potential for K� at37°C is as follows:

EK � �61 log � �96 mV

in which the potassium concentration inside[K�]i � 150 mM and the potassium concen-tration outside [K�]o � 4 mM. The –61 is de-rived from RT/zF, in which R is the gas con-stant, z is the number of ion charges (z � 1 forK�; z � 2 for divalent ions such as Ca��), F isFaraday’s constant, and T is temperature (°K).The equilibrium potential is the potential dif-ference across the membrane required tomaintain the concentration gradient acrossthe membrane. In other words, the equilib-rium potential for K� represents the electricalpotential necessary to keep K� from diffusingdown its chemical gradient and out of the cell.If the outside K� concentration increasedfrom 4 to 10 mM, the chemical gradient fordiffusion out of the cell would be reduced;therefore, the membrane potential requiredto maintain electrochemical equilibriumwould be less negative according to theNernst relationship.

The Em for a ventricular myocyte is about–90 mV, which is near the equilibrium poten-tial for K�. Because the equilibrium potentialfor K� is –96 mV and the resting membranepotential is –90 mV, a net driving force (netelectrochemical force) acts on the K�, caus-ing it to diffuse out of the cell. In the case ofK�, this net electrochemical driving force isthe Em (–90 mV) minus the EK (–96 mV), re-sulting in �6 mV. Because the resting cell hasa finite permeability to K� and a small net out-ward driving force is acting on K�, K� slowlyleaks outward from the cell.

The sodium ions also play a major role indetermining the membrane potential.Because the Na� concentration is higher out-side the cell, this ion would diffuse down itschemical gradient into the cell. To preventthis inward flux of Na�, a large positive chargeis needed inside the cell (relative to the out-side) to balance out the chemical diffusionforces. This potential is called the equilib-

[K�]i�[K�]o

rium potential for Na� (ENa) and is calcu-lated using the Nernst equation, as follows:

EK � �61 log � �52 mV

in which the sodium concentration inside[Na�]i � 20 mM and the sodium concentra-tion outside [Na�]o � 145 mM. The calcu-lated equilibrium potential for sodium indi-cates that to balance the inward diffusion ofNa� at these intracellular and extracellularconcentrations, the cell interior has to be �52mV to prevent Na� from diffusing into thecell.

The net driving or electrochemical forceacting on sodium (and each ionic species) hastwo components. First, the sodium concentra-tion gradient is driving sodium into the cell;according to the Nernst calculation, the elec-trical force necessary to counterbalance thischemical gradient is �52 mV. Second, be-cause the interior of the resting cell is verynegative (–90 mV), a large electrical force istrying to “pull” sodium into the cell. We canderive the net electrochemical force acting onsodium from these two component forces bysubtracting the Em minus ENa: –90 mV minus�52 mV equals –142 mV. This large electro-chemical force drives sodium into the cell;however, at rest, the permeability of the mem-brane to Na� is so low that only a smallamount of Na� leaks into the cell.

Ionic ConductancesAs explained, the Em in a resting, nonpace-maker cell is very near EK. This agreement oc-curs because the membrane is much more per-meable to K� in the resting state than to otherions such as Na� or Ca��. The membrane po-tential reflects not only the concentration gra-dients of individual ions (i.e., the equilibriumpotentials), but also the relative permeability ofthe membrane to those ions. If the membranehas a higher permeability to one ion over theothers, that ion will have a greater influence indetermining the membrane potential.

If the membrane is viewed as a set of par-allel electrical circuits (Fig. 2-2), with each ionrepresented as a voltage source (equilibriumpotential, EX) in series with a variable resis-

[Na�]i�[Na�]o

12 CHAPTER 2

Eq. 2-1

Eq. 2-2

Ch02_009-040_Klabunde 4/21/04 10:53 AM

tance (the inverse of which is conductance),the ion conductance (gX) and its equilibriumpotential will contribute to the overall mem-brane potential. We can represent this modelmathematically as follows:

Em �

If the equilibrium potential for each ionremains unchanged (i.e., the concentrationgradient does not change), then the currentflow for each ion will vary as the conductancechanges. This variance is a function of mem-brane permeability for that ion. Permeabilityand conductance refer to the ease of move-ment of solutes across membranes (see IonPermeability and Conductance on CD). Ifpotassium conductance (gK�) is finite and allother conductances are zero, the membranepotential will equal the equilibrium potentialfor potassium (approximately –96 mV).However, if sodium conductance (gNa�) is fi-nite and all other conductances are zero,then the membrane potential will be theequilibrium potential for sodium (approxi-mately �52 mV). According to Equation 2-3,if gK� and gNa� are equal and the other ionconductances are zero, the membrane poten-tial would lie between the two equilibriumpotentials.

The earlier model and equation showedthat the membrane potential depends on both

gK� (EK) � gNa� (ENa) � gCa�� (ECa) � gCl� (Ecl)��

gK� � gNa� � gCa�� gCl�

the equilibrium potential of the different ionsand their conductances. Equation 2-4 simpli-fies Equation 2-3 by expressing each ion con-ductance as a relative conductance (g�X). Thisis the conductance of a single ion divided bythe total conductance for all of the ions [e.g.,g�K� � gK�/(gK� � gNa� � gCa�� gCl�)].

Em � g’K� (EK) � g’Na� (ENa) � g’Ca�� (ECa) � g’Cl� (ECl)

In Equation 2-4, the membrane potential is thesum of the individual equilibrium potentials,each multiplied by the relative membrane con-ductance for that particular ion. If the equilib-rium potential values for K�, Na�, Ca�� andCl– are calculated by incorporating the concen-trations found in Table 2-1 in Equation 2-4, thisequation can be depicted as follows:

Em � g’K� (�96mV ) � g’Na� (�50mV ) � g’Ca�� (�134mV ) � g’Cl� (�46mV )

In a cardiac cell, the individual ion concen-tration gradients change very little, even whenNa� enters and K� leaves the cell during de-polarization. Therefore, changes in Em pri-marily result from changes in ionic conduc-tances. The resting membrane potential is nearthe equilibrium potential for K� because g’K�

is high relative to all of the other ionic conduc-tances in the resting cell. Therefore, the lowrelative conductances of Na�, Ca��, and Cl�,


–– –

–

+

+ ++

-90 mV

EK EClENa ECa

gK1

+ gNa1

+ gCa1

++ gCl1

–Em

FIGURE 2-2 Resistance model for membrane potential (Em). The voltage sources represent the equilibrium potentials(EX) for potassium (K�), sodium (Na�), calcium (Ca��), and chloride (Cl�) ions. The resistors represent the membraneresistances to the ions. Resistance equals the reciprocal of the ion conductances (i.e., 1/gX).

Eq. 2-3

Eq. 2-4

Eq. 2-5

Ch02_009-040_Klabunde 4/21/04 10:53 AM

multiplied by their equilibrium potential val-ues, causes those ions to contribute little to theresting membrane potential. When g’Na� in-creases and g’K� decreases (as occurs duringan action potential), the membrane potentialbecomes more positive (depolarized) becausethe sodium equilibrium potential has more in-fluence on the overall membrane potential.

In Equation 2-4, ion concentrations (whichdetermine the equilibrium potential) and ionconductances are separate variables. In real-ity, the conductance of some ion channels isinfluenced by the concentration of the ion(e.g., K�-sensitive K�-channels) or thechanges in membrane potential (e.g., voltage-dependent Na�, K�, and Ca�� ion channels).For example, a decrease in external K� con-centration (e.g., from 4 to 3 mM) can decreasegK� in some cardiac cells and lead to a smalldepolarization (less negative potential) insteadof the hyperpolarization (more negative po-tential) predicted by the Nernst relationshipor Equation 2-4. In some cells, small increasesin external K� concentration (e.g., from a nor-mal concentration of 4 mM to 6 mM) cancause a small hyperpolarization owing to acti-vation of K�-channels and an increase in gK�.

Maintenance of Ionic Gradients

Membrane potential depends on the mainte-nance of ionic concentration gradients acrossthe membrane. The maintenance of theseconcentration gradients requires the expendi-ture of energy (adenosine triphosphate [ATP]hydrolysis) coupled with ionic pumps.Consider the concentration gradients for Na�

and K�. Na� constantly leaks into the restingcell, and K� leaks out. Moreover, whenever anaction potential is generated, additional Na�

enters the cell and additional K� leaves.Although the number of ions moving acrossthe sarcolemmal membrane in a single actionpotential is small relative to the total numberof ions, many action potentials can lead to asignificant change in the extracellular and in-tracellular concentration of these ions. To pre-vent this change from happening (i.e., tomaintain the concentration gradients for Na�

and K�), an energy (ATP)-dependent pump

system (Na�/K�-adenosine triphosphatase[ATPase]), located on the sarcolemma,pumps Na� out and K� into the cell (Fig. 2-3).Normal operation of this pump is essential tomaintain Na� and K� concentrations acrossthe membrane. If this pump stops working(such as under hypoxic conditions, when ATPis lost), or if the activity of the pump is inhib-ited by cardiac glycosides such as digitalis,Na� accumulates within the cell and intracel-lular K� falls. This change results in a depo-larization of the resting membrane potential.It is important to note that this pump is elec-trogenic because it extrudes three Na� forevery two K� entering the cell. By pumpingmore positive charges out of the cell than intoit, the pump creates a negative potentialwithin the cell. This electrogenic potentialmay be up to –10 mV. Inhibition of this pump,therefore, causes depolarization resultingfrom changes in Na� and K� concentrationgradients and from the loss of an electrogeniccomponent of the membrane potential. In ad-dition, because the pump is electrogenic, in-creases in intracellular Na� or extracellular K�

stimulate the activity of the Na�/K�-ATPasepump and produce hyperpolarizing currents.

Because Ca�� enters the cell, especiallyduring action potentials, it is necessary to havea mechanism to maintain its concentrationgradient. This maintenance is accomplishedby Ca�� pumps and exchangers on the sar-colemma. Intracellular calcium concentra-tions in both cardiac and vascular smoothmuscle cells range from 10-7 M at rest to 10-5

M during depolarization. The extracellularconcentration of calcium is about 2 x 10-3 M (2mM), causing a large chemical gradient forcalcium to diffuse into the cell. Because cellshave a negative resting membrane potential,an electrical force drives calcium into the cell.However, little calcium leaks into the cell ex-cept during action potentials when the cellmembrane permeability to calcium increases.The calcium that enters the cell during actionpotentials must be removed from the cell; oth-erwise, an accumulation of calcium leads tocellular dysfunction.

Two primary mechanisms remove calciumfrom cells (see Fig. 2-3). The first involves an

14 CHAPTER 2

Ch02_009-040_Klabunde 4/21/04 10:53 AM

ATP-dependent Ca�� pump that activelypumps calcium out of the cell and generates asmall electrogenic potential. The secondmechanism is the sodium–calcium ex-changer. It is unclear exactly how this ex-changer works. It is known, however, that theexchanger can operate in either directionacross the sarcolemma. Furthermore, threesodium ions are exchanged for each calciumion; therefore, the exchanger generates anelectrogenic potential. The direction of move-ment of these ions (either inward or outward)depends upon the membrane potential andthe chemical gradient for the ions. We knowthat an increase in intracellular sodium con-centration leads to an increase in intracellularcalcium through this exchange mechanism.An example of this is when the activity of theNa�/K�-ATPase pump is decreased by cellu-lar hypoxia (which causes ATP levels to fall) or

inhibited by chemical inhibitors such as digi-talis. When the pump is inhibited, intracellu-lar sodium concentrations increase. Increasedintracellular sodium reduces the concentra-tion gradient for Na�, causing less Na� to en-ter the cell via the Na�/Ca�� exchanger. Theresult is less Ca�� being extruded by the ex-changer, leading to an accumulation of intra-cellular calcium.

Ion Channels

Ion conductance through the sarcolemma oc-curs because the sarcolemma is permeable toions. Ions move across the sarcolemmathrough specialized ion channels, or pores, inthe phospholipid bilayer of the cell mem-brane. These pores are made up of largepolypeptide chains that span the membraneand create an opening in the membrane.


Ca++

Ca++

Ca++Ca++

Na+

Na+

Na+

K+

K+

K+

1 2 3

1 = ATP-dependent Ca++ pump

2 = Na+/Ca++ exchanger (3:1)

3 = Na+/K+-ATPase pump (3:2)FIGURE 2-3 Sarcolemmal ion pumps and exchangers. These pumps maintain transmembrane ionic gradients for Na�,K�, and Ca��. Na� and Ca�� enter the cell down their electrochemical gradient, especially during action potentials,while K� is leaving the cell. Ca�� is removed by an adenosine triphosphate (ATP)-dependent Ca�� pump (1) and bythe Na�/Ca�� exchanger (2). Na� is actively removed from the cell by the Na�/K�-ATPase pump, which brings K� intothe cell; three Na� are pumped out for every two K�; therefore this pump is electrogenic (i.e., it generates a nega-tive potential across the sarcolemma). The Na�/Ca�� exchanger is also electrogenic because it exchanges three Na�

for every one Ca��. The Ca�� pump is electrogenic as well.

Ch02_009-040_Klabunde 4/21/04 10:53 AM

Conformational changes in the ion channelproteins alter the shape of the pore, therebypermitting ions to transverse the membranechannel.

Ion channels are selective for differentcations and anions. For example, some ionchannels are selective for sodium, potassium,calcium, and chloride ions (Table 2-2).Furthermore, a given ion may have severaldifferent types of ion channels responsible forits movement across a cell membrane. For ex-ample, several different types of potassiumchannels exist through which potassium ionsmove across the cell membrane during cellu-lar depolarization and repolarization.

Two general types of ion channels exist:voltage gated (voltage operated) and receptorgated (receptor operated) channels. Voltagegated channels open and close in responseto changes in membrane potential. Examplesof voltage gated channels include severalsodium, potassium, and calcium channels thatare involved in cardiac action potentials.Receptor gated channels open and close inresponse to chemical signals operatingthrough membrane receptors. For example,acetylcholine, which is the neurotransmitterreleased by the vagus nerves innervating theheart, binds to a sarcolemmal receptor thatsubsequently leads to the opening of specialtypes of potassium channels (IK, ACh).

Ion channels have both open and closedstates. Ions pass through the channel onlywhile it is in the open state. The open andclosed states of voltage gated channels areregulated by the membrane potential. Fastsodium channels have been the most exten-sively studied, and a conceptual model hasbeen developed based upon studies byHodgkin and Huxley in the 1950s using thesquid giant axon. In this model, two gates reg-ulate the movement of sodium through thechannel (Fig. 2-4). At a normal resting mem-brane potential (about –90 mV in cardiac myocytes), the sodium channel is in a resting,closed state. In this configuration, the m-gate(activation gate) is closed and the h-gate (in-activation gate) is open. These gates arepolypeptides that are part of the transmem-brane protein channel, and they undergo con-formational changes in response to changes involtage. The m-gates rapidly become acti-vated and open when the membrane is rapidlydepolarized. This permits sodium, driven byits electrochemical gradient, to enter the cell.As the m-gates open, the h-gates begin toclose; however, the m-gates open more rapidlythan the h-gates close. The difference in theopening and closing rates of the two gates per-mits sodium to briefly enter the cell. After afew milliseconds, however, the h-gates closeand sodium ceases to enter the cell. The clos-

16 CHAPTER 2

High concentrations of potassium are added to cardioplegic solutions used to arrestthe heart during surgery. Using the Nernst equation, calculate an estimate for the newresting membrane potential (Em) when external potassium concentration is increasedfrom a normal value of 4 mM to 40 mM. Assume that the internal concentration re-mains at 150 mM and that K� and other ion conductances are not altered.

Using Equation 2-1, the membrane potential (actually, the equilibrium potential forpotassium) with 4 mM external potassium would be –96 mV. Solving the equation for40 mM external potassium results in a membrane potential of –35 mV. This is the mem-brane potential predicted by the Nernst equation assuming that no other ions con-tribute to the membrane potential (see Equation 2-3). This calculation also neglects anycontribution of electrogenic pumps to the membrane potential. Nevertheless, a highconcentration of external potassium causes a large depolarization, as predicted by theNernst equation.

PROBLEM 2-1

Ch02_009-040_Klabunde 4/21/04 10:53 AM


TABLE 2-2 CARDIAC ION CHANNELS AND CURRENTS

CHANNELS GATING CHARACTERISTICS

Sodium

Fast Na� (INa) Voltage Phase 0 of myocytes

Slow Na� (If) Voltage & Receptor Contributes to phase 4 pacemakercurrent in SA and AV nodal cells

Calcium

L-type (ICa) Voltage Slow inward, long-lasting current;phase 2 of myocytes and phases 4and 0 of SA and AV nodal cells

T-type (ICa) Voltage Transient current; contributes tophase 4 pacemaker current in SAand AV nodal cells

Potassium

Inward rectifier (IK1) Voltage Maintains negative potential inphase 4; closes with depolariza-tion; its decay contributes to pace-maker currents

Transient outward (Ito) Voltage Contributes to phase 1 in myocytes

Delayed rectifier (IKr) Voltage Phase 3 repolarization

ATP-sensitive (IK, ATP) Receptor Inhibited by ATP; opens when ATPdecreases

Acetylcholine activated (IK, ACh) Receptor Activated by acetylcholine; Gi-protein coupled

IX, Name of specific current

Resting(closed)

Activated(open)

Inactivated(closed)

Resting(closed)

Na+ Na+ Na+ Na+

Depolarization Repolarization

outside

inside

FIGURE 2-4 Open and closed states of fast sodium channels in cardiac myocytes. In the resting (closed) state, the m-gates (activation gates) are closed, although the h-gates (inactivation gates) are open. Rapid depolarization to thresh-old opens the m-gates (voltage activated), thereby opening the channel and enabling sodium to enter the cell. Shortlythereafter, as the cell begins to repolarize, the h-gates close and the channel becomes inactivated. Toward the endof repolarization, the m-gates again close and the h-gates open. This brings the channel back to its resting state.

Ch02_009-040_Klabunde 4/21/04 10:53 AM

ing of the h-gates therefore limits the lengthof time that sodium can enter the cell. This in-activated, closed state persists throughout therepolarization phase as the membrane poten-tial recovers to its resting level. Near the endof repolarization, the negative membrane po-tential causes the m-gates to close and the h-gates to open. These changes cause the chan-nel to revert back to its initial resting, closedstate. Full recovery of the h-gates can take 100milliseconds or longer after the resting mem-brane potential has been restored.

The response of the activation and inacti-vation gates described above occurs when theresting membrane potential is normal (about–90 mV) and a rapid depolarization of themembrane occurs, as happens when a normaldepolarization current spreads from one car-diac cell to another during electrical activationof the heart. The response of the fast sodiumchannel, however, is different when the rest-ing membrane potential is partially depolar-ized or the cell is slowly depolarized. For ex-ample, when myocytes become hypoxic, thecell depolarizes to a less negative restingmembrane potential. This partially depolar-ized state inactivates sodium channels by clos-ing the h-gates. The more a cell is depolar-ized, the greater the number of inactivatedsodium channels. At a membrane potential ofabout –55 mV, virtually all fast sodium chan-nels are inactivated. If a myocyte has a normalresting potential, but then undergoes slow de-polarization, more time is available for the h-gates to close as the m-gates are opening. Thiscauses the sodium channel to transition di-rectly from the resting (closed) state to the in-activated (closed) state. The result is thatthere is no activated, open state for sodium topass through the channel, effectively abolish-ing fast sodium currents through these chan-nels. As long as the partial depolarized statepersists, the channel will not resume its rest-ing, closed state. As described later in thischapter, these changes significantly alter myocyte action potentials by abolishing fastsodium currents during action potentials.

A single cardiac cell has many sodiumchannels; each channel has a slightly differentvoltage activation threshold and duration of its

open, activated state. The amount of sodium(the sodium current) that passes throughsodium channels when a cardiac cell under-goes depolarization depends upon the num-ber of sodium channels, the duration of timethe channels are in the open state, and theelectrochemical gradient driving the sodiuminto the cell.

The open and closed states described forsodium channels are also found in other ionchannels. For example, slow calcium channelshave activation and inactivation gates (al-though they have different letter designationsthan fast sodium channels). Although this con-ceptual model is useful to help understandhow ions transverse the membrane, many ofthe details of how this actually occurs at themolecular level are still unknown. Never-theless, recent research is helping to showwhich regions of ion channel proteins act asvoltage sensors and which regions undergoconformational changes analogous to thegates described in the conceptual model.

Action Potentials

Action potentials occur when the membranepotential suddenly depolarizes and then repo-larizes back to its resting state. The two gen-eral types of cardiac action potentials includenonpacemaker and pacemaker action poten-tials. Nonpacemaker action potentials are trig-gered by depolarizing currents from adjacentcells, whereas pacemaker cells are capable ofspontaneous action potential generation. Bothtypes of action potentials in the heart differconsiderably from the action potentials foundin neural and skeletal muscle cells (Fig. 2-5).One major difference is the duration of theaction potentials. In a typical nerve, the actionpotential duration is about 1 millisecond. Inskeletal muscle cells, the action potential du-ration is approximately 2-5 milliseconds. Incontrast, the duration of ventricular action po-tentials ranges from 200 to 400 milliseconds.These differences among nerve, skeletal mus-cle, and cardiac myocyte action potentials re-late to differences in the ionic conductancesresponsible for generating the changes inmembrane potential.

18 CHAPTER 2

Ch02_009-040_Klabunde 4/21/04 10:53 AM

Nonpacemaker Action PotentialsFigure 2-6 shows the ionic mechanisms re-sponsible for the generation of nonpacemakeraction potentials. By convention, the actionpotential is divided into five numberedphases. Nonpacemaker cells, such as atrialand ventricular myocytes and Purkinje cells,have a true resting membrane potential(phase 4) that remains near the equilibriumpotential for K�. At the resting membrane po-tential, gK�, through inward rectifying potas-sium channels (see Table 2-2), is high relativeto gNa� and gCa��. When these cells arerapidly depolarized from –90 mV to a thresh-old voltage of about –70 mV (owing to, for ex-ample, an action potential conducted by anadjacent cell), a rapid depolarization (phase0) is initiated by a transient increase in fastNa�-channel conductance. At the same time,gK� falls. These two conductance changesmove the membrane potential away from thepotassium equilibrium potential and closer tothe sodium equilibrium potential (seeEquation 2-4). Phase 1 represents an initialrepolarization caused by the opening of aspecial type of K� channel (transient outward)and the inactivation of the Na� channel.However, because of the large increase inslow inward gCa��, the repolarization is de-layed and the action potential reaches aplateau phase (phase 2). This inward cal-cium movement is through long-lasting (L-

type) calcium channels that open when themembrane potential depolarizes to about –40mV. L-type calcium channels are the majorcalcium channels in cardiac and vascularsmooth muscle. They are opened by mem-brane depolarization (they are voltage-oper-ated) and remain open for a relatively long du-ration. These channels are blocked by classicalL-type calcium channel blockers (verapamil,diltiazem, and dihydropyridines such asnifedipine). Repolarization (phase 3) oc-curs when gK� increases through delayed rec-tifier potassium channels and gCa�� de-creases. Therefore, changes in Na�, Ca��, andK� conductances primarily determine the ac-tion potential in nonpacemaker cells.

During phases 0, 1, 2, and part of phase 3,the cell is refractory (i.e., unexcitable) to theinitiation of new action potentials. This is theeffective refractory period (ERP) (see Fig.


0

-50

+50

5000-100

Time (ms)

Cardiac Myocyte

Nerve CellM

embr

ane

Pot

entia

l (m

V)

FIGURE 2-5 Comparison of action potentials from anerve cell and a nonpacemaker cardiac myocyte.Cardiac action potentials are much longer in durationthan nerve cell action potentials.

ERP

FIGURE 2-6 Changes in ion conductances associatedwith a ventricular myocyte action potential. Phase 0 (de-polarization) primarily is due to the rapid increase insodium conductance (gNa�) accompanied by a fall inpotassium conductance (gK�); the initial repolarizationof phase 1 is due to opening of special potassium chan-nels (Ito); phase 2 (plateau) primarily is due to an in-crease in slow inward calcium conductance (gCa��)through L-type Ca�� channels; phase 3 (repolarization)results from an increase in gK� and a decrease in gCa��.Phase 4 is a true resting potential that primarily reflectsa high gK�. ERP, effective refractory period.

Ch02_009-040_Klabunde 4/21/04 10:53 AM

2-6). During the ERP, stimulation of the celldoes not produce new, propagated action po-tentials because the h-gates are still closed.The ERP acts as a protective mechanism inthe heart by limiting the frequency of actionpotentials (and therefore contractions) thatthe heart can generate. This enables the heartto have adequate time to fill and eject blood.The long ERP also prevents the heart fromdeveloping sustained, tetanic contractions likethose that occur in skeletal muscle. At the endof the ERP, the cell is in its relative refrac-tory period. Early in this period, supra-threshold depolarization stimuli are requiredto elicit actions potentials. Because not all thesodium channels have recovered to their rest-ing state by this time, action potentials gener-ated during the relative refractory period havea decreased phase 0 slope and lower ampli-tude. When the sodium channels are fully re-covered, the cell becomes fully excitable andnormal depolarization stimuli can elicit new,rapid action potentials.

Nonpacemaker action potentials are alsocalled “fast response” action potentials be-cause of their rapid phase 0 depolarization. Ifthe fast sodium channels that are responsiblefor the rapid phase 0 are blocked pharmaco-logically or inactivated by slow depolarization,the slope of phase 0 is significantly depressed,and the amplitude of the action potential is re-duced. The depolarization phase of the actionpotential under these conditions is broughtabout by slow inward calcium currents carriedthrough L-type calcium channels. These ac-

tion potentials are called “slow response” ac-tion potentials and resemble action potentialsfound in pacemaker cells.

Pacemaker Action PotentialsPacemaker cells have no true resting poten-tial, but instead generate regular, spontaneousaction potentials. Unlike most other cells thatexhibit action potentials (e.g., nerve cells, andmuscle cells), the depolarizing current of theaction potential is carried primarily by rela-tively slow, inward Ca�� currents (through L-type calcium channels) instead of by fast Na�

currents. Fast Na� channels are inactivated innodal cells because of their more depolarizedstate, which closes the h-gates.

Cells within the sinoatrial (SA) node, lo-cated within the posterior wall of the rightatrium, constitute the primary pacemaker sitewithin the heart. Other pacemaker cells existwithin the atrioventricular node and ventricu-lar conduction system, but their firing ratesare driven by the higher rate of the SA nodebecause the intrinsic pacemaker activity of thesecondary pacemakers is suppressed by amechanism termed overdrive suppression.This mechanism causes the secondary pace-maker to become hyperpolarized when drivenat a rate above its intrinsic rate. Hyper-polarization occurs because the increased ac-tion potential frequency stimulates the activityof the electrogenic Na�/K�-ATPase pump as aresult of enhanced entry of sodium per unittime into these cells. If the SA node becomesdepressed, or its action potentials fail to reach

20 CHAPTER 2

A drug is found to partially inactivate fast sodium channels. How would this drug alterthe action potential in a ventricular myocyte? How would the drug alter conductionvelocity within the ventricle?

Because phase 0 of myocyte action potentials is generated by activation of fastsodium channels, partial inactivation of these channels would decrease the upstroke ve-locity of phase 0 (decrease the slope of phase 0). Partial inactivation also would decreasethe maximal degree of depolarization. These changes in phase 0 would reduce the con-duction velocity within the ventricle. Blockade of fast sodium channels is the primarymechanism of action of Class I antiarrhythmic drugs such as quinidine and lidocaine.

PROBLEM 2-2

Ch02_009-040_Klabunde 4/21/04 10:53 AM

secondary pacemakers, overdrive suppressionceases, which permits a secondary site to takeover as the pacemaker for the heart. Whenthis occurs, the new pacemaker is called anectopic foci.

SA nodal action potentials are divided intothree phases: phase 0, upstroke of the actionpotential; phase 3, the period of repolariza-tion; and phase 4, the period of spontaneousdepolarization that leads to subsequent gener-ation of a new action potential (Fig. 2-7).

Phase 0 depolarization primarily is due toincreased gCa�� through L-type calcium chan-nels. These voltage-operated channels openwhen the membrane is depolarized to a thresh-old voltage of about –40 mV. Because themovement of Ca�� through calcium channelsis not rapid (hence, the term “slow calciumchannels”), the rate of depolarization (the slopeof phase 0) is much slower than that found inother cardiac cells (e.g., in Purkinje cells). Asthe calcium channels open and the membranepotential moves toward the calcium equilib-rium potential, a transient decrease in gK�

occurs, which contributes to the depolarizationas shown in the following equation:

Em � g’K (�96mV) � g’Ca (�134mV)

Depolarization causes voltage-operated,delayed rectifier potassium channels to open,and the increased gK� repolarizes the cell to-ward the equilibrium potential for K� (phase3). At the same time, the slow inward Ca��

channels that opened during phase 0 becomeinactivated, thereby decreasing gCa�� andcontributing to the repolarization. Phase 3ends when the membrane potential reachesabout –65 mV. The phase of repolarization isself-limited because the potassium channelsbegin to close again as the cell becomes repo-larized.

The ionic mechanisms responsible for thespontaneous depolarization of the pacemakerpotential (phase 4) are not entirely clear, butprobably involve several different ionic cur-rents. First, early in phase 4, gK� is still de-clining. This fall in gK� contributes to depolar-ization. Second, in the repolarized state, apacemaker current (If), or “funny” current,has been identified. This current may involve aslow inward movement of Na�. Third, in thesecond half of phase 4, there is a small increasein gCa�� through T-type calcium channels. T-type (“transient”) calcium channels differ fromL-type calcium channels in that they openbriefly only at very negative voltages (–50 mV)and are not blocked by the classical L-type cal-cium channel blockers. Fourth, as the depolar-ization begins to reach threshold, the L-typecalcium channels begin to open, causing a fur-ther increase in gCa�� until threshold isreached and phase 0 is initiated.

To summarize, the action potential in SAnodal cells primarily depends on changes ingCa�� and gK� conductances, with slow Na�

currents (If) and changes in gCa�� and gK�

conductances playing a role in the sponta-neous depolarization.

The SA node displays intrinsic automaticityat a rate of 100 to 110 depolarizations perminute. Heart rate, however, can vary be-tween low resting values of about 60 beats/min to over 200 beats/min. These changes in


I If f

FIGURE 2-7 Changes in ion conductances associatedwith a sinoatrial (SA) nodal action potential. Phase 0(depolarization) primarily is due to an increase in cal-cium conductance (gCa��) through L-type Ca�� chan-nels accompanied by a fall in potassium conductance(gK�); phase 3 (repolarization) results from an increasein gK� and a decrease in gCa��. Phase 4 undergoes aspontaneous depolarization owing to a pacemaker cur-rent (If) carried in part by Na�; decreased gK� and in-creased gCa�� also contribute to the spontaneous de-polarization.

Ch02_009-040_Klabunde 4/21/04 10:53 AM

rate primarily are controlled by autonomicnerves acting on the SA node. At resting heartrates, vagal influences are dominant over sym-pathetic influences. This is termed vagaltone. Autonomic nerves increase SA nodalfiring rate by both decreasing vagal tone andincreasing sympathetic activity on the SAnode in a reciprocal manner. An increase inheart rate is a positive chronotropic response(or positive chronotropy), whereas a reduc-tion in heart rate is a negative chronotropicresponse (or negative chronotropy).

Autonomic influences alter the rate ofpacemaker firing through the following mech-anisms: (1) changing the slope of phase 4; (2)altering the threshold for triggering phase 0;and (3) altering the degree of hyperpolariza-tion at the end of phase 3. Any of these threemechanisms will either increase or decreasethe time to reach threshold. Sympathetic acti-vation of the SA node increases the slope ofphase 4 (Fig. 2-8) and lowers the threshold,thereby increasing pacemaker frequency(positive chronotropy). In this mechanism,norepinephrine binds to �1-adrenoceptorscoupled to a stimulatory G-protein (Gs-protein), which activates adenylyl cyclase andincreases cyclic adenosine monophosphate(cAMP; see Chapter 3). This effect leads to anincreased opening of L-type calcium channelsand an increase in If, both of which increasethe rate of depolarization. Vagal stimulation

releases acetylcholine at the SA node, whichdecreases the slope of phase 4, hyperpolarizesthe cell, and increases threshold. All of theseeffects cause the pacemaker potential to takelonger to reach threshold, thereby slowing therate (negative chronotropy). Acetylcholinebinds to muscarinic receptors (M2) and de-creases cAMP via the inhibitory G-protein(Gi-protein), the opposite effect of sympa-thetic activation (see Chapter 3). Acetyl-choline may also increase cyclic guanosinemonophosphate (cGMP) through the nitricoxide (NO)–cGMP pathway, which inactivatesL-type calcium channels. Finally, acetyl-choline, acting through the Gi-protein, acti-vates a special type of potassium channel(KACh channel) that hyperpolarizes the cell byincreasing potassium conductance.

Nonneural mechanisms also alter pace-maker activity (Table 2-3). For example, circu-lating catecholamines (epinephrine and norepi-nephrine) cause tachycardia by a mechanismsimilar to norepinephrine released by sympa-thetic nerves. Hyperthyroidism induces tachy-cardia, and hypothyroidism induces bradycar-dia. Changes in the serum concentration ofions, particularly potassium, can cause changesin SA node firing rate. Hyperkalemia inducesbradycardia or can even stop SA nodal firing,whereas hypokalemia increases the rate ofphase 4 depolarization and causes tachycardia,apparently by decreasing potassium conduc-

22 CHAPTER 2

0

-50

mV

SA Nodal CellVagal

Threshold

MaximalHyperpolarization

FIGURE 2-8 Effects of sympathetic and parasympathetic (vagal) stimulation on sinoatrial (SA) nodal pacemaker ac-tivity. Sympathetic stimulation increases the firing rate by increasing the slope of phase 4 and lowering the thresholdfor the action potential. Vagal stimulation has the opposite effects, and it hyperpolarizes the cell.

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tance during phase 4. Cellular hypoxia depo-larizes the membrane potential, causing brady-cardia and abolition of pacemaker activity.

Various drugs used to treat abnormal heartrhythm (i.e., antiarrhythmic drugs) also affectSA nodal rhythm. Calcium channel blockers,for example, cause bradycardia by inhibitingL-type calcium channels and slow inwardCa�� currents during phase 4 and phase 0.Drugs affecting autonomic control or auto-nomic receptors (e.g., �-blockers and M2 re-ceptor antagonists; �-adrenoceptor agonists)alter pacemaker activity. Digitalis causesbradycardia by increasing parasympathetic ac-tivity and inhibiting the sarcolemmal Na�/K�-ATPase, which leads to depolarization.

Abnormal Action Potentials

By mechanisms not fully clear, nonpacemakercells may undergo spontaneous depolariza-tions either during phase 3 or early in phase 4,triggering abnormal action potentials. Thesespontaneous depolarizations (termed afterde-polarizations), if of sufficient magnitude, cantrigger self-sustaining action potentials result-ing in tachycardia (Fig. 2-9). Early afterde-polarizations occur during phase 3 and aremore likely to occur when action potential du-rations are prolonged. Because these afterde-polarizations occur at a time when fast Na�

channels are still inactivated, slow inwardCa�� carries the depolarizing current. Anothertype of afterdepolarization, delayed afterde-polarization, occurs at the end of phase 3 orearly in phase 4. It, too, can lead to self-

sustaining action potentials and tachycardia.This form of triggered activity appears to beassociated with elevations in intracellular cal-cium, as occurs during ischemia, digitalis toxi-city, and excessive catecholamine stimulation.

CONDUCTION OF ACTIONPOTENTIALS WITHIN THE HEART

Electrical Conduction within theHeart

The action potentials generated by the SAnode spread throughout the atria primarilythrough cell-to-cell conduction (Fig. 2-10).


TABLE 2-3 FACTORS INCREASING OR DECREASING THE SINOATRIAL NODEFIRING RATE

INCREASING DECREASING

Sympathetic stimulation Parasympathetic stimulation

Muscarinic receptor antagonist Muscarinic receptor agonists

�-Adrenoceptor agonists �-Blockers

Circulating catecholamines Ischemia/hypoxia

Hypokalemia Hyperkalemia

Hyperthyroidism Sodium and calcium channel blockers

Time

Early Afterdepolarizations

Delayed Afterdepolarizations

FIGURE 2-9 Early (top panel) and delayed (bottompanel) afterdepolarizations. If the magnitude of sponta-neous depolarization is sufficient, it can trigger self-sustaining action potentials.

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When a single myocyte depolarizes, positivecharges accumulate just inside the sar-colemma. Because individual myocytes arejoined together by low-resistance gap junc-tions located at the intercalated disks, ioniccurrents can flow between two adjoining cells.When these ionic intercellular currents aresufficient to depolarize the adjoining cell to itsthreshold potential, an action potential is

elicited in the second cell. Through this cur-rent spread or conduction between adjacentcells, action potentials are propagatedthroughout the atria. Action potentials in theatrial muscle have a conduction velocity ofabout 0.5 m/sec, which is similar to that of ven-tricular muscle (Fig. 2-11). Although the con-duction of action potentials within the atria isprimarily between myocytes, some functionalevidence (although controversial) points to theexistence of specialized conducting pathwayswithin the atria, termed internodal tracts. Aseach wave of action potentials originating fromthe SA node spreads across and depolarizesthe atrial muscle, it initiates excitation–contraction coupling (see Chapter 3).

Nonconducting connective tissue separatesthe atria from the ventricles. Action potentialsnormally have only one pathway available toenter the ventricles, a specialized region ofcells called the atrioventricular (AV) node.The AV node, located in the inferior–posteriorregion of the interatrial septum, is a highlyspecialized conducting tissue (cardiac, notneural in origin) that slows the impulse con-

24 CHAPTER 2

+ +++

+++++++ +

++++

–

––

–

––

–– –

––––

–

–

–

–

–

– ––––––

– ––

+

FIGURE 2-10 Cell-to-cell conduction. Cardiac cells areconnected together by low-resistance gap junctions be-tween the cells, forming a functional syncytium. Whenone cell depolarizes, depolarizing currents can passthrough the gap junctions and depolarize adjacent cells,resulting in a cell-to-cell propagation of action potentials.

RV LV

LA

RA

SA Node

PurkinjeFibers

(∼4 m/sec)

VentricularMuscle

(∼0.5 m/sec)

Left & RightBundle Branches

(∼2 m/sec)

Bundle of His(∼2 m/sec)

AV Node(∼0.05 m/sec)

Atrial Muscle(∼0.5 m/sec)

FIGURE 2-11 Conduction system within the heart. Conduction velocities of different regions are noted in parenthe-ses. Note that Purkinje fibers have the highest conduction velocity and the atrioventricular (AV) node has the lowestconduction velocity. SA, sinoatrial.

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duction velocity to about 0.05 m/sec. This isone-tenth the velocity found in atrial or ven-tricular myocytes (see Fig. 2-11).

The delay in conduction between the atriaand ventricles at the AV node is important.First, it allows sufficient time for completeatrial depolarization, contraction, and empty-ing of atrial blood into the ventricles prior toventricular depolarization and contraction(see Chapter 4). Second, the low conductionvelocity helps to limit the frequency of im-pulses traveling through the AV node and ac-tivating the ventricle. This is important inatrial flutter and fibrillation, in which exces-sively high atrial rates, if transmitted to theventricles, lead to severe ventricular tachycar-dia and reduced cardiac output caused by in-adequate time for ventricular filling.

Action potentials leaving the AV node enterthe base of the ventricle at the bundle of Hisand then follow the left and right bundlebranches along the interventricular septum.These specialized bundle branch fibers con-duct action potentials at a high velocity (about2 m/sec). The bundle branches divide into anextensive system of Purkinje fibers that con-duct the impulses at high velocity (about 4m/sec) throughout the ventricles. ThePurkinje fiber cells connect with ventricularmyocytes, which become the final pathway forcell-to-cell conduction within the heart.

The conduction system within the heart isimportant because it permits rapid, organized,near-synchronous depolarization and contrac-tion of ventricular myocytes, which is essentialto generate pressure efficiently during ven-tricular contraction. If the conduction systembecomes damaged or dysfunctional, as can oc-

cur during ischemic conditions or myocardialinfarction, this change can lead to alteredpathways of conduction and decreased con-duction velocity within the heart. The func-tional consequence is that it diminishes theability of the ventricles to generate pressure.Furthermore, damage to the conducting sys-tem can precipitate arrhythmias.

Regulation of Conduction Velocity

The rate of cell-to-cell conduction is deter-mined by several intrinsic and extrinsic factors.Intrinsic factors include the electrical resis-tance between cells and the nature of the ac-tion potential, particularly in the initial rate ofdepolarization (phase 0). As discussed earlierin this chapter, fast sodium channels are re-sponsible for the rapid upstroke velocity ofnonpacemaker action potentials. Increasingthe number of activated fast sodium channelsincreases the rate of depolarization. The morerapidly one cell depolarizes, the more quicklyan adjoining cell depolarizes. Therefore, con-ditions that decrease the availability of fastsodium channels (e.g., depolarization causedby cellular hypoxia), decrease the rate andmagnitude of phase 0, thereby decreasing con-duction velocity within the heart. In AV nodaltissue in which slow inward calcium primarilydetermines phase 0 of the action potential, al-terations in calcium conductance alter the rateof depolarization and therefore the rate of con-duction between AV nodal cells.

Extrinsic factors can influence conductionvelocity, including autonomic nerves, circulat-ing hormones (particularly catecholamines),and various drugs (Table 2-4). Autonomic


TABLE 2-4 EXTRINSIC FACTORS INCREASING OR DECREASING CONDUCTIONVELOCITY WITHIN THE HEART

INCREASING DECREASING

Sympathetic stimulation Parasympathetic stimulation

Muscarinic receptor antagonists Muscarinic receptor agonists

�1-Adrenoceptor agonists Beta-blockers

Circulating catecholamines Ischemia/hypoxia

Hyperthyroidism Sodium and calcium channel blockers

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nerve activity significantly influences the con-duction of electrical impulses throughout theheart, particularly in the specialized conduc-tion system. An increase in sympathetic firing(or increased circulating catecholamines) in-creases conduction velocity via norepineph-rine binding to �1-adrenoceptors. The activa-tion of parasympathetic (vagal) nervesdecreases conduction velocity via the action ofacetylcholine on M2 receptors. The signaltransduction mechanisms coupled to �1-adrenoceptors and M2 receptors (Gs- and Gi-proteins) are the same as described inChapter 3 (see Fig. 3-6) for the regulation ofcardiac contraction. A number of drugs can affect conduction velocity by altering auto-nomic influences or directly altering intercel-lular conduction. For example, antiarrhythmicdrugs that block fast sodium channels de-crease conduction velocity; digitalis com-pounds activate vagal influences on the con-duction system; and �-adrenoceptor agonistsor antagonists can increase or decrease con-duction velocity, respectively.

Abnormal Conduction

When electrical activation of the heart doesnot follow the normal pathways outlined ear-lier, ventricular contraction efficiency may bereduced and arrhythmias may be precipitated.For example, if the AV node becomes com-pletely blocked by ischemic damage or exces-sive vagal stimulation, impulses cannot travelfrom the atria into the ventricles. Fortunately,latent pacemakers within the ventricular con-duction system usually take over to activatethe ventricles; however, the lower firing rateof these pacemakers results in ventricularbradycardia and decreased cardiac output. Asanother example, if one of the bundlebranches is blocked, ventricular depolariza-tion still occurs, but the depolarization path-ways will be altered leading to a delay in ven-tricular activation and reduced contractionefficiency. An ectopic beat originating withinthe ventricle can cause altered pathways ofconduction as well. When this occurs outsideof the normal fast conducting system, it altersthe pathway of depolarization, and ventricular

depolarization has to rely on the relativelyslow cell-to-cell conduction between myo-cytes.

In addition, abnormal conduction can arisefrom accessory conduction pathways, such asmay be found between the atria and ventri-cles. These accessory pathways alter the routeand sequence of ventricular depolarizationand often result in arrhythmias (e.g.,supraventricular tachycardias), which occur asa result of reentry mechanisms (see ReentryMechanisms on CD).

THE ELECTROCARDIOGRAM (ECG)

The ECG is a crucial diagnostic tool in clinicalpractice. It is especially useful in diagnosingrhythm disturbances, changes in electricalconduction, and myocardial ischemia and in-farction. The remaining sections of this chap-ter describe how the ECG is generated andhow it can be used to examine changes in car-diac electrical activity. For more in-depth in-formation about this topic, particularly how tointerpret abnormal ECGs, consult detailedclinical textbooks such as those listed at theend of this chapter.

ECG Tracing

As cardiac cells depolarize and repolarize,electrical currents spread throughout thebody because the tissues surrounding theheart are able to conduct electrical currentsgenerated by the heart. When these electricalcurrents are measured by an array of elec-trodes placed at specific locations on the bodysurface, the recorded tracing is called an ECG(Fig. 2-12). The repeating waves of the ECGrepresent the sequence of depolarization andrepolarization of the atria and ventricles. TheECG does not measure absolute voltages, butvoltage changes from a baseline (isoelectric)voltage. ECGs are generally recorded on pa-per at a speed of 25 mm/sec and with a verti-cal calibration of 1 mV/cm.

By convention, the first wave of the ECG isthe P wave. It represents the wave of depolar-ization that spreads from the SA node through-out the atria; it is usually 0.08 to 0.1 seconds

26 CHAPTER 2

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(80-100 m/sec) in duration (Table 2-5). No dis-tinctly visible wave represents atrial repolariza-tion in the ECG because it occurs during ven-tricular depolarization and is of relatively smallamplitude. The brief isoelectric (zero voltage)

period after the P wave represents the time inwhich the atrial cells are depolarized and theimpulse is traveling within the AV node, whereconduction velocity is greatly reduced. The pe-riod of time from the onset of the P wave to thebeginning of the QRS complex, the P-R inter-val, normally ranges from 0.12 to 0.20 seconds.This interval represents the time between theonset of atrial depolarization and the onset ofventricular depolarization. If the P-R interval isgreater than 0.2 seconds, a conduction defect(usually within the AV node) is present (e.g.,first-degree heart block).

The QRS complex represents ventriculardepolarization. The duration of the QRS com-plex is normally 0.06 to 0.1 seconds, indicatingthat ventricular depolarization occurs rapidly.If the QRS complex is prolonged (greater than0.1 seconds), conduction is impaired withinthe ventricles. Impairment can occur with de-fects (e.g., bundle branch blocks) or aberrantconduction, or it can occur when an ectopicventricular pacemaker drives ventricular de-polarization. Such ectopic foci nearly alwayscause impulses to be conducted over slowerpathways within the heart, thereby increasingthe time for depolarization and the durationof the QRS complex.

The isoelectric period (ST segment) fol-lowing the QRS is the period at which the en-tire ventricle is depolarized and roughly cor-responds to the plateau phase of theventricular action potential. The ST segmentis important in the diagnosis of ventricular


FIGURE 2-12 Components of the ECG trace. A rhythmstrip at the top shows a typical ECG recording. An en-largement of one of the repeating waveform unitsshows the P wave, QRS complex, and T wave, whichrepresent atrial depolarization, ventricular depolariza-tion, and ventricular repolarization, respectively. The P-R interval represents the time required for the depolar-ization wave to transverse the atria and theatrioventricular node; the Q-T interval represents theperiod of ventricular depolarization and repolarization;and the ST segment is the isoelectric period when theentire ventricle is depolarized.

TABLE 2-5 SUMMARY OF ECG WAVES, INTERVALS, AND SEGMENTS

ECG COMPONENT REPRESENTS NORMAL DURATION (SEC)

P wave Atrial depolarization 0.08 – 0.10

QRS complex Ventricular depolarization 0.06 – 0.10

T wave Ventricular repolarization 1

P-R interval Atrial depolarization plus AV nodal delay 0.12 – 0.20

ST segment Isoelectric period of depolarized ventricles 1

Q-T interval Length of depolarization plus repolarization – 0.20 – 0.40 2

corresponds to action potential duration

1 Duration not normally measured. 2 High heart rates reduce the action potential duration and therefore the Q-T in-terval.

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ischemia, in which the ST segment can be-come either depressed or elevated, indicatingnonuniform membrane potentials in ventricu-lar cells. The T wave represents ventricularrepolarization (phase 3 of the action potential)and lasts longer than depolarization.

During the Q-T interval, both ventriculardepolarization and repolarization occur. Thisinterval roughly estimates the duration of ven-tricular action potentials. The Q-T intervalcan range from 0.2 to 0.4 seconds dependingon heart rate. At high heart rates, ventricularaction potentials are shorter, decreasing theQ-T interval. Because prolonged Q-T inter-vals can be diagnostic for susceptibility to cer-tain types of arrhythmias, it is important to de-termine if a given Q-T interval is excessivelylong. In practice, the Q-T interval is expressedas a corrected Q-T (Q-Tc) interval by takingthe Q-T interval and dividing it by the squareroot of the R-R interval (the interval betweenventricular depolarizations). This calculationallows the Q-T interval to be assessed inde-pendent of heart rate. Normal corrected Q-Tcintervals are less than 0.44 seconds.

Interpretation of Normal andAbnormal Cardiac Rhythms from the ECG

One important use of the ECG is that it lets aphysician evaluate abnormally slow, rapid, orirregular cardiac rhythm. Atrial and ventricu-lar rates of depolarization can be determinedfrom the frequency of P waves and QRS com-plexes by recording a rhythm strip. A rhythmstrip is usually generated from a single elec-trocardiogram lead (often lead II). In a nor-mal ECG, a consistent, one-to-one correspon-dence exists between P waves and the QRScomplex; i.e., each P wave is followed by aQRS complex. This correspondence, whenfound, indicates that ventricular depolariza-tion is being triggered by atrial depolarization.Under these normal conditions, the heart issaid to be in sinus rhythm, because the SAnode is controlling the cardiac rhythm.Normal sinus rhythm can range from 60–100beats/min. Although the term “beats” is beingused here, strictly speaking, the electrocardio-

gram gives information only about the fre-quency of electrical depolarizations. However,a depolarization usually results in contractionand therefore a “beat.”

Abnormal rhythms (arrhythmias) can becaused by abnormal formation of action po-tentials. A sinus rate less than 60 beats/min istermed sinus bradycardia. The resting sinusrhythm, as previously described, is highly de-pendent on vagal tone. Some people, espe-cially highly conditioned athletes, may havenormal resting heart rates that are signifi-cantly less than 60 beats/min. In other indi-viduals, sinus bradycardia may result from de-pressed SA nodal function. A sinus rate of100–180 beats/min, sinus tachycardia, is anabnormal condition for a person at rest; how-ever, it is a normal response when a person ex-ercises or becomes excited.

In a normal ECG, a QRS complex followseach P wave. Conditions exist, however, whenthe frequency of P waves and QRS complexesmay be different (Fig. 2-13). For example,atrial rate may become so high in atrial flut-ter (250-350 beats/min) that not all of the im-pulses are conducted through the AV node;therefore, the ventricular rate (as determinedby the frequency of QRS complexes) may beonly half of the atrial rate. In atrial fibrilla-tion, the SA node does not trigger the atrialdepolarizations. Instead, depolarization cur-rents arise from many sites throughout theatria, leading to uncoordinated, low-voltage,high-frequency depolarizations with no dis-cernable P waves. In this condition, the ven-tricular rate is irregular and usually rapid.Atrial fibrillation illustrates an important func-tion of the AV node; it limits the frequency ofimpulses that it conducts, thereby limitingventricular rate. This feature is mechanicallyconsequential because when ventricular ratesbecome very high (e.g., greater than 200beats/min), cardiac output falls owing to inad-equate time for ventricular filling betweencontractions.

Atrial rate is greater than ventricular ratein some forms of AV nodal blockade (seeFig. 2-13). This is an example of an arrhyth-mia caused by abnormal (depressed) impulseconduction. With AV nodal blockade, atrial

28 CHAPTER 2

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rate is normal, but every atrial depolarizationmay not be followed by a ventricular depolar-ization. A second-degree AV nodal blockmay have two or three P waves precedingeach QRS complex because the AV node doesnot successfully conduct every impulse. In aless severe form of AV nodal blockade, theconduction through the AV node is delayed,but the impulse is still able to pass throughthe AV node and excite the ventricles. Withthis condition, termed first-degree AVnodal block, a consistent one-to-one corre-spondence remains between the P waves andQRS complexes; however, the P-R interval isfound to be greater than 0.2 seconds. In an

extreme form of AV nodal blockade, third-degree AV nodal block, no atrial depolar-izations are conducted through the AV node,and P waves and QRS complexes are com-pletely dissociated. The ventricles still un-dergo depolarization because of the expres-sion of secondary pacemaker sites (e.g., at theAV nodal junction or from some ectopic fociwithin the ventricles); however, the ventricu-lar rate is generally slow (less than 40beats/min). Bradycardia occurs because theintrinsic firing rate of secondary, latent pace-makers is much slower than in the SA node.For example, pacemaker cells within the AVnode and bundle of His have rates of 50–60beats/min, whereas those in the Purkinje sys-tem have rates of only 30–40 beats/min. If theectopic foci is located within the ventricle,the QRS complex will have an abnormalshape and be wider than normal because de-polarization does not follow the normal con-duction pathways.

A condition can arise in which ventricularrate is greater than atrial rate; i.e., the fre-quency of QRS complexes is greater than thefrequency of P waves (see Fig. 2-13). Thiscondition is termed ventricular tachycar-dia (100–200 beats/min) or ventricular flut-ter (greater than 200 beats/min). The mostcommon causes of ventricular arrhythmiasare reentry circuits caused by abnormal im-pulse conduction within the ventricles orrapidly firing ectopic pacemaker sites withinthe ventricles (which may be caused by after-depolarizations). With ventricular arrhyth-mias, there is a complete dissociation be-tween atrial and ventricular rates. Bothventricular tachycardia and ventricular flutterare serious clinical conditions because theycompromise ventricular mechanical functionand can lead to ventricular fibrillation.This latter condition is seen in the ECG asrapid, low-voltage, uncoordinated depolariza-tions (having no discernable QRS com-plexes), which results in cardiac output goingto zero. This lethal condition can sometimesbe reverted to a sinus rhythm by applyingstrong but brief electrical currents to theheart by placing electrodes on the chest (elec-trical defibrillation).


Normal

Atrial Flutter

Atrial Fibrillation

First-Degree AV Block

Second-Degree AV Block (2:1)

Third-Degree AV Block

Premature Ventricular Complex

Ventricular Tachycardia

Ventricular Fibrillation

FIGURE 2-13 ECG examples of abnormal rhythms. AV,atrioventricular.

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The ECG can reveal another type of ar-rhythmia, premature depolarizations (seeFig. 2-13). These depolarizations can occurwithin either the atria (premature atrial com-plex) or the ventricles (premature ventricularcomplex). They are usually caused by ectopicpacemaker sites within these cardiac regionsand appear as extra (and early) P waves orQRS-complexes. These premature depolar-izations are often abnormally shaped, particu-larly in ventricles, because the impulses gen-erated by the ectopic site are not conductedthrough normal pathways.

Volume Conductor Principles andECG Rules of Interpretation

The previous section defined the componentsof the ECG trace and what they represent interms of electrical events within the heart.This section examines in more detail how therecorded ECG waveform depends on (1) lo-cation of recording electrodes on the bodysurface; (2) conduction pathways and speed ofconduction; and (3) changes in muscle mass.To interpret the significance of changes in theappearance of the ECG, we must first under-stand the basic principles of how the ECG isgenerated and recorded.

Recording Depolarization andRepolarization using External ElectrodesFigure 2-14 depicts a piece of living ventricu-lar muscle placed into a bath containing a con-ducting, physiologic salt solution. Electrodes

are located on either side of the muscle tomeasure potential differences. Initially, no po-tential difference exists between the two elec-trodes (i.e., an isoelectric voltage), becauseall of the cells are completely polarized (i.e., atrest). The reason for isoelectric voltage is thatthe outside of all of the cells is positive relativeto the inside (see Fig. 2-14, panel A).Normally in cell physiology, the inside of thecell is considered negative relative to the out-side (which is zero by convention); however,for this model, assume that the outside is pos-itive relative to the inside so that a separationof charges can be displayed on the surface ofthe model. Because the entire surface is posi-tive, no current is flowing along the surface ofthe muscle. If the left side of the muscle wassuddenly depolarized to generate action po-tentials, a wave of depolarization would sweepacross the muscle from left to right as actionpotentials were propagated by cell-to-cell con-duction. Midway through this depolarizationprocess, depolarized cells on the left would benegative on the outside relative to the inside,whereas nondepolarized cells on the right sideof the muscle would be still polarized (positiveon the outside) (see Fig. 2-14, panel B). A po-tential difference between the positive andnegative electrodes would now exist owing toa separation of charges (i.e., an electrical di-pole). By convention, a wave of depolariza-tion heading toward the positive electrode isrecorded as a positive voltage (an upward de-flection in the recording). Immediately afterthe wave of depolarization sweeps across the

30 CHAPTER 2

A patient is being treated for hypertension with a �-blocker (a drug that blocks to �-adrenoceptors in the heart) in addition to a diuretic. A routine ECG reveals that the pa-tient’s P-R interval is 0.24 seconds (first-degree AV nodal block). Explain how removalof the �-blocker might improve AV nodal conduction.

Sympathetic nerve activity increases conduction velocity within the AV node (positivedromotropic effect). This effect on the AV node is mediated by norepinephrine bindingto �-adrenoceptors within the nodal tissue. A �-blocker would remove this sympatheticinfluence and slow conduction within the AV node, which might prolong the P-R inter-val. Therefore, taking the patient off the �-blocker might improve AV nodal conductionand thereby decrease the P-R interval to within the normal range (0.12 to 0.20 seconds).

CASE 2-1

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entire muscle mass, all of the cells on the out-side are negative, and once again, no potentialdifference exists between the two electrodes(i.e., isoelectric voltage) (Fig. 2-14, panel C).Because the movement of the wave of depo-larization is time dependent, we initially seezero voltage (panel A) followed by a transientpositive voltage deflection (panel B), endingonce again at zero voltage (panel C). This pat-tern depicts in simplistic terms the process ofatrial and ventricular depolarizations, and theway the P wave and QRS complex, respec-tively, are generated.

All of the cells are depolarized for only abrief period of time, after which they undergorepolarization. For this model, assuming thatthe last cells to depolarize are the first to re-polarize, a wave of repolarization would movefrom right-to-left (panel D). As repolarizationoccurs, cells on the right (nearest to the posi-tive electrode) are the first to become positiveagain on the outside. This event results in apotential difference between the electrodes,with the positive electrode “seeing” a positivepolarity and therefore recording a positivevoltage. After the wave of repolarizationsweeps across the entire mass and all the cellsbecome repolarized, the entire surface is onceagain positive and no potential difference ex-ists between the electrodes (i.e., isoelectric

voltage) (Fig. 2-14, panel E). By convention, awave of repolarization moving away from apositive electrode produces a positive voltagedifference. This repolarization direction iswhat happens in the ventricle and explainswhy the T wave, which represents ventricularrepolarization, is normally positive. If thewave of repolarization were to begin with thefirst cells that depolarized, the wave wouldtravel toward the positive electrode, and anegative voltage deflection would berecorded. Therefore, by convention, a wave ofrepolarization moving toward a positive elec-trode produces a negative voltage deflection inthe ECG. This repolarization direction is whathappens in the atria. If atrial repolarizationcould be seen in the ECG, the waveformwould have a negative voltage deflection.

Vectors and Mean Electrical AxisThe simplified model presented in Figure 2-14 depicts single waves of depolarizationand repolarization. In reality, there is no singlewave of electrical activity through the muscle.As illustrated for the atria in Figure 2-15,when the SA node fires, many separate depo-larization waves emerge from the SA nodeand travel throughout the atria. These sepa-rate waves can be depicted as arrows repre-senting individual electrical vectors. At any


0 00 0 0

Resting Depolarized Repolarized

A B C D E

FIGURE 2-14 A model of the way depolarization and repolarization of ventricular muscle results in voltage changesrecorded by external electrodes. Ventricular muscle is placed in a conducting solution, and electrodes are located oneither side of the muscle to record potential differences. (A) Resting (polarized) muscle has the same potential acrossthe surface, as indicated by positive charges outside of the cells (relative to the negative cell interior; see text); there-fore, the electrodes record no potential difference between them (0 voltage; i.e., isoelectric). (B) Muscle depolarizesbeginning at the left side, and a wave of depolarization (arrow) travels from left to right across the muscle. The sep-aration of charges in the partially depolarized muscle results in a positive voltage recording (analogous to the QRScomplex). (C) All of the muscle is depolarized (all cells negative on the outside), so that there is no separation ofcharge and therefore no potential difference (isoelectric; analogous to the ST segment). (D) Partially repolarized mus-cle; the last cells to depolarize are the first to repolarize, resulting in a wave of repolarization (arrow) moving fromright to left. The separation of charges results in a positive voltage recording (analogous to the T wave). (E) Musclefully repolarized as in A.

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given instant, many individual vectors exist;each one represents action potential conduc-tion in a different direction. A mean electri-cal vector can be derived at that instant bysumming the individual vectors.

The direction of the mean electrical vectorrelative to the axis between the recordingelectrodes determines the polarity and magni-tude of the recorded voltage (Fig. 2-16). If themean electrical vector is pointing toward thepositive electrode, the ECG displays a positivedeflection (positive voltage). If at some otherinstant the mean electrical vector is pointingaway from the positive electrode, there is anegative deflection (negative voltage). If the

mean electrical vector is oriented perpendicu-lar to the axis between the positive and nega-tive electrodes, there is no net change in volt-age.

The preceding discussion describes a meanelectrical vector determined at a specific pointin time (i.e., an instantaneous mean vec-tor). If a series of instantaneous mean vectorsis determined over time, it is possible to de-rive an average mean vector that represents allof the individual vectors over time. Figure 2-17 depicts the sequence of depolarizationwithin the ventricles by showing four differentmean vectors representing different timesduring depolarization. This model shows theseptum and free walls of the left and rightventricles; each of the four vectors is depictedas originating from the AV node. The size ofthe vector arrow is related to the mass of tis-sue undergoing depolarization. The larger thearrow (and tissue mass), the greater the mea-sured voltage. The electrode placement rep-resents lead II (see the next section, ECGLeads). Early during ventricular activation,the interventricular septum depolarizes fromleft to right as depicted by mean electricalvector 1. This small vector is heading awayfrom the positive electrode (to the right of aline perpendicular to the lead axis) and there-fore records a small negative deflection (the Q

32 CHAPTER 2

+

–

SA Node

Atrial Muscle

FIGURE 2-15 Electrical vectors. Instantaneous individualvectors of depolarization (black arrows) spread acrossthe atria after the sinoatrial (SA) node fires. The meanelectrical vector (red arrow) represents the sum of theindividual vectors at a given instant in time.

1

2

3

4

1

2

3

4QRS Complex

Lead II

+

_

FIGURE 2-17 Generation of QRS complex from vectorsrepresenting ventricular depolarization. Arrows 1-4 rep-resent the time-dependent sequence of ventricular de-polarization and the way these time-dependent vectorsgenerate the QRS complex. The relationship of the pos-itive and negative recording electrodes relative to theventricle depicts lead II. See the text for more details.

+1

23

4

5

6 78

–

FIGURE 2-16 Recording of electrical vectors.Orientation of the mean electrical vector of depolariza-tion relative to the recording electrodes determines thepolarity of the recording. Arrow 1, which is heading di-rectly toward the positive electrode, gives the greatestpositive deflection. As the vector moves around the axisto the left, and therefore moves away from the positiveelectrode, the recorded voltage becomes less positive,and then negative as the vector heads away from thepositive electrode. No net voltage is present when thevector is perpendicular to the axis between the twoelectrodes.

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wave of the QRS). About 20 millisecondslater, the mean electrical vector points down-ward toward the apex (vector 2), and heads to-ward the positive electrode. This directiongives a very tall, positive deflection (the Rwave of the QRS). After another 20 millisec-onds, the mean vector is directed toward theleft arm and anterior chest as the free wall ofthe ventricle depolarizes from the endocardial(inside) to epicardial (outside) surface (vector3). This vector still records a small positivevoltage in lead II and corresponds to a voltagepoint between the R and S waves. Finally, thelast regions to depolarize result in vector 4,which causes a slight negative deflection (theS wave) of the QRS because it is pointed awayfrom the positive electrode. If the four vectorsin Figure 2-15 are summed, the resultant vec-tor (red arrow) is the mean electrical axis.The mean electrical axis is the average ven-tricular depolarization vector over time;therefore, it is the average of all of the instan-taneous mean electrical vectors occurring se-quentially during ventricular depolarization.The determination of mean electrical axis isparticularly significant for the ventricles. It isused diagnostically to identify left and rightaxis deviations, which can be caused by anumber of factors, including conductionblocks in a bundle branch and ventricular hy-pertrophy.

It is important to note that the shape of theQRS complex can change considerably de-pending on the placement of the recordingelectrodes. For example, if the polarity of theelectrodes were reversed in Figure 2-17, theQRS complex would be inverted: a small pos-itive deflection, followed by a large negativedeflection, and ending with a small positivedeflection.

Based on the previous discussion, the fol-lowing rules can be used in interpreting theECG:

1. A wave of depolarization traveling to-ward a positive electrode results in apositive deflection in the ECG trace.[Corollary: A wave of depolarization travel-ing away from a positive electrode resultsin a negative deflection.]

2. A wave of repolarization traveling to-ward a positive electrode results in anegative deflection. [Corollary: A waveof repolarization traveling away from a pos-itive electrode results in a positive deflec-tion.]

3. A wave of depolarization or repolariza-tion oriented perpendicular to an elec-trode axis has no net deflection.

4. The instantaneous amplitude of themeasured potentials depends upon theorientation of the positive electroderelative to the mean electrical vector.

5. Voltage amplitude (positive or nega-tive) is directly related to the mass oftissue undergoing depolarization orrepolarization.

The first three rules are derived from thevolume conductor models described earlier.The fourth rule takes into consideration that,at any given point in time during depolariza-tion in the atria or ventricles, many separatewaves of depolarization are traveling in differ-ent directions relative to the positive elec-trode. The recording by the electrode reflectsthe average, instantaneous direction and mag-nitude (i.e., the mean electrical vector) for allof the individual depolarization waves. Thefifth rule states that the amplitude of the waverecorded by the ECG is directly related to themass of the muscle undergoing depolarizationor repolarization. For example, when the massof the left ventricle is increased (i.e., ventricu-lar hypertrophy), the amplitude of the QRScomplex, which largely represents left ventric-ular depolarization, is sometimes increased(depending on the degree of hypertrophy).

ECG Leads: Placement of RecordingElectrodes

The ECG is recorded by placing an array ofelectrodes at specific locations on the bodysurface. Conventionally, electrodes are placedon each arm and leg, and six electrodes areplaced at defined locations on the chest.Three basic types of ECG leads are recordedby these electrodes: standard limb leads, aug-mented limb leads, and chest leads. These


Ch02_009-040_Klabunde 4/21/04 10:53 AM

electrode leads are connected to a device thatmeasures potential differences between se-lected electrodes to produce the characteristicECG tracings. The limb leads are sometimesreferred to as bipolar leads because each leaduses a single pair of positive and negative elec-trodes. The augmented leads and chest leadsare unipolar leads because they have a singlepositive electrode with the other electrodescoupled together electrically to serve as acommon negative electrode.

ECG Limb LeadsStandard limb leads are shown in Figure 2-18. Lead I has the positive electrode on theleft arm and the negative electrode on theright arm, therefore measuring the potentialdifference across the chest between the twoarms. In this and the other two limb leads, anelectrode on the right leg is a reference elec-trode for recording purposes. In the lead IIconfiguration, the positive electrode is on theleft leg and the negative electrode is on theright arm. Lead III has the positive electrodeon the left leg and the negative electrode onthe left arm. These three limb leads roughlyform an equilateral triangle (with the heart at

the center), called Einthoven’s triangle inhonor of Willem Einthoven who developedthe ECG in 1901. Whether the limb leads areattached to the end of the limb (wrists and an-kles) or at the origin of the limbs (shoulderand upper thigh) makes virtually no differencein the recording because the limb can beviewed as a wire conductor originating from apoint on the trunk of the body. The electrodelocated on the right leg is used as a ground.

When using the ECG rules described inthe previous section, it is clear that a wave ofdepolarization heading toward the left armgives a positive deflection in lead I becausethe positive electrode is on the left arm.Maximal positive deflection of the tracing oc-curs in lead I when a wave of depolarizationtravels parallel to the axis between the rightand left arms. If a wave of depolarizationheads away from the left arm, the deflection isnegative. In addition, a wave of repolarizationmoving away from the left arm is seen as apositive deflection.

Similar statements can be made for leads IIand III, with which the positive electrode islocated on the left leg. For example, a wave ofdepolarization traveling toward the left leggives a positive deflection in both leads II andIII because the positive electrode for bothleads is on the left leg. A maximal positive de-flection is obtained in lead II when the depo-larization wave travels parallel to the axis be-tween the right arm and left leg. Similarly, amaximal positive deflection is obtained in leadII when the depolarization wave travels paral-lel to the axis between the left arm and leftleg.

If the three limbs of Einthoven’s triangle(assumed to be equilateral) are broken apart,collapsed, and superimposed over the heart(Fig. 2-19), the positive electrode for lead I isdefined as being at zero degrees relative to theheart (along the horizontal axis; see Figure 2-19). Similarly, the positive electrode for leadII is �60º relative to the heart, and the posi-tive electrode for lead III is �120º relative tothe heart, as shown in Figure 2-19. This newconstruction of the electrical axis is called theaxial reference system. Although the desig-nation of lead I as being 0º, lead II as being

34 CHAPTER 2

LL

I

II III

+

+ +

__

_ LARA

RLFIGURE 2-18 Placement of the standard ECG limb leads(leads I, II, and III) and the location of the positive andnegative recording electrodes for each of the threeleads. RA, right arm; LA, left arm; RL, right leg; LL, leftleg.

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�60º, and so forth is arbitrary, it is the ac-cepted convention. With this axial referencesystem, a wave of depolarization oriented at�60º produces the greatest positive deflectionin lead II. A wave of depolarization oriented�90º relative to the heart produces equallypositive deflections in both leads II and III. Inthe latter case, lead I shows no net deflectionbecause the wave of depolarization is headingperpendicular to the 0º, or lead I, axis (seeECG rules).

Three augmented limb leads exist in ad-dition to the three bipolar limb leads de-scribed. Each of these leads has a single posi-tive electrode that is referenced against acombination of the other limb electrodes. Thepositive electrodes for these augmented leadsare located on the left arm (aVL), the right arm(aVR), and the left leg (aVF; the “F” stands for“foot”). In practice, these are the same posi-tive electrodes used for leads I, II, and III.(The ECG machine does the actual switchingand rearranging of the electrode designa-tions.) The axial reference system in Figure 2-20 shows that the aVL lead is at –30º relativeto the lead I axis; aVR is at –150º, and aVF is at�90º. It is critical to learn which lead is asso-ciated with each axis.

The three augmented leads, coupled withthe three standard limb leads, constitute thesix limb leads of the ECG. These leads recordelectrical activity along a single plane, thefrontal plane relative to the heart. The direc-tion of an electrical vector can be determined

at any given instant using the axial referencesystem and these six leads. If a wave of depo-larization is spreading from right to left alongthe 0º axis (heading toward 0º), lead I showsthe greatest positive amplitude. Likewise, ifthe direction of the electrical vector for depo-larization is directed downward (�90º), aVF

shows the greatest positive deflection.

Determining the Mean Electrical Axis from the Six Limb LeadsThe mean electrical axis for the ventricle canbe estimated by using the six limb leads andthe axial reference system. The mean electri-cal axis corresponds to the axis that is perpen-dicular to the lead axis with the smallest netQRS amplitude (net amplitude � positive mi-nus negative deflection voltages of the QRS


0° Lead

+60°Lead II

+120°Lead III

I

III II

I

IIIII

LL

LARA

Axial Reference SystemEinthoven’s Triangle

I

FIGURE 2-19 Transformation of leads I, II, and III from Einthoven’s triangle into the axial reference system. Leads I, II,and III correspond to 0º, 60º, and 120º in the axial reference system. RA, right arm; LA, left arm; LL, left leg.

I

IIaV

aV aV

IIIF

LR

0°

+60°+90°

-30° -150°

+120°

FIGURE 2-20 The axial reference system showing thelocation within the axis of the positive electrode for allsix limb leads.

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complex). If, for example, lead III has thesmallest net amplitude (a biphasic ECG withequal positive and negative deflections) andleads I and II are equally positive, the meanelectrical axis is perpendicular to lead III,which is 120º minus 90º, or �30º (see Figure2-20). In this example, lead aVR has the great-est negative deflection.

It is often important to determine if thereis a significant deviation in the mean electricalaxis from a normal range, which is between–30º and �90º (some authors define the nor-mal range as between 0º and �90º). Less than–30º is considered a left axis deviation, andgreater than �90º is considered a right axisdeviation. Axis deviations can occur becauseof the physical position of the heart within thechest or changes in the sequence of ventricu-lar activation (e.g., conduction defects). Axisdeviations also can occur if ventricular regionsare incapable of being activated (e.g., in-farcted tissue). Ventricular hypertrophy candisplay axis deviation (a left shift for left ven-tricular hypertrophy and a right shift for rightventricular hypertrophy).

ECG Chest LeadsThe last ECG leads to consider are the unipo-lar, precordial chest leads. These six positiveelectrodes are placed on the surface of the

chest over the heart to record electrical activ-ity in a horizontal plane perpendicular to thefrontal plane (Fig. 2-21). The six leads arenamed V1–V6. V1 is located to the right of thesternum over the fourth intercostal space,whereas V6 is located laterally (midaxillaryline) on the chest over the fifth intercostalspace. With this electrode placement, V1 over-lies the right ventricular free wall, and V6

overlies the left ventricular lateral wall. Therules of interpretation are the same as for thelimb leads. For example, a wave of depolariza-

36 CHAPTER 2

A patient’s ECG recording shows that the net QRS deflection is zero (equally positiveand negative deflections) in lead I, and that leads II and III are equally positive. What isthe mean electrical axis? How would leads aVL and aVR appear in terms of net negativeor net positive deflections?

The QRS complex has no net deflection in lead I (i.e., equally positive and negativedeflections), which indicates that the mean electrical axis is perpendicular (90º) to leadI (see Rule 3); therefore, it is either at –90º or �90º because the axis for lead I is 0º bydefinition. Because the QRS is positive in leads II and III, the mean electrical axis mustbe oriented toward the positive electrode on the left leg, which is used for leads II andIII. Therefore, the mean electrical axis cannot be –90º, but is instead �90º. Both aVL

and aVR leads would have net negative deflections because the direction of the meanelectrical axis is away from these two leads, which are oriented at –30º and –150º, re-spectively (see Figure 2-20). Furthermore, the net negative deflections in these twoaugmented leads would be of equal magnitude because each lead axis differs from themean electrical axis by the same number of degrees.

CASE 2-2

V1V2

V3 V4V5

V6

FIGURE 2-21 Placement of the six precordial chestleads. These electrodes record electrical activity in thehorizontal plane, which is perpendicular to the frontalplane of the limb leads.

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tion traveling toward a particular electrode onthe chest surface elicits a positive deflection.Normal electrical activation of the ventriclesresults in a net negative deflection in V1 and anet positive deflection in V6.

ELECTROPHYSIOLOGICAL CHANGESDURING CARDIAC ISCHEMIA

The ECG is a key tool for diagnosing myocar-dial ischemia and infarction. When the heartbecomes ischemic (i.e., when oxygen deliveryis inadequate relative to oxygen demand),electrophysiological changes occur that can al-ter both rhythm and conduction. The ECGcan identify the extent, location, and progressof damage to the heart following ischemic in-jury. This assessment is made by evaluatingchanges in the electrical activity of the heartby using the 12-lead ECG recording. For ex-ample, altered conduction can result in exag-gerated Q waves in specific leads followingsome types of myocardial infarction. Ischemiacan also damage conduction pathways, leadingto arrhythmias or changes in the shape of theQRS complex. Furthermore, ischemia canproduce injury currents flowing from the de-polarized ischemic regions to normal regionsthat can shift the isoelectric portions of theECG, resulting in upward or downward shiftsin the ST segment. The mechanisms by whichischemia and infarction alter the ECG arecomplex and not fully understood. We doknow, however, that tissue hypoxia caused byischemia results in membrane depolarization.As ATP levels decline during hypoxia, there isa net loss of K� as it leaks out of cells throughKATP channels (normally inhibited by ATP)and as a result of decreased activity of theNa�/K�-ATPase pump. Increased extracellu-lar K�, coupled with decreased intracellularK�, causes membrane depolarization. Thisdepolarization inactivates fast sodium chan-nels as previously described, thereby decreas-ing action potential upstroke velocity. One re-sult is decreased conduction velocity. Changesin refractory period and conduction velocitycan lead to reentry currents and tachycardia.Membrane depolarization also alters pace-maker activity and can cause latent pacemak-

ers to be active, leading to changes in rhythmand ectopic beats. Finally, cellular hypoxia re-sults in the accumulation of intracellular cal-cium, which can lead to afterdepolarizationsand tachycardia.


• The membrane potential is determinedprimarily by the concentration differencesof ions, particularly sodium, potassium, andcalcium, across the cell membrane and bythe relative conductances of the membraneto these ions.

• The resting membrane potential is veryclose to the potassium equilibrium poten-tial (calculated from Nernst equation) be-cause the relative conductance of potas-sium is much higher than the relativeconductances of sodium and calcium in theresting cell.

• Ions move across the cell membranethrough ion selective channels, which haveopen (activated) and closed (inactivated)states that are regulated by either mem-brane voltage or by receptor-coupled signaltransduction mechanisms.

• Concentrations of sodium, potassium, andcalcium across the cell membrane aremaintained by the Na�/K�-ATPase pump,the Na�/Ca�� exchanger, and the Ca��-ATPase pump. These ion transport systemsare electrogenic and therefore contributeseveral millivolts to the negative mem-brane potential.

• Nonpacemaker cardiac action potentials arecharacterized as having very negative restingpotentials (approximately –90 mV), a rapidphase 0 depolarization produced primarilyby a transient increase in sodium conduc-tance, and a prolonged plateau phase (phase2) generated primarily by inward calciumcurrents through L-type calcium channels;increased potassium conductance repolar-izes the cells during phase 3.

• Pacemaker action potentials (e.g., thosefound in SA nodal cells) have no true rest-ing potential. Instead, these cells sponta-neously depolarize from about –65 mV to a


Ch02_009-040_Klabunde 4/21/04 10:53 AM

threshold voltage of about –40 mV (phase4) owing in part to special pacemaker cur-rents (If). Upon reaching the threshold foraction potential generation, calcium con-ductance increases as L-type calcium chan-nels become activated (fast sodium chan-nels are inactivated in pacemaker cells),which causes depolarization (phase 0). Asthe calcium channels close, potassium con-ductance increases and the cell repolarizes.

• Pacemaker activity is regulated by sympa-thetic and parasympathetic (vagal) nervesas well as circulating hormones. At rest, SAnodal activity is strongly influenced by va-gal activity (vagal tone), which significantlyreduces the intrinsic SA nodal firing rate toapproximately 60 to 80 beats/minute.Pacemaker activity, and therefore heartrate (chronotropy), is increased by sympa-thetic activation and vagal inhibition.

• Conduction of action potentials within theheart is primarily cell-to-cell, although spe-cialized conduction pathways (e.g., bundleof His, bundle branches, Purkinje fibers)exist within the heart that ensure rapid dis-tribution of the conducted action poten-tials. Conduction velocity (dromotropy) isincreased by activation of sympatheticnerves and decreased by parasympatheticactivation.

• The AV node, which is normally the onlyelectrical bridge between the atria and ven-tricles, decreases the conduction velocitybetween the atria and ventricles, therebyallowing sufficient time for atrial contrac-tion to contribute to ventricular filling.

• Although the SA node is the primary pace-maker within the heart, cells located withinthe AV node and ventricular conductingsystem can also serve as pacemakers if theSA node fails or conduction is blocked be-tween the atria and ventricles (AV nodalblock).

• The ECG measures electrical activity ofthe heart through an array of electrodesplaced on the arms, legs, and chest (12-leadECG). The ECG evaluates rhythm andconduction by examining the appearance(amplitude, duration, and shape) of specificwaveforms that represent atrial depolariza-

tion (P wave), ventricular depolarization(QRS complex), and ventricular repolariza-tion (T wave).

• Different ECG leads view the electrical ac-tivity of the heart from different angles.Each limb lead (I, II, III, aVR, aVL, and aVF)can be represented by an electrical axis on afrontal plane from which the direction ofdepolarization and repolarization vectorswithin the heart can be determined usingstandard rules of interpretation (e.g., a waveof depolarization traveling toward a positiveelectrode produces a positive voltage in theECG). Chest leads (V1-V6) measure theelectrical activity in a horizontal plane thatis perpendicular to the frontal plane.

Review Questions

Please refer to the appendix for the answersto the review questions.For each question, choose the one best answer:1. Which one of the following depolarizes

the resting membrane potential in a car-diac myocyte?

a. Decreased calcium conductanceb. Decreased sodium conductancec. Increased potassium conductanced. Inhibition of the sarcolemmal

Na�/K�-ATPase

2. Fast sodium channels are inactivateda. During phase 0 of a ventricular ac-

tion potential.b. When the h-gates open.c. By slow depolarization of the cell.d. More slowly than L-type calcium

channels are inactivated.

3. The relative potassium conductance ishighest during which of the followingphases of a ventricular action potential?

a. Phase 0b. Phase 2c. Early phase 3d. Phase 4

4. In sinoatrial (SA) nodal action potentials,a. �1-adrenoceptor activation increases

pacemaker current (If).

38 CHAPTER 2

Ch02_009-040_Klabunde 4/21/04 10:53 AM

b. Fast sodium channels are responsi-ble for phase 0.

c. Potassium conductance is highestduring phase 0.

d. Vagal stimulation increases the slopeof phase 4.

5. The normal sequence of conductionwithin the heart is

a. SA node → atrioventricular (AV)node → bundle of His → bundlebranches → Purkinje fibers

b. SA node → bundle of His → AVnode →bundle branches → Purkinjefibers

c. AV node → SA node → bundle ofHis → bundle branches → Purkinjefibers

d. SA node → AV node → bundle ofHis → Purkinje fibers → bundlebranches

6. Conduction velocity within the AV node isincreased by

a. Blocking �1-adrenoceptors.b. Blocking muscarinic (M2) receptors.c. Depolarizing the AV node.d. Blocking L-type calcium channels.

7. In a normal ECG,a. The P-R interval is greater than 0.2

seconds.b. The ST segment represents the du-

ration of the ventricular action po-tential.

c. The T wave represents ventricularrepolarization.

d. The duration of the QRS is greaterthan 0.2 seconds.

8. Which one of the following ECG leadshas the positive electrode on the left arm?

a. Lead Ib. Lead IIc. aVR

d. aVF

9. What is the approximate mean electricalaxis for ventricular depolarization whenthe QRS is equally biphasic in lead II (nonet deflection), and aVL has the mostpositive deflection?

a. –30ºb. 0ºc. �60ºd. �120º

10. An ECG rhythm strip shows a completedissociation between P waves and QRScomplexes. The atrial rate is 95 beats/minand regular, and the ventricular rate isabout 60 beats/min and regular. The QRScomplexes are of normal shape and dura-tion. This ECG represents

a. First-degree AV nodal block.b. Second-degree AV nodal block.c. Third-degree AV nodal block.d. Premature ventricular complexes.

SUGGESTED READINGSDubin D. Rapid Interpretation of EKGs. 6th Ed.

Tampa: Cover Publishing, 2000.Katz AM. Physiology of the Heart. 3rd Ed. Philadelphia:

Lippincott Williams & Wilkins, 2000.Lilly LS. Pathophysiology of Heart Disease. 3rd Ed.

Philadelphia: Lippincott Williams & Wilkins, 2003.Opie LH. The Heart: Physiology from Cell to

Circulation. 3rd Ed. Philadelphia: LippincottWilliams & Wilkins, 1998.


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Ch02_009-040_Klabunde 4/21/04 10:53 AM

CD-ROM CONTENTSLEARNING OBJECTIVESINTRODUCTIONCARDIAC CELL STRUCTURE AND

FUNCTIONMyocytes and SarcomeresExcitation–Contraction CouplingRegulation of Contraction (Inotropy)Regulation of Relaxation (Lusitropy)Cardiac Myocyte Metabolism

VASCULAR STRUCTURE AND FUNCTIONVascular Smooth Muscle CellsVascular Endothelial Cells


c h a p t e r

3Cellular Structure and Function

1. Formation and Physiologic Actions of Nitric Oxide2. Formation and Physiologic Actions of Endothelin-13. Formation and Physiologic Actions of Metabolites of Arachidonic Acid

CD CONTENTS

LEARNING OBJECTIVES

Understanding the concepts presented in this chapter will enable the student to:1. Describe the function of the following cellular components of cardiac myocytes: sar-

colemma, intercalated disks, transverse (T)-tubules, myofibrils, myofilaments, sarcomeres,sarcoplasmic reticulum, and terminal cisternae.

2. Describe the composition of thick and thin myofilaments in cardiac myocytes.3. Describe the significance of a functional syncytium within the heart.4. Describe the steps of excitation–contraction coupling, including the role of T tubules, L-

type calcium channels, trigger calcium, terminal cisternae, ryanodine receptors (calcium-release channels), troponin-C (TN-C), troponin-I (TN-I), troponin-T (TN-T), actin, myosinheads, adenosine triphosphate (ATP) hydrolysis, and sarco-endoplasmic reticulum calciumadenosine triphosphatase (SERCA) pump.

5. List several mechanisms involved in the regulation of cardiac inotropy and lusitropy.6. List in order of preference the metabolic substrates used by the heart, and summarize the

importance of oxidative metabolism relative to anaerobic metabolism.7. Draw the cross section of a muscular artery, label the three layers, and list the major com-

ponents of each layer.8. Contrast the organization of actin and myosin in vascular smooth muscle with the organi-

zation of these myofilaments in cardiac myocytes.9. Describe the mechanism of vascular smooth muscle contraction and include descriptions

of the roles of calcium, calmodulin, and myosin light chain kinase.10. Compare the effects of inositol triphosphate (IP3) and cyclic adenosine monophosphate

(cAMP) signal transduction pathways on the contraction of cardiac muscle and vascularsmooth muscle.

41

Ch03_041-058_Klabunde 4/21/04 10:57 AM

INTRODUCTION

Many different cell types are associated withthe cardiovascular system. This chapter exam-ines the structure and function of three majortypes of structural cells that serve importantroles in cardiovascular function: cardiac myo-cytes, vascular smooth muscle, and vascularendothelium.

CARDIAC CELL STRUCTURE ANDFUNCTION

Myocytes and Sarcomeres

Cardiac myocytes represent a type of striatedmuscle, so-called because crossbands or crossstriations are observed microscopically.Although cardiac muscle shares some struc-tural and functional similarities with skeletalmuscle, it has several important differences.Cardiac myocytes are generally single nucle-ated and have a diameter of approximately 25�m and a length of about 100 �m. In contrast,although some types of skeletal muscle myo-cytes may have a similar diameter, their celllengths run the entire length of the muscleand therefore can be many centimeters long.Cardiac myocytes form a branching networkof cells that is sometimes referred to as a func-tional syncytium, which results from a fusionof cells. Individual myocytes connect to eachother by way of specialized cell membranescalled intercalated disks. Gap junctionswithin these intercellular regions serve as low-resistance pathways between cells, permittingcell-to-cell conduction of electrical (ionic)currents. Therefore, if one cardiac myocyte iselectrically stimulated, cell-to-cell conductionensures that the electrical impulse will travelto all of the interconnected myocytes. Thisarrangement allows the heart to contract as a

unit (i.e., as a syncytium). In contrast, individ-ual skeletal muscle cells are innervated by mo-tor neurons, which utilize neuromusculartransmission to activate individual musclefibers to contract. No cell-to-cell electricalconduction occurs in skeletal muscle.

The cardiac myocyte is composed of bundlesof myofibrils that contain myofilaments (Fig. 3-1). When myocytes are viewed microscopi-cally, distinct repeating lines and bands can beseen, each of which represents different myofil-ament components. The segment between twoZ-lines represents the basic contractile unit ofthe myocyte, the sarcomere. The length ofeach sarcomere under physiologic conditionsranges from about 1.6 to 2.2 �m in humanhearts. As described later and in Chapter 4, thelength of the sarcomere is an important deter-minant of the force of myocyte contraction.

The sarcomere contains thick and thin fil-aments, which represent about 50% of thecell volume (see Fig. 3-1). Thick filaments arecomprised of myosin, whereas thin filamentscontain actin and other associated proteins.Chemical interactions between the actin andmyosin filaments during the process of excita-tion–contraction coupling (see the next sec-tion) cause the sarcomere to shorten as themyosin and actin filaments slide past eachother, thereby shortening the distance be-tween the Z-lines. Within the sarcomere, alarge, filamentous protein called titin exists. Itconnects the myosin filament to the Z-lines,which helps to keep the thick filament cen-tered within the sarcomere. Because of itselastic properties, titin plays an important rolein the passive mechanical properties of theheart (see Chapter 4). In addition to titin,myosin, and actin, a number of other proteinsform the cytoskeleton of myocytes, connect-ing the internal and external cell components.

42 CHAPTER 3

11. List the major agonists that are associated with the following guanine nucleotide-binding regulatory protein (G-protein) coupled systems: inhibitory G-protein (Gi-protein), stimulatory G-protein (Gs-protein), and phospholipase C-coupled Gq-protein.Describe the effects of these agonists on cardiac and smooth muscle contraction.

12. Describe the vascular effects of endothelial-derived nitric oxide (NO), prostacyclin (PGI2),and endothelin-1 (ET-1).

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Myosin is a large molecular weight pro-tein. Within each sarcomere, myosin mole-cules are bundled together so that there areabout 300 molecules of myosin per thick fila-ment. Each myosin molecule contains twoheads, which serve as the site of myosinadenosine triphosphatase (myosin ATPase),an enzyme that hydrolyzes adenosine triphos-phate (ATP). ATP is required for the cross-bridge formation between the thick and thinfilaments. The molecule’s heads interact witha binding site on actin (Fig. 3-2). Regulatorysubunits (myosin light chains) that can alterthe ATPase activity when phosphorylated areassociated with each myosin head.

Each thick filament is surrounded by ahexagonal arrangement of six thin filaments.The thin filaments are composed of actin,tropomyosin, and troponin (Fig. 3-2). Actin isa globular protein arranged as a chain of re-peating globular units, forming two helicalstrands. Interdigitated between the actinstrands are rod-shaped proteins calledtropomyosin. Each tropomyosin molecule isassociated with seven actin molecules.Attached to the tropomyosin at regular inter-vals is the troponin regulatory complex, madeup of three subunits: troponin-T (TN-T),which attaches to the tropomyosin; troponin-C (TN-C), which serves as a binding site for

Ca�� during excitation–contraction coupling;and troponin-I (TN-I), which binds to actin.The troponin complex holds tropomyosin inposition to prevent binding of myosin heads toactin. When Ca�� binds to TN-C, a confor-

CELLULAR STRUCTURE AND FUNCTION 43

Z Z

Sarcomere

Myofibrils

Myofilaments

Actin Titin

Myosin

Intercalateddisc

Myocyte

FIGURE 3-1 Structure of cardiac myocytes. The myocytes are joined together by intercalated discs to form a func-tional syncytium (right side of the figure). Myocytes are composed of myofibrils, each of which contains myofilamentsthat are composed largely of actin (thin filaments) and myosin (thick filaments) (left side of the figure). Myosin is an-chored to the Z-line by the protein titin. The sarcomere, or basic contractile unit, lies between two Z-lines.

Myosin MyosinHeads

Actin

TN-I TN-T

TN-C

Tropomyosin

FIGURE 3-2 Composition of cardiac thick and thin myo-filaments. The thick filaments are composed of myosinmolecules, with each molecule having two myosin heads,which serve as the site of the myosin ATPase. Thin fila-ments are composed of actin, tropomyosin, and regula-tory proteins (troponin complex, TN) having three sub-units: TN-T (binds to tropomyosin), TN-C (binds tocalcium ions), and TN-I (inhibitory troponin, which bindsto actin). Calcium binding to TN-C produces a conforma-tion change in the troponin-tropomyosin complex thatexposes a myosin binding site on the actin, leading toATP hydrolysis. For simplicity, this figure shows only oneactin strand and its associated tropomyosin filament.

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mational change occurs in the troponin com-plex such that the troponin–tropomyosin complex moves away from the myosin-bindingsite on the actin, thereby making the actin accessible to the myosin head for binding.When Ca�� is removed from the TN-C, thetroponin–tropomyosin complex resumes its inactivated position, thereby inhibitingmyosin-actin binding. As a clinical aside, bothTN-I and TN-T are used as diagnostic markersfor myocardial infarction because of their release into the circulation when myocytes die.

Excitation–Contraction Coupling

Transverse Tubules and the SarcoplasmicReticulumThe coupling between myocyte action poten-tials and contraction is called excitation–contraction coupling. To understand thisprocess, the internal structure of the myocyteneeds to be examined in more detail. The sar-colemmal membrane of the myocyte sur-rounds the bundle of myofibrils and has deepinvaginations called transverse (T) tubules(Fig. 3-3). The T tubules, being a part of theexternal sarcolemma, are open to the external

environment of the cell. This permits ionic ex-changes between extracellular and intracellu-lar compartments to occur deep within themyocyte during electrical depolarization andrepolarization of the myocyte. Within the cell,and in close association with the T tubules, isan extensive, branching tubular networkcalled the sarcoplasmic reticulum. Termi-nal cisternae are end pouches of the sar-coplasmic reticulum that are adjacent to the Ttubules. Between the terminal cisternae andthe T tubules are electron-dense regionscalled feet that are believed to sense calciumbetween the T tubules and the terminal cis-ternae. Closely associated with the sarcoplas-mic reticulum are large numbers of mitochon-dria, which provide the energy necessary formyocyte contraction.

Calcium Cycling and the Function of Regulatory ProteinsWhen an action potential causes depolariza-tion of a myocyte (see Chapter 2), it initiatesexcitation–contraction coupling. When themyocyte is depolarized, calcium ions enter thecell during the action potential through long-lasting (L-type) calcium channels located on

44 CHAPTER 3

Ca++

Ca++

Ca++

SR

Myosin

TN-C

SERCA Phospho-lamban

T-tubule

L-typecalcium

channels

Sarcolemma

Actin

“feet”RyR

FIGURE 3-3 Role of calcium (Ca��) in cardiac excitation-contraction coupling. During action potentials, Ca�� enterscell through L-type Ca�� channels. This so-called trigger Ca�� is sensed by the “feet” of the calcium release channel(ryanodine receptor, RyR) of the sarcoplasmic reticulum (SR), which releases Ca�� into the cytoplasm. This Ca�� bindsto troponin-C (TN-C), inducing a conformational change in the troponin-tropomyosin complex so that movement ofthe troponin-tropomyosin complex exposes a myosin binding site on actin, leading to ATP hydrolysis and movementof actin relative to myosin. Ca�� is resequestered into the SR by an ATP-dependent Ca�� pump, sarco-endoplasmicreticulum calcium ATPase (SERCA) that is inhibited by phospholamban. Not shown are Ca�� pumps that remove Ca��

from the cell. TN-1, troponin-I.

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the external sarcolemma and T tubules (seeFig. 3-3). It is important to note that a rela-tively small amount of calcium enters the cellduring depolarization. By itself, this calciuminflux does not significantly increase intracel-lular calcium concentrations except in localregions just inside the sarcolemma. This cal-cium is sensed by the “feet” of the calcium re-lease channels (ryanodine receptors, orryanodine-sensitive calcium-release channels)associated with the terminal cisternae. Thistriggers the subsequent release of large quan-tities of calcium stored in the terminal cister-nae through the calcium-release channels,which increases intracellular calcium concen-trations a hundred-fold, from about 10�7 to 10�5 M. Therefore, the calcium that entersthe cell during depolarization is sometimes re-ferred to as “trigger calcium.”

The free calcium binds to TN-C in a con-centration-dependent manner. This induces aconformational change in the regulatory com-plex such that the troponin–tropomyosin com-plex moves away from and exposes a myosinbinding site on the actin molecule. The bind-ing of the myosin head to the actin results inATP hydrolysis, which supplies energy so thata conformational change can occur in the

actin–myosin complex. This results in a move-ment (“ratcheting”) between the myosinheads and the actin. The actin and myosin fil-aments slide past each other, thereby shorten-ing the sarcomere length (this is referred to asthe sliding filament theory of muscle con-traction) (Fig. 3-4). Ratcheting cycles will oc-cur as long as the cytosolic calcium remainselevated. Toward the end of the myocyte ac-tion potential, calcium entry into the cell di-minishes and the sarcoplasmic reticulum se-questers calcium by an ATP-dependentcalcium pump, sarco-endoplasmic reticulumcalcium ATPase (SERCA; see Fig. 3-3). As in-tracellular calcium concentration declines,calcium dissociates from TN-C, which causesa conformational change in the troponin–tropomyosin complex; this again leads to tro-ponin–tropomyosin inhibition of the actin-binding site. At the end of the cycle, a newATP binds to the myosin head, displacing theadenosine diphosphate (ADP), and the initialsarcomere length is restored. Thus, ATP is re-quired both for providing the energy of con-traction and for relaxation. In the absence ofsufficient ATP as occurs during cellular hyp-oxia, cardiac muscle contraction and relax-ation will be impaired. The events associated


+ Calcium

– Calcium

ZZ

MyosinActin

Actin-myosinbinding

Titin

FIGURE 3-4 Sarcomere shortening and the sliding filament theory. Calcium binding to TN-C permits actin-myosinbinding (cross-bridge formation) and ATP hydrolysis. This results in the thin filaments sliding over the myosin duringcross-bridge cycling, thereby shortening the sarcomere (distance between Z-lines). Removal of calcium from the TN-C inhibits actin-myosin binding so that cross-bridge cycling ceases and the sarcomere resumes its relaxed length.

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with excitation–contraction coupling are sum-marized in Table 3-1.

Regulation of Contraction(Inotropy)

Several cellular mechanisms regulate contrac-tion (Fig. 3-5). Most of these mechanisms ul-timately affect calcium handling by the cell.Changes in contraction resulting from alteredcalcium handling and myosin ATPase activityare referred to as inotropic changes (ino-

tropy). Inotropy is modulated by 1) calciumentry into the cell through L-type calciumchannels; 2) calcium release by the sarcoplas-mic reticulum; 3) calcium binding to TN-C; 4)myosin phosphorylation; 5) SERCA activity;and 6) calcium efflux across the sarcolemma.

Calcium Entry into MyocytesThe amount of calcium that enters the cellduring depolarization (Fig. 3-5, site 1) is regu-lated largely by phosphorylation of the L-typecalcium channel. The primary mechanism for

46 CHAPTER 3

TABLE 3-1 SUMMARY OF EXCITATION–CONTRACTION COUPLING.

1. Ca�� enters cell during depolarization and triggers release of Ca�� by terminal cisternae.

2. Ca�� binds to TN-C, inducing a conformational change in the troponin complex.

3. Myosin heads bind to actin, leading to cross-bridge movement (requires ATP hydrolysis)and reduction in sarcomere length.

4. Ca�� is resequestered by sarcoplasmic reticulum by the SERCA pump.

5. Ca�� is removed from TN-C, and myosin unbinds from actin (requires ATP); this allowsthe sarcomere to resume its original, relaxed length.

ATP, adenosine triphosphate; SERCA, sarco-endoplasmic reticulum calcium ATPase; TN-C, troponin-C.

+ +

SR

Myosin

SERCA Phospho-lamban

L-typecalcium

channels

RyR

Na /K -ATPase+

TN-C

Actin

Ca++

Ca++Ca++

Ca++

13

4 2

6

5

FIGURE 3-5 Intracellular mechanisms regulating inotropy. Inotropy can be increased by increasing Ca�� influxthrough L-type Ca�� channels (site 1); increasing release of Ca�� by the sarcoplasmic reticulum (SR) (site 2); increas-ing troponin-C (TN-C) affinity for Ca�� (site 3); increasing myosin-ATPase activity through phosphorylation of myosinheads (site 4); increasing sarco-endoplasmic reticulum calcium ATPase (SERCA) activity by phosphorylation of phos-pholamban (site 5); or inhibiting Ca�� efflux across the sarcolemma (site 6), which can occur secondarily to inhibi-tion of the Na�/K�-ATPase.

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this regulation involves cyclic adenosinemonophosphate (cAMP), the formation ofwhich is coupled to �-adrenoceptors (Fig. 3-6). Norepinephrine released by sympatheticnerves, or circulating epinephrine released bythe adrenal glands, binds primarily to �1-adrenoceptors located on the sarcolemma.This receptor is coupled to a specific guaninenucleotide-binding regulatory protein (stimu-latory G-protein; Gs-protein), that activatesadenylyl cyclase, which in turn hydrolyzesATP to cAMP. The cAMP acts as a secondmessenger to activate protein kinase A(cAMP-dependent protein kinase, PK-A),which is capable of phosphorylating differentsites within the cell. One important site ofphosphorylation is the L-type calcium chan-nel. Phosphorylation increases the permeabil-ity of the channel to calcium, thereby increas-ing calcium influx during action potentials.This increase in trigger calcium enhances cal-cium release by the sarcoplasmic reticulum,thereby increasing inotropy. Therefore, nor-

epinephrine and epinephrine are positive ino-tropic agents.

Another G-protein, the inhibitory G-protein (Gi-protein), inhibits adenylyl cyclaseand decreases intracellular cAMP. Therefore,activation of this pathway decreases inotropy.This pathway is coupled to muscarinic receptors(M2) that bind acetylcholine released byparasympathetic (vagal) nerves within the heart.Adenosine receptors (A1) also are coupled tothe Gi-protein. Therefore, acetylcholine andadenosine are negative inotropic agents.

Calcium Release by the SarcoplasmicReticulumEnhanced calcium release by the sarcoplas-mic reticulum also can increase inotropy (Fig.3-5, site 2). During �-adrenoceptor andcAMP activation, PK-A phosphorylates siteson the sarcoplasmic reticulum, leading to anincrease in calcium release.

Besides the cAMP pathway, a second pathway within myocytes can affect calcium


Gq

SR

PL-C

PIP2

DAG PK-C

PK-A

ATP

+

+

+

+

++

++

+ _

R

R RAC

NEEpi

AChAdo

Contraction

NEAET-1

II

L-typeCalciumChannel

IP3

Ca++

cAMP

Ca++

Ca++

FIGURE 3-6 Signal transduction pathways regulating cardiac myocyte contraction. The two major pathways involveformation of either cyclic adenosine monophosphate (cAMP) or inositol 1,4,5-triphosphate (IP3), both of which affectCa�� release by sarcoplasmic reticulum and therefore affect contraction. R, receptor; Gs, stimulatory G-protein; Gi,inhibitory G-protein; Gq, phospholipase C-coupled G-protein; AC, adenylyl cyclase; PL-C, phospholipase C; PIP2,phosphatidylinositol 4,5-bisphosphate; DAG, diacylglycerol; PK-C, protein kinase C; PK-A, protein kinase A; SR, sar-coplasmic reticulum; ATP, adenosine triphosphate; NE, norepinephrine; AIl, angiotensin II; ET-1, endothelin-1; Epi, ep-inephrine; ACh, acetylcholine; Ado, adenosine.

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release by the sarcoplasmic reticulum, al-though this pathway appears to be less impor-tant physiologically than the cAMP/PK-Apathway. This second pathway involves a classof G-proteins (Gq-proteins) that are associ-ated with �1-adrenoceptors (binds norepi-nephrine), angiotensin II receptors (AT1), andendothelin-1 receptors (ETA; see Fig. 3-6).Activation of these receptors stimulates phos-pholipase-C to form inositol triphosphate(IP3) from phosphatidylinositol 4,5-bisphos-phate (PIP2), which stimulates calcium releaseby the sarcoplasmic reticulum.

Calcium Binding to TN-CAnother mechanism by which inotropy can bemodulated is by altered binding of calcium toTN-C (Fig. 3-5, site 3). The binding of cal-cium to TN-C is determined by the free intra-cellular concentration of calcium and thebinding affinity of TN-C to calcium. Thegreater the intracellular calcium concentra-tion, the more calcium that is bound to TN-C,and the more force that is generated betweenactin and myosin. Increasing the affinity ofTN-C for calcium increases binding at anygiven calcium concentration, thereby increas-ing force generation. Acidosis, which occursduring myocardial hypoxia, has been shown todecrease TN-C affinity for calcium. This maybe one mechanism by which acidosis de-creases the force of contraction.

Changes in calcium sensitivity may explainin part how increases in sarcomere length (alsoknown as preload; see Chapter 4) leads to anincrease in force generation. It appears that in-creased preload increases calcium sensitivityof TN-C, thereby increasing calcium binding.The mechanism by which changes in length in-crease calcium affinity by TN-C is unknown.

Myosin ATPase ActivityThe myosin heads have sites (myosin lightchains) that can be phosphorylated by the en-zyme myosin light chain kinase (Fig. 3-5, site4). Increased cAMP is known to be associatedwith increased phosphorylation of the myosinheads, which may increase inotropy. Thephysiologic significance of this mechanism,however, is uncertain.

Calcium Uptake by SarcoplasmicReticulumIn addition to influencing relaxation, increas-ing calcium transport into the sarcoplasmicreticulum by the SERCA pump can indirectlyincrease the amount of calcium released bythe sarcoplasmic reticulum (Fig. 3-5, site 5).PK-A phosphorylation of phospholamban,which removes the inhibitory effect of phos-pholamban on SERCA, increases the rate ofcalcium transport into the sarcoplasmic retic-ulum. SERCA activity can also be stimulatedby increased intracellular calcium caused byincreased calcium entry into the cell or de-creased cellular efflux. Enhanced sequester-ing of calcium by the sarcoplasmic reticulumincreases subsequent release of calcium bythe sarcoplasmic reticulum, thereby increas-ing inotropy.

Regulation of Calcium Efflux from the MyocyteThe final mechanisms that can modulate ino-tropy are the sarcolemmal Na�/Ca�� ex-change pump and the ATP-dependent cal-cium pump (Fig. 3-5, site 6). As described inChapter 2, these pumps transport calcium outof the cell, thereby preventing the cell frombecoming overloaded with calcium. If calciumextrusion is inhibited, the rise in intracellularcalcium can increase inotropy because morecalcium is available to TN-C.

Digitalis and related cardiac glycosides in-hibit the Na�/K�-ATPase, which increases in-tracellular Na�(see Chapter 2). This leads toan increase in intracellular Ca�� through theNa�/Ca�� exchange pump, leading to en-hanced inotropy.

Regulation of Relaxation (Lusitropy)

The rate of myocyte relaxation (lusitropy) isdetermined by the ability of the cell to rapidlyreduce the intracellular concentration of cal-cium following its release by the sarcoplasmicreticulum. This reduction in intracellular cal-cium causes calcium that is bound to tro-ponin-C to be released, thereby permittingthe troponin-tropomyosin complex to resumeits resting, inactivated conformation.

48 CHAPTER 3

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Several intracellular mechanisms help toregulate lusitropy, most of which influence in-tracellular calcium concentrations.

1. The rate that calcium enters the cell at restand during action potentials influences in-tracellular concentrations. Under somepathologic conditions (e.g., myocardialischemia), the cell becomes more perme-able to calcium, leading to “calcium over-load,” which impairs relaxation.

2. The rate with which calcium leaves the cellthrough the sarcolemmal calcium ATPasepump and the Na�/Ca�� exchange pump(see Chapter 2) affects intracellular con-centrations. Inhibiting these transport sys-tems can cause intracellular calcium con-centrations to increase to a point at whichrelaxation is impaired.

3. The activity of the SERCA pump, whichpumps calcium back into the sarcoplasmicreticulum, has a major role in determiningintracellular calcium concentrations.Lusitropy can be increased by increasingSERCA activity through phosphorylation

of phospholamban, a regulatory protein as-sociated with SERCA. Phosphorylation ofphospholamban removes its inhibitory ef-fect on SERCA. This is a normal physio-logic mechanism in response to �-adreno-ceptor stimulation, which increases cAMPand PK-A, the latter of which phosphory-lates phospholamban. The impairment ofthe activity of the SERCA pump, as occursin some forms of heart failure, causes in-tracellular calcium concentrations to rise,leading to impaired relaxation.

4. The binding affinity of troponin-C for cal-cium also influences lusitropy. Calciumbinding to troponin-C can be modulated byPK-A phosphorylation of troponin-I. Thisincreases calcium dissociation from tro-ponin-C, thereby increasing relaxation.The increased lusitropy caused by �-adrenoceptor stimulation may be partly re-lated to troponin-I phosphorylation. Somedrugs used to increase the force of contrac-tion (inotropic drugs) do so by increasingtroponin-C affinity for calcium. Althoughthis may increase inotropy, it also may lead


Describe the mechanisms by which norepinephrine, after being released by sympatheticnerve activation, increases myocardial inotropy and lusitropy. Note that norepinephrineprimarily binds to b1-adrenoceptors, although it also can bind to �1-adrenoceptors.

Sympathetic nerve stimulation releases norepinephrine, which binds to �1-adreno-ceptors and �1-adrenoceptors found on cardiac myocytes. �1-adrenoceptor activationstimulates cAMP production through the Gs-protein. cAMP production activates pro-tein kinase A (PK-A), which can phosphorylate L-type calcium channels, leading to anincrease in calcium influx during the action potential. Increased calcium influx triggersincreased calcium release by the sarcoplasmic reticulum, leading to increased calciumbinding by TN-C. Calcium binding increases myosin ATPase activity and forces genera-tion. PK-A also phosphorylates phospholamban and removes its inhibition of SERCA,which leads to increased calcium reuptake by the sarcoplasmic reticulum and increasesthe rate of relaxation, or lusitropy. Increased calcium within the sarcoplasmic reticulumsubsequently enhances the release of calcium from the sarcoplasmic reticulum. In addi-tion, PK-A may phosphorylate sites on the sarcoplasmic reticulum to enhance calciumrelease. PK-A phosphorylation of TN-I also may contribute to enhanced lusitropy by al-tering TN-C affinity for calcium. Although physiologically less important than the �1-adrenoceptor-Gs protein pathway, norepinephrine binding to �1-adrenoceptors in-creases the formation of IP3 via Gq-protein and phospholipase C activation, whichstimulates the release of calcium from the sarcoplasmic reticulum.

PROBLEM 3-1

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to reduced lusitropy because the calcium ismore tightly bound to the troponin-C.

Cardiac Myocyte Metabolism

The maintenance of ionic pumps and othertransport systems in living cells requires sig-nificant amounts of energy, primarily in theform of ATP. Cardiac myocytes have an ex-ceptionally high metabolic rate because theirprimary function is to contract repetitively.Unlike skeletal muscle, in which contraction isoften intermittent and relatively short, cardiacmuscle contracts one to three times per sec-ond throughout life. Repetitive cycles of con-traction and relaxation require an enormousamount of ATP, which the heart must produceaerobically. This is why cardiac myocytes con-tain such large numbers of mitochondria. Inthe absence of oxygen, myocytes can contractfor no more than a minute. Unlike some typesof skeletal muscle fibers (e.g., fast twitch, gly-colytic), cardiac myocytes have only a limitedanaerobic capacity for meeting ATP require-ments. This limited anaerobic capacity cou-pled with a high use of ATP explains why cel-lular ATP concentrations fall and contractionsweaken so rapidly under hypoxic conditions.

Unlike many other cells in the body, car-diac myocytes can use a variety of substratesto regenerate ATP oxidatively. For example, inan overnight fasted state, the heart uses pri-marily fatty acids (~60%) and carbohydrates(~40%). Following a high-carbohydrate meal,the heart can adapt to using carbohydrates

(primarily glucose) almost exclusively. Lactatecan be used in place of glucose, and it be-comes an important substrate during exercisewhen circulating concentrations of lactate in-crease. The heart also can use amino acids andketones (e.g., acetoacetate) instead of fattyacids.

Myocyte ATP use and oxygen consumptionincrease dramatically when the frequency ofcontraction (i.e., heart rate) and the force ofcontraction are increased. Under these condi-tions, more oxygen must be delivered to theheart by the coronary circulation to supportmyocyte metabolic demands. As Chapter 8discusses, biochemical signals from the myo-cytes dilate the coronary blood vessels to sup-ply additional blood flow and oxygen to meetgreater oxygen demands. This ensures thatthe heart is able to generate ATP by aerobicmechanisms.

VASCULAR STRUCTURE ANDFUNCTION

Large blood vessels, both arterial and venous,are composed of three layers – intima, media,and adventitia (Fig. 3-7). The intima, or in-nermost layer, is composed of a single layer ofthin endothelial cells, which are separatedfrom the media by a basal lamina. In largervessels, a region of connective tissue also ex-ists between the endothelial cells and thebasal lamina. The media contains smoothmuscle cells, imbedded in a matrix of colla-gen, elastin, and various glycoproteins.

50 CHAPTER 3

AdventitiaCollagen

FibroblastsVasa vasorum

Nerves

MediaSmooth muscle

CollagenElastin

IntimaEndothelium

Lumen

FIGURE 3-7 Blood vessel components. Blood vessels, except capillaries and small postcapillary venules, are composedof three layers: intima, media, and adventitia. Capillaries and small postcapillary venules do not have media and ad-ventitia. The primary components are given for each layer.

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Depending on the size of the vessel, theremay be several layers of smooth muscle cells,some arranged circumferentially and othersarranged helically along the longitudinal axisof the vessel. The smooth muscles cells are or-ganized so that their contraction reduces thevessel diameter. The ratio of smooth muscle,collagen, and elastin, each of which has differ-ent elastic properties, determines the overallmechanical properties of the vessel. For ex-ample, the aorta has a large amount of elastin,which enables it to passively expand and con-tract as blood is pumped into it from theheart. This mechanism enables the aorta todampen the arterial pulse pressure (seeChapter 5). In contrast, smaller arteries andarterioles have a relatively large amount ofsmooth muscle, which is required for thesevessels to contract and thereby regulate arte-rial blood pressure and organ blood flow. Theoutermost layer, or adventitia, is separatedfrom the media by the external elastic lamina.The adventitia contains collagen, fibroblasts,blood vessels (vasa vasorum found in largevessels), lymphatics, and autonomic nerves(primarily sympathetic adrenergic). Thesmallest vessels, capillaries, are composed ofendothelial cells and a basal lamina; they aredevoid of smooth muscle.

Vascular Smooth Muscle Cells

Cellular Structure of Vascular SmoothMuscleVascular smooth muscle cells are typically5–10 �m in diameter and vary from 50–200µm in length. Numerous small invaginations(caveolae) found in the cell membrane sig-nificantly increase the surface area of the cell(Fig. 3-8). The sarcoplasmic reticulum ispoorly developed compared with the sar-coplasmic reticulum found in cardiac myo-cytes. Contractile proteins (actin and myosin)are present; however, the actin and myosin insmooth muscle are not organized into distinctbands of repeating units as they are in cardiacand skeletal muscle. Instead, bands of actinfilaments are joined together and anchored bydense bodies within the cell or dense bandson the inner surface of the sarcolemma, whichfunction like Z-lines in cardiac myocytes.Each myosin filament is surrounded by sev-eral actin filaments. Similar to cardiac my-ocytes, vascular smooth muscle cells are elec-trically connected by gap junctions. Theselow-resistance intercellular connections allowpropagated responses along the length of the blood vessels. For example, electrical de-polarization and contraction of a local site on


CalveolaeDenseBand

DenseBody

Enlarged cross-sectionof actin and myosin

N

FIGURE 3-8 Vascular smooth muscle cell structure. Actin and myosin filaments are connected by dense bodies anddense bands. Each myosin filament is surrounded by several actin filaments. N, nucleus.

Ch03_041-058_Klabunde 4/21/04 10:57 AM

an arteriole can result in depolarization at adistant site along the same vessel, indicatingcell-to-cell propagation of the depolarizingcurrents.

Vascular Smooth Muscle ContractionContractile characteristics and the mecha-nisms responsible for contraction differ con-siderably between vascular smooth muscleand cardiac myocytes. Vascular smooth mus-cle tonic contractions are slow and sustained,whereas cardiac muscle contractions are rapidand relatively short (a few hundred millisec-onds). In blood vessels, the smooth muscle isnormally in a partially contracted state, whichdetermines the resting tone or diameter of thevessel. This tonic contraction is determined bya number of stimulatory and inhibitory influ-ences acting on the vessel (see Chapter 5, Fig.5-9, and Chapters 6 and 7); the most impor-tant of these are sympathetic adrenergicnerves, circulating hormones (e.g., epineph-rine, angiotensin II), substances released bythe endothelium lining the vessel, and vasoac-tive substances released by the tissue sur-rounding the blood vessel.

Vascular smooth muscle contraction can beinitiated by electrical, chemical, and mechan-ical stimuli. Electrical depolarization of the

vascular smooth muscle cell membrane elicitscontraction primarily by opening voltage-dependent calcium channels (L-type calciumchannels), which causes an increase in the in-tracellular concentration of calcium. Elec-trical depolarization occurs through changesin ion concentrations (e.g., depolarization in-duced by increased extracellular potassium)or by the receptor-coupled opening of ionchannels, particularly calcium channels.

Many different chemical stimuli, such asnorepinephrine, epinephrine, angiotensin II,vasopressin, endothelin-1, and thromboxaneA2 can elicit contraction. Each of these sub-stances binds to specific receptors on the vas-cular smooth muscle cell. Different signaltransduction pathways converge to increaseintracellular calcium, thereby eliciting con-traction.

Mechanical stimuli in the form of pas-sive stretching of smooth muscle in some arteries can cause a contraction that origi-nates from the smooth muscle itself and istherefore termed a myogenic response.This probably results from stretch-inducedactivation of ionic channels that leads to cal-cium influx.

Figure 3-9 illustrates the mechanism bywhich an increase in intracellular calcium

52 CHAPTER 3

Calmodulin

Ca++ Calmodulin

MLCK

+

Pi

ATP

Phosphatase

MLC

+

–

–

L-typeCalciumChannel

SR

Ca++

Ca++

cAMP

FIGURE 3-9 Regulation of vascular smooth muscle contraction by myosin light chain kinase (MLCK). Increased intra-cellular calcium, by either increased entry into the cell (through L-type Ca�� channels) or release from the sarcoplas-mic reticulum (SR), forms a complex with calmodulin, activating MLCK, which phosphorylates myosin light chains(MLC), causing contraction. Cyclic adenosine monophosphate (cAMP) inhibits MLCK, thereby causing relaxation. ATP,adenosine triphosphate; Pi, phosphate group.

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stimulates vascular smooth muscle contrac-tion. An increase in free intracellular calciumcan result from either increased entry of cal-cium into the cell through L-type calciumchannels or release of calcium from internalstores (e.g., sarcoplasmic reticulum). The freecalcium binds to a special calcium-bindingprotein called calmodulin. The calcium-calmodulin complex activates myosin lightchain kinase, an enzyme that phosphorylatesmyosin light chains in the presence of ATP.Myosin light chains are regulatory subunitsfound on the myosin heads. Myosin lightchain phosphorylation leads to cross-bridgeformation between the myosin heads and theactin filaments, thus leading to smooth musclecontraction.

Intracellular calcium concentrations,therefore, are very important in regulatingsmooth muscle contraction. The concentra-tion of intracellular calcium depends on the

balance between the calcium that enters thecells, the calcium that is released by intracel-lular storage sites, and the movement of cal-cium either back into intracellular storagesites or out of the cell. Calcium is rese-questered by the sarcoplasmic reticulum byan ATP-dependent calcium pump similar tothe SERCA pump found in cardiac myocytes.Calcium is removed from the cell to the exter-nal environment by either an ATP-dependentcalcium pump or the sodium–calcium ex-changer, as in cardiac muscle (see Chapter 2).

Several signal transduction mechanismsmodulate intracellular calcium concentrationand therefore the state of vascular tone. Thissection describes three different pathways: (1)IP3 via Gq-protein activation of phospholipaseC; (2) cAMP via Gs-protein activation ofadenylyl cyclase; and (3) cyclic guanosinemonophosphate (cGMP) via nitric oxide (NO)activation of guanylyl cyclase (Fig. 3-10).


Gq

AC

SR

GDP

GTP

PL-C

PIP2

DAG PK-C

GTP GDP GTPATP

+

+

++

+

+

+

+

_

_

_MLCK

EpiAdoPGI2

R

R

NEEpiAIIET-1

NO

GC

Contraction

L-typeCalciumChannelIP3

Ca++

cAMP

Ca++

Ca++

cGMP

FIGURE 3-10 Receptors and signal transduction pathways that regulate vascular smooth muscle contraction. R, re-ceptor; Gs, stimulatory G-protein; Gq, phospholipase C-coupled G-protein; AC, adenylyl cyclase; PL-C, phospholipaseC; PIP2, phosphatidylinositol 4,5-bisphosphate; IP3, inositol triphosphate; DAG, diacylglycerol; PK-C, protein kinase C;SR, sarcoplasmic reticulum; MLCK, myosin light chain kinase; Ado, adenosine; PGI2, prostacyclin; Epi, epinephrine;NO, nitric oxide; GC, guanylyl cyclase; AII, angiotensin receptor agonist; ET-1, endothelin-1; NE, norepinephrine; ACh,acetylcholine; GDP, guanosine diphosphate; GTP, guanosine triphosphate; ATP, adenosine triphosphate; cAMP, cyclicadenosine monophosphate; cGMP, cyclic guanosine monophosphate.

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The IP3 pathway in vascular smooth muscleis similar to that found in the heart.Norepinephrine and epinephrine (via �1-adrenoceptors), angiotensin II (via AT1 recep-tors), endothelin-I (via ETA receptors), andacetylcholine (via M3 receptors) activate phos-pholipase C through the Gq-protein, causingthe formation of IP3 from PIP2. IP3 then di-rectly stimulates the sarcoplasmic reticulumto release calcium. The formation of diacyl-glycerol from PIP2 activates protein kinase C,which can modulate vascular smooth musclecontraction as well via protein phosphoryla-tion.

Receptors coupled to the Gs-protein stim-ulate adenylyl cyclase, which catalyzes the for-mation of cAMP. In vascular smooth muscle,unlike cardiac myocytes, an increase in cAMPby a �2-adrenoceptor agonist such as isopro-terenol causes relaxation. The mechanism forthis process is cAMP inhibition of myosin lightchain kinase (see Fig. 3-9), which decreasesmyosin light chain phosphorylation, therebyinhibiting the interactions between actin andmyosin. Adenosine and prostacyclin (PGI2)also activate Gs-protein through their recep-tors, leading to an increase in cAMP andsmooth muscle relaxation. Epinephrine bind-ing to �2-adrenoceptors relaxes vascularsmooth muscle through the Gs-protein.

A third important mechanism for regulat-ing vascular smooth muscle contraction is the

nitric oxide (NO)–cGMP system. Many en-dothelial-dependent vasodilator substances(e.g., acetylcholine, bradykinin, substance P),when bound to their respective endothelialreceptors, stimulate the conversion of L-arginine to NO by activating NO synthase.The NO diffuses from the endothelial cell tothe vascular smooth muscle cells, where it ac-tivates guanylyl cyclase, increases cGMP for-mation, and causes smooth muscle relaxation.The precise mechanisms by which cGMP re-laxes vascular smooth muscle are unclear;however, cGMP can activate a cGMP-depen-dent protein kinase, inhibit calcium entry intothe vascular smooth muscle, activate K� chan-nels causing cellular hyperpolarization, anddecrease IP3.

Vascular Endothelial Cells

The vascular endothelium is a thin layer ofcells that line all blood vessels. Endothelialcells are flat, single-nucleated, elongated cellsthat are 0.2–2.0 �m thick and 1-20 µm across(varying by vessel type). Depending on thetype of vessel (e.g., arteriole versus capillary)and tissue location (e.g., renal glomerular ver-sus skeletal muscle capillaries), endothelialcells are joined together by different types ofintercellular junctions. Some of these junc-tions are very tight (e.g., all arteries and skele-tal muscle capillaries), whereas others have

54 CHAPTER 3

cAMP is degraded by a phosphodiesterase. Milrinone, a drug sometimes used in thetreatment of acute heart failure, is a phosphodiesterase inhibitor that increases cardiacinotropy and relaxes blood vessels by inhibiting the degradation of cAMP. Explain whyan increase in cAMP in cardiac muscle increases the force of contraction, whereas an in-crease in cAMP in vascular smooth muscle cells diminishes the force of contraction.

Increasing cAMP in the heart activates protein kinase A, which phosphorylates dif-ferent sites within the cells (see the answer to Problem 3-1). Phosphorylation enhancescalcium influx into the cell and calcium release by the sarcoplasmic reticulum, leadingto an increase in inotropy. In vascular smooth muscle, myosin light chain kinase, whenactivated by calcium-calmodulin, phosphorylates myosin light chains to stimulatesmooth muscle contraction. cAMP inhibits myosin light chain kinase; therefore, an in-crease in cAMP by a phosphodiesterase inhibitor such as milrinone further inhibits themyosin light chain kinase, thereby reducing smooth muscle contraction.

PROBLEM 3-2

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gaps between the cells (e.g., capillaries inspleen and bone marrow) that enable bloodcells to move in and out of the capillary easily.See Chapter 8 for information about differenttypes of capillaries and endothelium.

Endothelial cells have several importantfunctions, including:

1. Serving as a barrier for the exchange offluid, electrolytes, macromolecules, andcells between the intravascular and ex-travascular space (see Chapter 8);

2. Regulating smooth muscle functionthrough the synthesis of several differentvasoactive substances, the most importantof which are NO, PGI2, and endothelin-1;

3. Modulating platelet aggregation primarilythrough biosynthesis of NO and PGI2;

4. Modulating leukocyte adhesion andtransendothelial migration through thebiosynthesis of NO and the expression ofsurface adhesion molecules.

Vascular endothelial cells continuouslyproduce NO by the enzyme NO synthase,which converts L-arginine to NO. This basalNO production can be enhanced by (1) spe-cific agonists (e.g., acetylcholine, bradykinin)binding to endothelial receptors; (2) in-creased shearing forces acting on the en-dothelial surface (e.g., as occurs with in-creased blood flow); and (3) cytokines suchas tumor necrosis factor and interleukins,which are released by leukocytes during in-flammation and infection. NO, although verylabile, rapidly diffuses out of endothelial cellsto cause smooth muscle relaxation or inhibitplatelet aggregation in the blood. Both ofthese actions of NO result from increasedcGMP formation, which occurs in responseto NO activation of guanylyl cyclase (see Fig.3-10). Increased NO within the endotheliumstimulates endothelial cGMP production,which inhibits the expression of adhesion mol-ecules involved in attaching leukocytes to theendothelial surface. Therefore, endothelial-derived NO relaxes smooth muscle, inhibitsplatelet function, and inhibits inflammatory responses (Fig. 3-11). (See Formationand Physiologic Actions of Nitric Oxide on CD.)

In addition, endothelial cells synthesize endothelin-1 (ET-1), a powerful vasocon-strictor (see Fig. 3-11). Synthesis is stimu-lated by angiotensin II, vasopressin, throm-bin, cytokines, and shearing forces, and it isinhibited by NO and PGI2. ET-1 leaves theendothelial cell and can bind to receptors(ETA) on vascular smooth muscle, whichcauses calcium mobilization and smoothmuscle contraction. The smooth muscle ac-tions of ET-1 occur through activation of theIP3 signaling pathway (see Fig. 3-10). (SeeFormation and Physiologic Actions ofEndothelin-1 on CD.)

PGI2 is a product of arachidonic acid me-tabolism within endothelial cells. (SeeFormation and Physiologic Actions ofMetabolites of Arachidonic Acid on CD.) Thetwo primary roles of PGI2 formed by endothe-lial cells are smooth muscle relaxation and in-hibition of platelet aggregation (see Fig. 3-11),both of which are induced by the formation ofcAMP (see Fig. 3-10).

The importance of normal endothelialfunction is made clear from examining howendothelial dysfunction contributes to dis-ease states. For example, endothelial damageand dysfunction occurs in atherosclerosis,hypertension, diabetes, and hypercholes-terolemia. Endothelial dysfunction results inless NO and PGI2 production, causing vaso-


ET-1 PGI NO

Contraction

VSM

EC

Blood

2

PlateletsLeukocytes

–

– –+

– –

FIGURE 3-11 Endothelial cell (EC) production of nitricoxide (NO), prostacyclin (PGI2), and endothelin-1 (ET-1)stimulates (�) or inhibits (-) vascular smooth muscle(VSM) contraction, platelet aggregation and adhesion,and leukocyte-endothelial cell adhesion.

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constriction, loss of vasodilatory capacity,thrombosis, and vascular inflammation.Evidence exists that enhanced ET-1 produc-tion contributes to hypertension and othervascular disorders. Damage to the endothe-lium at the capillary level increases capillarypermeability (see Chapter 8), which leads toincreased capillary fluid filtration and tissueedema.


• The basic contractile unit of a cardiac myo-cyte is the sarcomere, which contains thickfilaments (myosin) and thin filaments(actin, troponin, and tropomyosin). Duringmyocyte contraction, the sarcomere short-ens as the thick and thin filaments slidepast each other (the sliding filament theoryof muscle contraction).

• The process of excitation–contractioncoupling is initiated by depolarization ofthe cardiac myocyte, which causes cal-cium to enter the cell across the sar-colemmal membrane, particularly in theT-tubules. This entering calcium triggersthe release of calcium through calcium-release channels associated with the ter-minal cisternae of the sarcoplasmic retic-ulum, which increases intracellular

calcium concentration. Calcium thenbinds to TN-C, which induces a confor-mation change in the troponin-tropomyosin complex and exposes amyosin binding site on the actin.Hydrolysis of ATP occurs during actinand myosin binding; it provides the en-ergy for the subsequent movement of thethin filament across the thick filament.Relaxation (also requiring ATP) occurswhen calcium is removed from the TN-Cand is resequestered by the sarcoplasmicreticulum by means of the SERCA pump.

• Calcium serves as the primary regulator ofthe force of contraction (inotropy).Increased calcium entry into the cell, in-creased release of calcium by the sar-coplasmic reticulum, and enhanced bind-ing of calcium by TN-C are majormechanisms controlling inotropy. Phos-phorylation of myosin light chains may alsoplay a role in modulating inotropy.

• Relaxation of cardiac myocytes (lusitropy)is primarily regulated by the reuptake ofcalcium by the sarcoplasmic reticulum bythe SERCA pump. Phospholamban, a reg-ulatory protein associated with SERCA,regulates the activity of SERCA.

• The contractile function of cardiac myo-cytes requires large amounts of ATP, whichis generated primarily by oxidative metabo-

56 CHAPTER 3

When acetylcholine is infused into normal coronary arteries, the vessels dilate; how-ever, if the vessel is diseased and the endothelium damaged, acetylcholine can causevasoconstriction. Explain why acetylcholine can have opposite effects on vascular func-tion depending on the integrity of the vascular endothelium.

Acetylcholine has two effects on blood vessels. When acetylcholine binds to M2 re-ceptors on the vascular endothelium, it stimulates the formation of nitric oxide (NO) byconstitutive NO synthase. The NO can then diffuse from the endothelial cell into theadjacent smooth muscle cells, where it activates guanylyl cyclase to form cGMP.Increased cGMP within the smooth muscle cell inhibits calcium entry into the cell,which leads to relaxation. Acetylcholine, however, also can bind to M3 receptors lo-cated on the smooth muscle. This activates the IP3 pathway and stimulates calcium re-lease by the sarcoplasmic reticulum, which leads to increased smooth muscle contrac-tion. If the endothelium is intact, stimulation of the NO–cGMP pathway dominatesover the actions of the IP3 pathway; therefore, acetylcholine will cause vasodilation.

PROBLEM 3-3

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lism of fatty acids and carbohydrates, al-though the heart is flexible in its use of sub-strates and can also metabolize aminoacids, ketones, and lactate.

• Arteries and veins are arranged as threelayers: adventitia, media, and intima.Autonomic nerves and small blood vessels(vasa vasorum in large vessels) are found inthe adventitia; vascular smooth muscle isfound in the media; and the intima is linedby the endothelium. The relative propor-tions of elastin and collagen in the adventi-tia and media influence the elastic proper-ties of blood vessels.

• Vascular smooth muscle contains actin andmyosin; however, these components arenot arranged in the same repetitive patternas that found in cardiac myocytes. Vascularsmooth muscle contraction is slow andtonic, in contrast to the contraction of car-diac myocytes, which is fast and phasic.Vascular smooth muscle contraction is reg-ulated by calcium and the phosphorylationof myosin light chains by myosin light chainkinase.

• Cardiac muscle and vascular smooth mus-cle contraction is regulated by G-proteinscoupled to membrane receptors. Ac-tivation of stimulatory Gs-proteins through�-adrenoceptor stimulation (e.g., by norep-inephrine) increases intracellular cAMP,whereas activation of inhibitory Gi-pro-teins through specific muscarinic or adeno-sine receptors decreases intracellularcAMP. Increased cAMP in cardiac my-ocytes increases the force of contraction,whereas increased cAMP in vascularsmooth muscle causes relaxation. Ac-tivation of the Gq-protein through an-giotensin II receptors, endothelin-1 recep-tors, or �1-adrenoceptors stimulates theactivity of phospholipase C, which causesthe formation of inositol triphosphate (IP3).Increased IP3 enhances calcium release bythe sarcoplasmic reticulum and increasedcontraction in both cardiac muscle and vas-cular smooth muscle.

• The vascular endothelium synthesizes ni-tric oxide and prostacyclin, both of which relax vascular smooth muscle.

Endothelin-1, which is also synthesized bythe endothelium, contracts vascular smoothmuscle.

Review Questions

Please refer to the appendix for the answersto the review questions.For each question, choose the one best answer:1. Which of the following is common to both

cardiac myocytes and vascular smoothmuscle cells?

a. Dense bodiesb. Myosin light chain kinasec. Terminal cisternaed. T tubules

2. Thick filaments within cardiac myocytescontain

a. Actinb. Myosinc. Tropomyosind. Troponin

3. During excitation–contraction coupling incardiac myocytes,

a. Calcium binds to myosin causingATP hydrolysis.

b. Calcium binds to troponin-I.c. Myosin heads bind to actin.d. SERCA pumps calcium out of the

sarcoplasmic reticulum.

4. Cardiac inotropy is enhanced bya. Agonists coupled to Gi-protein.b. Decreased calcium binding to tro-

ponin-C.c. Decreased release of calcium by ter-

minal cisternae.d. Protein kinase A phosphorylation of

L-type calcium channels.

5. �2-adrenoceptor activation in vascularsmooth muscle leads to

a. Activation of myosin light chain ki-nase.

b. Contraction.c. Decreased intracellular cAMP.d. Dephosphorylation of myosin light

chains.


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6. Angiotensin II causes contraction of vas-cular smooth muscle by

a. Activating Gs-protein.b. Increasing cAMP.c. Increasing IP3.d. Inhibiting release of calcium by sar-

coplasmic reticulum.

7. Vascular smooth muscle contraction isstimulated by

a. cGMP.b. Endothelin-1.c. Nitric oxide.d. Prostacyclin.

SUGGESTED READINGSGoldstein MA, Schroeter JP. Ultrastructure of the heart.

In: Page E, Fozzard HA, Solaro RJ, eds. Handbookof Physiology, vol 1. Bethesda: AmericanPhysiological Society, 2002; 3-74.

Katz AM. Physiology of the Heart. 3rd Ed. Philadelphia:Lippincott Williams & Wilkins, 2000.

Moss RL, Buck SH. Regulation of cardiac contraction bycalcium. In: Page E, Fozzard HA, Solaro RJ, eds.Handbook of Physiology, vol 1. Bethesda: AmericanPhysiological Society, 2002; 420-454.

Opie LH. The Heart: Physiology from Cell toCirculation. 3rd Ed. Philadelphia: LippincottWilliams & Wilkins, 1998.

Rhodin JAG. Architecture of the vessel wall. In: BohrDF, Somlyo AP, Sparks HV, eds. Handbook ofPhysiology, vol 2. Bethesda: American PhysiologicalSociety, 1980; 1-31.

Sanders KM. Invited review: mechanisms of calciumhandling in smooth muscles. J Appl Physiol2001;91:1438-1449.

Somlyo AV: Ultrastructure of vascular smooth muscle.In: Bohr DF, Somlyo AP, Sparks HV, eds. Handbookof Physiology, vol 2. Bethesda: AmericanPhysiological Society, 1980; 33-67.

58 CHAPTER 3

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CD-ROM CONTENTSLEARNING OBJECTIVESINTRODUCTIONCARDIAC ANATOMY

Functional Anatomy of the HeartAutonomic Innervation

THE CARDIAC CYCLECardiac Cycle DiagramSummary of Intracardiac PressuresVentricular Pressure-Volume

RelationshipAltered Pressure and Volume

Changes during the Cardiac Cycle

REGULATION OF CARDIAC OUTPUTInfluence of Heart Rate on Cardiac

OutputRegulation of Stroke Volume

MYOCARDIAL OXYGEN CONSUMPTIONHow Myocardial Oxygen

Consumption is DeterminedFactors Influencing Myocardial

Oxygen ConsumptionSUMMARY OF IMPORTANT CONCEPTSREVIEW QUESTIONSSUGGESTED READINGS

c h a p t e r

4Cardiac Function

1. Compliance2. Energetics of Flowing Blood 3. Valve Disease4. Ventricular Hypertrophy5. Ventricular Stroke Work

CD CONTENTS

LEARNING OBJECTIVES

Understanding the concepts presented in this chapter will enable the student to:1. Describe the basic anatomy of the heart, including the names of venous and arterial ves-

sels entering and leaving the heart, cardiac chambers, and heart valves; trace the flow ofblood through the heart.

2. Describe how each of the following changes during the cardiac cycle:a. electrocardiogramb. left ventricular pressure and volumec. aortic pressured. aortic flowe. left atrial pressuref. jugular pulse waves

3. Describe the origin of the four heart sounds and show when they occur during the car-diac cycle.

4. Know normal values for end-diastolic and end-systolic left ventricular volumes, atrial andventricular pressures, and systolic and diastolic aortic and pulmonary arterial pressures.

5. Draw and label ventricular pressure-volume loops derived from ventricular pressure andvolume changes during the cardiac cycle.

6. Calculate stroke volume, cardiac output, and ejection fraction from ventricular end-diastolic and end-systolic volumes and heart rate.

7. Describe how an increase in heart rate affects ventricular filling time, ventricular end-diastolic volume, and stroke volume.

59

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INTRODUCTION

The heart is a specialized muscular organ thatrhythmically contracts and pumps blood fromthe low-pressure venous side to the high-pres-sure arterial side of the circulation. Efficientpumping occurs because of the orderly con-traction sequence of the different heart cham-bers, and the presence of valves within theheart that ensure a unidirectional flow ofblood. This chapter describes the basicanatomy of the heart—its chambers, valves,and vessels entering and leaving the heart—and the sequence of electrical and mechanicalevents that occur during a cycle of contractionand relaxation. It then describes the mecha-nisms that regulate cardiac output, particu-larly those mechanisms that influence theamount of blood ejected into the aorta witheach contraction of the left ventricle. The lastsection of this chapter discusses the relation-ship between myocardial oxygen consumptionand the mechanical activity of the heart.

CARDIAC ANATOMY

Functional Anatomy of the Heart

The heart consists of four chambers: rightatrium, right ventricle, left atrium, and left

ventricle (Fig. 4-1). The right atrium re-ceives blood from the superior and inferiorvena cavae, which carry blood returningfrom the systemic circulation. The rightatrium is a highly distensible chamber that caneasily expand to accommodate the venous re-turn at a low pressure (0-4 mm Hg). Bloodflows from the right atrium, across the tricus-pid valve, and into the right ventricle. Thefree wall of the right ventricle wraps aroundpart of the larger and thicker left ventricle.The outflow tract of the right ventricle is thepulmonary artery, which is separated fromthe ventricle by the semilunar pulmonicvalve. Blood returns to the heart from thelungs via four pulmonary veins that enterthe left atrium. The pressure within the leftatrium normally ranges from 8–12 mm Hg.Blood flows from the left atrium, across themitral valve (left atrioventricular valve), andinto the left ventricle. The left ventricle hasa thick muscular wall that allows it to generatehigh pressures during contraction. The leftventricle ejects blood across the aortic valveand into the aorta.

The tricuspid and mitral valves (also calledright and left atrioventricular, or AV valves, re-spectively) have fibrous strands (chordaetendineae) on their leaflets that attach to

60 CHAPTER 4

8. Define preload, afterload, and inotropy.9. List factors that determine or modify preload, afterload, and inotropy.

10. Describe the Frank-Starling mechanism and discuss its importance in regulating cardiacoutput.

11. Describe the biophysical basis for the Frank-Starling mechanism using the length-tensiondiagram for cardiac muscle.

12. Show how changes in preload, afterload, and inotropic state affect ventricular end-diastolic volume, end-systolic volume, and stroke volume by using Frank-Starling curves(plotting stroke volume versus preload) and ventricular pressure-volume loops.

13. Describe how changes in preload, afterload, and inotropy alter the force-velocity rela-tionship for cardiac muscle, and explain how changes in this relationship affect ventricu-lar stroke volume.

14. Describe mechanisms that have been proposed to account for the way preload and inotropy affect force generation by myocytes.

15. Calculate myocardial oxygen consumption given coronary blood flow, and coronary ar-terial and venous oxygen contents.

16. Explain why a given percentage increase in stroke volume in response to an increase invenous return increases myocardial oxygen consumption less than the same percentageincrease in aortic pressure.

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papillary muscles located on the respectiveventricular walls. The papillary muscles con-tract when the ventricles contract. This gener-ates tension on the valve leaflets via the chor-dae tendineae, preventing the AV valves frombulging back and leaking blood into the atria(i.e., preventing regurgitation) as the ventri-cles develop pressure. The semilunar valves(pulmonic and aortic) do not have analogousattachments.

Autonomic Innervation

Autonomic innervation of the heart plays animportant role in regulating cardiac function.The heart is innervated by parasympathetic(vagal) and sympathetic efferent fibers. (SeeChapter 6 for details on the origin of these au-tonomic nerves.) The right vagus nerve pref-erentially innervates the sinoatrial (SA) node,whereas the left vagus nerve innervates theAV node; however, significant overlap can oc-cur in the anatomical distribution. Atrial mus-cle is also innervated by vagal efferents; theventricular myocardium is only sparsely inner-vated by vagal efferents. Sympathetic efferentnerves are present throughout the atria (espe-cially in the SA node) and ventricles and in theconduction system of the heart.

Vagal activation of the heart decreasesheart rate (negative chronotropy), decreasesconduction velocity (negative dromotropy),and decreases contractility (negative ino-tropy) of the heart. Vagal-mediated inotropicinfluences are moderate in the atria and rela-tively weak in the ventricles. Activation of thesympathetic nerves to the heart increasesheart rate, conduction velocity, and inotropy.Sympathetic influences are pronounced inboth the atria and ventricles.

As Chapter 6 describes in more detail, theheart also contains vagal and sympathetic af-ferent nerve fibers that relay information fromstretch and pain receptors. The stretch recep-tors involve feedback regulation of blood vol-ume and arterial pressure, whereas the painreceptors produce chest pain when activatedduring myocardial ischemia.

THE CARDIAC CYCLE

Cardiac Cycle Diagram

To understand how cardiac function is regu-lated, one must know the sequence of me-chanical events during a complete cardiac cy-cle and how these mechanical events relate tothe electrical activity of the heart. The cardiac

CARDIAC FUNCTION 61

RV

RA

LV

LA

PapillaryMuscle

SVC

Aorta

PulmonicValve

IVC

Mitral Valve

Aortic Valve

Septum

PA

PV

TricuspidValve

ChordaeTendineae

FIGURE 4-1 Anatomy of the heart. SVC, superior vena cava; RA, right atrium; IVC, inferior vena cava; PA, pulmonaryartery; PV, pulmonary veins; LA, left atrium; LV, left ventricle; RV, right ventricle.

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cycle diagram in Figure 4-2 depicts changes inthe left side of the heart (left ventricular pres-sure and volume, left atrial pressure, and aor-tic pressure) as a function of time. Pressureand volume changes in the right side of theheart (right atrium and ventricle and pul-monary artery) are qualitatively similar tothose in the left side. Furthermore, the timingof mechanical events in the right side of theheart is very similar to that of the left side.

The main difference is that the pressures inthe right side of the heart are much lowerthan those found in the left side.

A catheter can be placed in the ascendingaorta and left ventricle to obtain the pressureand volume information shown in the cardiaccycle diagram and to measure simultaneouschanges in aortic and intraventricular pressureas the heart beats. This catheter can also beused to inject a radiopaque contrast agent into

62 CHAPTER 4

MitralValve

Closes

AorticValveOpens

AorticValve

Closes

MitralValveOpens

1

120

80

40

0

120

80

40

Pressure(mmHg)

LVVolume

(ml)

ECG

Seconds

0 0.80.4

HeartSounds

2 3Phase

4 5 6 7

FIGURE 4-2 Cardiac cycle. The seven phases of the cardiac cycle are (1) atrial systole; (2) isovolumetric contraction;(3) rapid ejection; (4) reduced ejection; (5), isovolumetric relaxation; (6) rapid filling; and (7) reduced filling. LV , leftventricle; ECG, electrocardiogram; a, a-wave; c, c-wave; v, v-wave; AP, aortic pressure; LVP, left ventricular pressure;LAP, left atrial pressure; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume, S1-S4,four heart sounds.

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the left ventricular chamber. This permits flu-oroscopic imaging (contrast ventriculography)of the ventricular chamber, from which esti-mates of ventricular volume can be obtained;however, real time echocardiography and nu-clear imaging of the heart are more commonlyused to obtain clinical assessment of volumeand function.

In the following discussion, a complete car-diac cycle is defined as the cardiac events ini-tiated by the P wave in the electrocardiogram(ECG) and continuing until the next P wave.The cardiac cycle is divided into two generalcategories: systole and diastole. Systole refersto events associated with ventricular contrac-tion and ejection. Diastole refers to the restof the cardiac cycle, including ventricular re-laxation and filling. The cardiac cycle is fur-ther divided into seven phases, beginningwhen the P wave appears. These phases areatrial systole, isovolumetric contraction, rapidejection, reduced ejection, isovolumetric re-laxation, rapid filling, and reduced filling. Theevents associated with each of these phasesare described below.

PHASE 1. ATRIAL SYSTOLE: AVVALVES OPEN; AORTIC ANDPULMONIC VALVES CLOSED

The P wave of the ECG represents electricaldepolarization of the atria, which initiates con-traction of the atrial musculature. As the atriacontract, the pressures within the atrial cham-bers increase; this drives blood from the atria,across the open AV valves, and into the ventri-cles. Retrograde atrial flow back into the venacava and pulmonary veins is impeded by theinertial effect of venous return and by thewave of contraction throughout the atria,which has a “milking effect.” However, atrialcontraction produces a small increase in prox-imal venous pressure (i.e., within the pul-monary veins and vena cava). On the rightside of the heart, this produces the “a-wave”of the jugular pulse, which can be observedwhen a person is recumbent and the jugularvein in the neck expands with blood.

Atrial contraction normally accounts foronly about 10% of left ventricular filling

when a person is at rest and the heart rate islow, because most of the ventricular fillingoccurs before the atria contract. Therefore,ventricular filling is mostly passive and de-pends on the venous return. However, athigh heart rates (e.g., during exercise), theperiod of diastolic filling is shortened consid-erably (because overall cycle length is de-creased), and the amount of blood that en-ters the ventricle by passive filling isreduced. Under these conditions, the relativecontribution of atrial contraction to ventricu-lar filling increases greatly and may accountfor up to 40% of ventricular filling. In addi-tion, atrial contribution to ventricular fillingis enhanced by an increase in the force ofatrial contraction caused by sympatheticnerve activation. Enhanced ventricular fillingowing to increased atrial contraction is some-times referred to as the “atrial kick.” Duringatrial fibrillation (see Chapter 2), the contri-bution of atrial contraction to ventricular fill-ing is lost. This leads to inadequate ventricu-lar filling, particularly when ventricular ratesincrease during physical activity.

After atrial contraction is complete, theatrial pressure begins to fall, which causes aslight pressure gradient reversal across the AVvalves. This fall in atrial pressure following thepeak of the a-wave is termed the “x-descent.”As the pressures within the atria fall, the AVvalves float upward (pre-position) before clo-sure.

At the end of this phase, the ventricularvolumes are maximal (end-diastolic volume,EDV). The left ventricular end-diastolic vol-ume (typically about 120 mL) is associatedwith end-diastolic pressures of 8–12 mm Hg.The right ventricular end-diastolic pressuretypically ranges from 3–6 mm Hg.

A heart sound is sometimes heard duringatrial contraction (Fourth Heart Sound, S4).The sound is caused by vibration of the ven-tricular wall during atrial contraction. Thissound generally is noted when the ventriclecompliance is reduced (i.e., “stiff” ventricle),as occurs in ventricular hypertrophy (seeVentricular Hypertrophy on CD. The sound iscommonly present as a normal finding inolder individuals.

CARDIAC FUNCTION 63

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PHASE 2. ISOVOLUMETRICCONTRACTION: ALL VALVES CLOSED

This phase of the cardiac cycle is initiated bythe QRS complex of the ECG, which repre-sents ventricular depolarization. As the ventri-cles depolarize, myocyte contraction leads to arapid increase in intraventricular pressure.The abrupt rise in pressure causes the AVvalves to close as the intraventricular pressureexceeds atrial pressure. Contraction of thepapillary muscles with their attached chordaetendineae prevents the AV valve leaflets frombulging back or prolapsing into the atria andbecoming incompetent (i.e., “leaky”). Closureof the AV valves results in the First heartsound (S1). A heart sound is generated whensudden closure of a heart valve and the ac-companying oscillation of the blood cause vi-brations (i.e., sound waves) that can be heardwith a stethoscope overlying the heart. Thefirst heart sound is normally split (~0.04 sec)because mitral valve closure precedes tricus-pid closure; however, because this very shorttime interval normally cannot be perceivedthrough a stethoscope, only a single sound isheard.

During the time between the closure of theAV valves and the opening of the semilunarvalves, ventricular pressure rises rapidly with-out a change in ventricular volume (i.e., noejection of blood into the aorta or pulmonaryartery occurs). Ventricular contraction, there-fore, is said to be “isovolumic” or “isovolumet-ric” during this phase. However, individualmyocyte contraction is not necessarily isomet-ric. Some individual fibers contract isotoni-cally (i.e., concentric, shortening contraction),whereas others contract isometrically (i.e.,with no change in length) or eccentrically (i.e.,lengthening contraction). Ventricular cham-ber geometry changes considerably as theheart becomes more spheroid in shape, al-though the volume does not change. Early inthis phase, the rate of pressure developmentbecomes maximal. The maximal rate of pres-sure development, abbreviated “dP/dt max,” isthe maximal slope of the ventricular pressuretracing plotted against time during isovolu-metric contraction.

Atrial pressures transiently increase owingto continued venous return and possibly tobulging of AV valves back into the atrialchambers. The “c-wave” noted in the jugularpulse is thought to occur owing to increasedright atrial pressure that results from bulgingof tricuspid valve leaflets back into rightatrium.

PHASE 3. RAPID EJECTION: AORTICAND PULMONIC VALVES OPEN; AVVALVES REMAIN CLOSED

When the intraventricular pressures exceedthe pressures within the aorta and pulmonaryartery, the aortic and pulmonic valves openand blood is ejected out of the ventricles.Ejection occurs because the total energy ofthe blood within the ventricle exceeds the to-tal energy of blood within the aorta. The totalenergy of the blood is the sum of the pressureenergy and the kinetic energy; the latter is re-lated to the square of the velocity of the bloodflow (see Energetics of Flowing Blood onCD). In other words, ejection occurs becausean energy gradient is present (mostly owing topressure energy) that propels blood into theaorta and pulmonary artery. During thisphase, ventricular pressure normally exceedsoutflow tract pressure by only a few millime-ters of mercury (mm Hg). Although bloodflow across the valves is high, the relativelylarge valve opening (i.e., providing low resis-tance) requires only a few mm Hg of a pres-sure gradient to propel flow across the valve.Maximal outflow velocity is reached early inthe ejection phase, and maximal (systolic) aor-tic and pulmonary artery pressures areachieved.

While blood is being ejected and ventricu-lar volumes decrease, the atria continue to fillwith blood from their respective venous in-flow tracts. Although atrial volumes are in-creasing, atrial pressures initially decrease (x�-descent) as the base of the atria is pulleddownward, expanding the atrial chambers.

No heart sounds are ordinarily heard dur-ing ejection. The opening of healthy valves issilent. The presence of a sound during ejec-tion (i.e., ejection murmurs) indicates valve

64 CHAPTER 4

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disease or intracardiac shunts (see ValveDisease on CD).

PHASE 4. REDUCED EJECTION:AORTIC AND PULMONIC VALVESOPEN; AV VALVES REMAIN CLOSED

Approximately 150–200 milliseconds after theQRS, ventricular repolarization (T wave) oc-curs. This causes ventricular active tension todecrease (i.e., muscle relaxation occurs) andthe rate of ejection (ventricular emptying) tofall. Ventricular pressure falls slightly belowoutflow tract pressure; however, outward flowstill occurs owing to kinetic (or inertial) en-ergy of the blood that helps to propel theblood into the aorta and pulmonary artery.Atrial pressures gradually rise during thisphase owing to continued venous return intothe atrial chambers.

PHASE 5. ISOVOLUMETRICRELAXATION: ALL VALVES CLOSED

As the ventricles continue to relax and intra-ventricular pressures fall, a point is reached atwhich the total energy of blood within theventricles is less than the energy of blood inthe outflow tracts. When this occurs, a pres-sure gradient reversal causes the aortic andpulmonic valves to abruptly close (aortic be-fore pulmonic), causing a Second HeartSound (S2) that is physiologically and audiblysplit. Normally, little or no blood backflowsinto the ventricles as these valves close. Valveclosure is associated with a characteristicnotch (incisura) in the aortic and pulmonaryartery pressure tracings. Unlike in the ventri-cles, where pressure rapidly falls, the declinein aortic and pulmonary artery pressures is notabrupt because of potential energy stored intheir elastic walls and because systemic andpulmonic vascular resistances impede the flowof blood into distributing arteries of the sys-temic and pulmonary circulations.

Ventricular volumes remain constant (iso-volumetric) during this phase because allvalves are closed. The residual volume ofblood that remains in a ventricle is called theend-systolic volume (ESV). For the left

ventricle, this is approximately 50 mL ofblood. The difference between the end-diastolic volume and the end-systolic volumerepresents the stroke volume (SV) of the ven-tricle and is about 70 mL. In a normal ventri-cle, about 60% or more of the end-diastolicvolume is ejected. The volume of bloodejected (stroke volume) divided by the end-diastolic volume is called the ejection frac-tion of the ventricle, which normally is greaterthan 0.55 (or 55%). Although ventricular vol-ume does not change during isovolumetric re-laxation, atrial volumes and pressures continueto increase owing to venous return.

PHASE 6. RAPID FILLING: AV VALVESOPEN; AORTIC AND PULMONICVALVES CLOSED

When the ventricular pressures fall belowatrial pressures, the AV valves open and ven-tricular filling begins. The ventricles brieflycontinue to relax, which causes intraventricu-lar pressures to continue to fall by several mmHg despite on-going ventricular filling. Fillingis very rapid because the atria are maximallyfilled just prior to AV valve opening. Once thevalves open, the elevated atrial pressures cou-pled with the low resistance of the opened AVvalves results in rapid, passive filling of theventricles. Rapid, active relaxation of the leftventricle early in this phase causes left ven-tricular pressure to fall more rapidly than leftatrial pressure, thereby producing diastolicsuction, which aids in the initial filling.

The opening of the AV valves causes arapid fall in atrial pressures and proximal ve-nous pressures. On the right side of the heart,the peak of the jugular pulse just before thevalve opens is the “v-wave.” This peak is fol-lowed by the “y-descent” of the jugularpulse.

If the AV valves are functioning normally,no prominent sounds will be heard during fill-ing. When a Third Heart Sound (S3) is audi-ble during ventricular filling, it may representtensing of chordae tendineae and the AV ring,which is the connective tissue support for thevalve leaflets. This S3 heart sound is normal inchildren, but it is considered pathologic in

CARDIAC FUNCTION 65

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adults because it is often associated with ven-tricular dilation.

PHASE 7. REDUCED FILLING: AVVALVES OPEN; AORTIC ANDPULMONIC VALVES CLOSED

No clear demarcation exists between thephases of rapid and reduced ventricular fill-ing. The reduced filling phase is the periodduring diastole when passive ventricular fillingis nearing completion. As the ventricles con-tinue to fill with blood and expand, they be-come less compliant (i.e., “stiffer”). Thiscauses the intraventricular pressures to rise, asdescribed later in this chapter. Increased in-traventricular pressure reduces the pressuregradient across the AV valve (the pressure gra-dient is the difference between the atrial andventricular pressure) so that the rate of fillingdeclines, even though atrial pressures con-tinue to increase slightly as venous blood con-tinues to flow into the atria. Aortic pressureand pulmonary arterial pressure continue tofall during this period as blood flows into thesystemic and pulmonary circulations.

It is important to note that Figure 4-2 de-picts the cardiac cycle at a relatively low heartrate (75 beats/minute). At low heart rates, thelength of time allotted to diastole is relativelylong, which lengthens the time of the reducedfilling phase. High heart rates reduce theoverall cycle length and are associated with re-ductions in the duration of both systole anddiastole, although diastole shortens muchmore than systole. Without compensatorymechanisms, this cycle reduction would leadto less ventricular filling (i.e., reduced end-diastolic volume). Compensatory mechanismsare important for maintaining adequate ven-tricular filling during exercise (see Chapter 9).

Summary of Intracardiac Pressures

It is important to know normal values of in-tracardiac pressures, as well as the pressureswithin the veins and arteries entering andleaving the heart, because abnormal pressurescan be used to diagnose certain types of car-diac disease and dysfunction. Figure 4-3 sum-

marizes normal, typical pressures in an adultheart. Note that the pressures on the rightside of the heart are considerably lower thanthose on the left side of the heart, and that thepulmonary circulation has low pressures com-pared to the systemic arterial system. Theranges in pressures in the right and left atriaindicate the extent by which atrial pressurechanges during the cardiac cycle.

Ventricular Pressure-VolumeRelationship

Although measurements of pressures and vol-umes over time can provide important in-sights into ventricular function, pressure-volume loops provide another powerful toolfor analyzing the cardiac cycle, particularlyventricular function.

Pressure-volume loops (Fig. 4-4, bottompanel) are generated by plotting left ventricu-lar pressure against left ventricular volume atmany time points during a complete cardiaccycle (Fig. 4-4, top panel). In Figure 4-4, theletters represent the periods of ventricular fill-ing (a), isovolumetric contraction (b), ventric-ular ejection (c), and isovolumetric relaxation(d). The EDV is the maximal volume achieved

66 CHAPTER 4

25/10

0-4

25/4*

120/10*

8-10

120/80

RV

LV

LAPARA

A

FIGURE 4-3 Summary of normal pressures within thecardiac chambers and great vessels. The higher valuesfor pressures (expressed in mm Hg) in the right ventricle(RV), left ventricle (LV), pulmonary artery (PA), and aorta(A) represent the peak pressures during ejection (systolicpressure), whereas the lower pressure values representthe end of diastole (ventricles) or the lowest pressure(diastolic pressure) found in the pulmonary artery andaorta.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

at the end of filling, and ESV is the minimalvolume (i.e., residual volume) of the ventriclefound at the end of ejection. The width of theloop, therefore, represents the difference be-tween EDV and ESV, which is the SV. Thearea within the pressure-volume loop is theventricular stroke work (see VentricularStroke Work on CD).

The filling phase moves along the end-diastolic pressure-volume relationship(EDPVR), or passive filling curve for the ven-tricle. The slope of the EDPVR at any point

along the curve is the reciprocal of ventricu-lar compliance, as described later in thischapter.

The maximal pressure that can be devel-oped by the ventricle at any given left ventric-ular volume is described by the end-systolicpressure-volume relationship (ESPVR).The pressure-volume loop, therefore, cannotcross over the ESPVR, because the ESPVRdefines the maximal pressure that can be gen-erated at any given volume under a given ino-tropic state, as described later in this chapter.

CARDIAC FUNCTION 67

LV Volume (ml)

0 200100ESV EDV

AorticValve

Opening

AorticValve

Opening

MitralValve

Opening

MitralValve

Opening

MitralValve

Closing

MitralValve

Closing

AorticValve

Closing

AorticValve

Closing

ESPVR

EDPVR

SV

ESV

EDV

ab

c

d

FIGURE 4-4 Ventricular pressure-volume loops. The left ventricular pressure-volume loop (bottom panel) is generatedby plotting ventricular pressure against ventricular volume at many different corresponding points during a single cardiac cycle (upper panel). a, ventricular filling; b, isovolumetric contraction; c, ventricular ejection; d, isovolumetricrelaxation; EDV and ESV, left ventricular end-diastolic and end-systolic volumes, respectively; EDPVR, end-diastolicpressure-volume relationship; ESPVR, end-systolic pressure-volume relationship; SV, stroke volume (EDV – ESV).

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Altered Pressure and VolumeChanges during the Cardiac Cycle

The changes in pressures and volumes de-scribed in the cardiac cycle diagram and bythe pressure-volume loop are for normaladult hearts at resting heart rates. The pres-sures and volumes can appear very differentlyin the presence of valve disease and heart fail-ure. Changes in cardiac pressures and vol-umes in different types of valve disease aredescribed in the accompanying CD-ROM.Heart failure and the way it alters cardiacpressures and volumes is discussed inChapter 9.

REGULATION OF CARDIAC OUTPUT

The primary function of the heart is to impartenergy to blood to generate and sustain an ar-terial blood pressure sufficient to adequatelyperfuse organs. The heart achieves this bycontracting its muscular walls around a closedchamber to generate sufficient pressure topropel blood from the left ventricle, throughthe aortic valve, and into the aorta. Each timethe left ventricle contracts, a volume of bloodis ejected into the aorta. This stroke volume(SV), multiplied by the number of beats perminute (heart rate, HR), equals the cardiacoutput (CO) (Equation 4-1).

CO � SV � HR

Therefore, changes in either stroke volume orheart rate alter cardiac output.

The units for cardiac output are expressedas either mL/min or liters/min. The units forstroke volume are milliliters/beat (mL/beat),and the units for heart rate are beats/min. In a

resting adult, cardiac output typically rangesfrom 5–6 L/min. Sometimes cardiac output isexpressed as a cardiac index, which is thecardiac output divided by the estimated bodysurface area (BSA) in square meters. Severaldifferent formulas can be used to estimateBSA. One formula is BSA (m2) equals thesquare root of the (height [cm] times weight[kg] divided by 3600); BSA � (cm · kg/3600)1/2

(Mosteller formula). Calculating the cardiacindex normalizes cardiac output to individualsof different size. A normal range for cardiacindex is 2.6 to 4.2 L/min/m2.

Influence of Heart Rate on CardiacOutput

Although cardiac output is determined byboth heart rate and stroke volume, changes inheart rate are generally more important quan-titatively in producing changes in cardiac out-put. For example, heart rate may increase by100% to 200% during exercise, whereasstroke volume may increase by less than 50%.These changes in heart rate are brought aboutprimarily by changes in sympathetic andparasympathetic nerve activity at the sinoatrialnode.

Changes in heart rate alone inversely affectstroke volume. For example, doubling heartrate from 70–140 beats/minute by pacemakerstimulation alone does not double cardiac out-put because stroke volume falls nearly propor-tionately. This occurs because the ventricularfilling time decreases as the length of diastoleshortens. However, when physiological mech-anisms during exercise cause the heart rate todouble, cardiac output more than doubles be-cause stroke volume actually increases. This

68 CHAPTER 4

Calculate left ventricular stroke volume in milliliters/beat when the cardiac output is8.8 liters/minute and the heart rate is 110 beats/min.

Stroke volume equals cardiac output divided by heart rate. Because stroke volumeuses milliliters for units, cardiac output (8.8 liters/min) must be expressed in mL/min(8,800 mL/min). This value, divided by a heart rate of 110 beats/min, gives a stroke vol-ume of 80 mL/beat.

PROBLEM 4-1

Eq. 4-1

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increase in stroke volume, despite the eleva-tion in heart rate, is brought about by severalmechanisms acting on the heart and systemiccirculation (see Chapter 9). When thesemechanisms fail, stroke volume cannot bemaintained at elevated heart rates. It is im-portant to understand the mechanisms thatregulate stroke volume because impairedstroke volume regulation can lead to a state ofheart failure and limited exercise capacity (seeChapter 9).

Regulation of Stroke Volume

Ventricular stroke volume is the differencebetween the ventricular EDV and the ESV. Ina typical heart, the EDV may be 120 mL ofblood and the ESV 50 mL of blood. The dif-ference in these two volumes, 70 mL, repre-sents the stroke volume. Therefore, any factorthat alters either the EDV or the ESV changesstroke volume.

Three primary mechanisms regulate EDVand ESV, and therefore stroke volume: pre-load, afterload, and inotropy (Fig. 4-5). Achange in preload primarily alters EDV,whereas changes in afterload and inotropy pri-marily affect ESV. For example, increasedpreload increases stroke volume by increasingEDV, whereas increased afterload decreasesstroke volume by increasing ESV. EDV andESV are interdependent variables, so achange in one variable leads to a change in theother. The following section highlights the im-portance of preload, afterload, and inotropy in

the regulation of EDV, ESV, and stroke vol-ume.

Effects of Preload on Stroke VolumePreload is the initial stretching of the car-diac myocytes prior to contraction; therefore,it is related to the sarcomere length at the endof diastole. Sarcomere length cannot be de-termined in the intact heart so indirect in-dices of preload, such as ventricular end-di-astolic volume or pressure, must be used.These measures of preload are not ideal be-cause they may not reflect sarcomere length.For example, with an acute increase in ven-tricular volume, an increase in sarcomerelength occurs. However, in a chronically di-lated ventricle, as occurs in some types ofheart failure, the sarcomere length might benormal because of the addition of new sar-comeres in series. End-diastolic pressure is apoor index of preload because compliance ofthe ventricle determines the actual stretch-ing of sarcomeres and hence ventricular vol-ume, and this may change to accommodatechronic conditions (see next section).Nevertheless, acute changes in end-diastolicpressure and volume are useful indices forexamining the effects of acute preloadchanges on stroke volume. Note that the con-cepts on the influence of preload on cardiacfunction described in the following sectionscan be applied to both the atria and the ven-tricles.

Effects of Ventricular Compliance on PreloadAs the left ventricle (or other cardiac cham-ber) fills with blood, the pressure generated ata given volume is determined by the compli-ance of the ventricle, in which compliance isdefined as the ratio of a change in volume di-vided by a change in pressure. Normally, com-pliance curves are plotted with the volume asa function of pressure, and the compliance isthe slope of the line at any given pressure (i.e.,the slope of the tangent at a particular pointon the line). (See Compliance on CD.) Forthe ventricle, however, it is common to plotpressure versus volume (Fig. 4-6). Plotted inthis manner, the slope of the tangent at a given

CARDIAC FUNCTION 69

EDV ESV

+

+ +

–

–

SV

Preload Afterload Inotropy

FIGURE 4-5 Factors determining stroke volume (SV).Because SV equals end-diastolic volume (EDV) minusend systolic volume (ESV), factors that increase EDV(preload) or decrease ESV (afterload and inotropy) willincrease SV. (�), increase; (�), decrease.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

point on the line is the reciprocal of the com-pliance, which is sometimes referred to asventricular elastance or “stiffness.”

The relationship between pressure and vol-ume is nonlinear in the ventricle (as in mostbiological tissues); therefore, compliance de-creases with increasing pressure or volume.When pressure and volume are plotted as inFigure 4-6, we find that the slope of the fillingcurve (the end-diastolic pressure-volume rela-tionship described in Figure 4-4) increasesdramatically at higher volumes; i.e., the ven-tricle becomes less compliant or “stiffer” athigher volumes.

Ventricular compliance is determined bythe physical properties of the tissues makingup the ventricular wall and the state of ven-tricular relaxation. For example, in ventricularhypertrophy the increased muscle thicknessdecreases the ventricular compliance; there-fore, ventricular end-diastolic pressure ishigher for any given end-diastolic volume.This is shown in Figure 4-6, in which the fill-ing curve of the hypertrophied ventricle shiftsupwards and to the left. From a different per-spective, for a given end-diastolic pressure, aless compliant ventricle will have a smallerend-diastolic volume (i.e., filling will be de-creased). If ventricular relaxation is impaired,

as occurs in some forms of diastolic ventricu-lar failure (see Chapter 9), the effective ven-tricular compliance will be reduced. This willimpair ventricular filling and increase end-diastolic pressure. If the ventricle becomeschronically dilated, as occurs in other forms ofheart failure, the filling curve shifts downwardand to the right. This enables a dilated heartto have a greater end-diastolic volume withoutcausing a large increase in end-diastolic pres-sure.

The length of a sarcomere prior to contrac-tion, which represents its preload, depends onthe interplay between ventricular end-diastolicvolume, end-diastolic pressure, and compli-ance. Although end-diastolic pressure and end-diastolic volume are sometimes used as indicesof preload, care must be taken when interpret-ing the significance of these values in terms ofhow they relate to the preload of individual sarcomeres. For example, an elevated end-diastolic pressure may be associated with sar-comere lengths that are increased, decreased,or unchanged, depending on the ventricularvolume and compliance at that volume.

Factors Determining Ventricular PreloadIn the normal heart, right ventricular preloadis determined by the volume of blood that fills

70 CHAPTER 4

LV Volume (ml)

0 200100 300

DecreasedCompliance

(e.g., hypertrophy)Increased

Compliance(e.g., dilation)Normal

(EDP)

(EDV)

FIGURE 4-6 Ventricular compliance (or filling) curves. The slope of the tangent of the passive pressure-volume curveat a given volume represents the reciprocal of the ventricular compliance. The slope of the normal compliance curveis increased by a decrease in ventricular compliance (e.g., ventricular hypertrophy), whereas the slope of the compli-ance curve is reduced by an increase in ventricular compliance (e.g., ventricular dilation). Decreased compliance in-creases the end-diastolic pressure (EDP) at a given end-diastolic volume (EDV), whereas increased compliance de-creases EDP at a given EDV. LV, left ventricle.

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the ventricle at the end of passive filling andatrial contraction (i.e., the end-diastolic vol-ume). Figure 4-7 summarize several factorsthat alter ventricular filling and therefore pre-load.

An increase in venous blood pressure in-creases ventricular preload. Venous blood vol-ume and compliance determine venous pres-sure (see Chapter 5). Venous compliancerelates to the state of smooth muscle contrac-tion within venous blood vessels and is de-creased, for example, by sympathetic activa-tion, which contracts the venous smoothmuscle. The reduced compliance leads to anincrease in venous pressure. Venous bloodvolume, particularly in the thoracic (central)compartment, is influenced by the total bloodvolume (regulated by the kidneys) and therate of venous return into the thoracic com-partment. The rate of venous return is influ-enced by gravity, the mechanical pumping ac-tivity of skeletal muscles, and respiratoryactivity.

Several other important factors determineventricular preload. (1) Ventricular compli-ance determines the end-diastolic volume for

any given intraventricular filling pressure, aspreviously described. (2) Heart rate, throughits influence on filling time, has an inverse ef-fect on preload. (3) Atrial contraction (atresting heart rates) normally has only a smallinfluence on ventricular preload becausemost of ventricular filling occurs during thepassive filling phases. At high heart rates,however, increased atrial contractility (owingto sympathetic activation) significantly en-hances (up to about 40%) the contribution ofatrial contraction to ventricular filling,thereby helping to maintain preload. (4)Elevated inflow resistance decreases ventric-ular preload. For example, in tricuspid valvestenosis, the inflow resistance is increasedand ventricular preload is reduced. (5) An in-crease in outflow resistance, as caused bypulmonic valve stenosis or pulmonary hyper-tension, impairs the ability of the right ven-tricle to empty, leading to an increase in pre-load. (6) In ventricular systolic failure, whenventricular inotropy is diminished, the ven-tricular preload increases because of the in-ability of the ventricle to eject normal vol-umes of blood. This causes blood to back up

CARDIAC FUNCTION 71

↑ HeartRate

↑ VenousPressure

↑ InflowResistance

↑ OutflowResistance& Afterload

VenousCompliance

↑ AtrialContractility

VentricularFailure

•••••

Venous ReturnTotal Blood VolumeR e s p i r a t i o nMusc le Con t rac t i onGravity

Venous Volume

↑ VentricularCompliance

–

–

–

RightVentricular

Preload

++

+ +

+

+

FIGURE 4-7 Factors determining right ventricular preload. (�) indicates that an increase in a variable increases rightventricular end-diastolic volume, and therefore preload; (�) indicates that the variable decreases preload.

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in the ventricle and proximal venous circu-lation.

Left ventricular preload is determined bythe same factors as for right ventricular pre-load, except that the venous pressure is pul-monary venous pressure instead of central ve-nous pressure, the inflow resistance is themitral valve, and the outflow resistance is theaortic valve and aortic pressure. Respiratoryactivity also influences left ventricular pre-load, as described later in this chapter.

Effects of Venous Return on Stroke Volume(Frank-Starling Mechanism)Altered preload is an important mechanism bywhich the ventricle changes its force of con-traction. When venous return to the heart isincreased, ventricular filling increases, as doespreload. This stretching of the myocytescauses an increase in force generation, which

enables the heart to eject the additional ve-nous return and thereby increase stroke vol-ume (Fig. 4-8). This is called the Frank-Starling mechanism in honor of thescientific contributions of Otto Frank (late19th century) and Ernest Starling (early 20thcentury). Another term for this mechanism is“Starling’s law of the heart.” In summary, theFrank-Starling mechanism states that increas-ing venous return and ventricular preloadleads to an increase in stroke volume.

There is no single Frank-Starling curve(sometimes called ventricular function curves)for the ventricle. Instead, there is a family ofcurves (Fig. 4-9), with each curve defined bythe afterload imposed on the heart and the inotropic state of the heart. (These conceptsare described later in this chapter.) Increasingafterload and decreasing inotropy shifts thecurve down and to the right, whereas decreas-

72 CHAPTER 4

A hospitalized patient is given a diuretic drug (which increases renal sodium and waterexcretion) to reduce blood volume. Using Frank-Starling curves, describe how the acutedecrease in blood volume will affect ventricular stroke volume. Assume no significantchanges in heart rate, inotropy, or aortic pressure.

A decrease in blood volume reduces venous return and ventricular preload (e.g.,ventricular end-diastolic volume and pressure), which decreases force generation bythe myocytes. This causes the stroke volume to fall from point A to B along a givenStarling curve, as shown in Figure 4-26.

CASE 4-1

10

100

50

2000

SV(ml)

LVEDP (mmHg)

A

B DecreasedBlood Volume

Effects of reducing blood volume on stroke volume. Reducing blood volume with a diuretic decreases ven-tricular filling so that the preload (left ventricular end-diastolic pressure, LVEDP) decreases. This causes strokevolume (SV) to fall from point A to point B along the Frank-Starling curve.

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ing afterload and increasing inotropy shifts thecurve up and to the left. To summarize,changes in venous return cause a ventricle tofunction along a Frank-Starling curve that isdefined by the existing conditions of afterloadand inotropy.

The Frank-Starling mechanism plays animportant role in balancing the output of thetwo ventricles. For example, when venous re-turn increases to the right side of the heartduring physical activity, the Frank-Starlingmechanism enables the right ventricular

CARDIAC FUNCTION 73

10

100

50

2000

SV(ml)

LVEDP (mmHg)

A

B

IncreasedVenous Return

FIGURE 4-8 Frank-Starling mechanism. Increasing ve-nous return to the left ventricle increases left ventricularend-diastolic pressure (LVEDP) by increasing ventricularvolume; this increases ventricular preload, resulting inan increase in stroke volume (SV) from point A to B. The“normal” operating point (A) is at a LVEDP of about 8mm Hg and a SV of about 70 mL/beat.

10

100

50

2000

SV(ml)

LVEDP (mmHg)

FIGURE 4-9 A family of Frank-Starling curves generatedat different afterloads and inotropic states. Increased af-terload or decreased inotropy shifts the Frank-Starlingcurve downward, whereas the opposite changes in af-terload and inotropy shift the curve upward. Shiftingthe curves increases or decreases the stroke volume (SV)at any given left ventricular end-diastolic pressure(LVEDP).

If the left ventricular output is 60 mL/beat and the right ventricular stroke volume isonly 0.1% greater, by how much would the pulmonary blood volume increase over 1hour if the heart rate is 75 beats/min? Describe how the Frank-Starling mechanism nor-mally prevents this large shift of blood from systemic to pulmonary circulation.

Because the right ventricular stroke volume is 0.1% greater than the left ventricularstroke volume of 60 mL/beat, the right ventricular stroke volume can be calculated bymultiplying 60 times 1.001, which gives a stroke volume of 60.06 mL/beat. The differ-ence in stroke volume between the two ventricles therefore is 0.06 mL/beat. To obtainthe difference in total stroke volume over 1 hour when the rate is 75 beats/min, multi-ply the rate (75 beats/min) � 60 min/hr � stroke volume difference (0.06 mL/beat). Thiscalculation yields a value of 270 mL.

This calculation demonstrates how a small difference in the output of the two ven-tricles (right being greater than left) can lead to a significant increase in pulmonaryblood volume over time. Normally, this increase in pulmonary blood volume would in-crease pulmonary vascular pressures and the filling pressure for the left ventricle. Thiswould increase the left ventricular stroke volume output by the Frank-Starling mecha-nism, which would maintain a balance in output over time between the two sides ofthe heart.

PROBLEM 4-2

Ch04_059-090_Klabunde 4/21/04 11:08 AM

stroke volume to increase, thereby matchingits output to the increased venous return. Theincreased right ventricular output increasesthe venous return to the left side of the heart,and the Frank-Starling mechanism operatesto increase the output of the left ventricle.This mechanism ensures that the outputs ofthe two ventricles are matched over time; oth-erwise blood volume would shift between thepulmonary and systemic circulations.

This analysis using Frank-Starling curvesshows how changes in venous return and ven-tricular preload lead to changes in stroke vol-ume. These curves, however, do not show howchanges in venous return affect end-diastolic

and end-systolic volumes. These changes inventricular volumes are best illustrated by us-ing pressure-volume diagrams.

When venous return is increased, in-creased filling of the ventricle occurs along itspassive filling curve. This leads to an increasein end-diastolic volume (Fig. 4-10). If the ven-tricle now contracts at this increased preload,and the aortic pressure is held constant, theventricle will empty to the same end-systolicvolume, and therefore stroke volume will beincreased. This is shown as an increase in thewidth of the pressure-volume loop. In reality,the increase in stroke volume that results fromthe increase in venous return will lead to an

74 CHAPTER 4

Echocardiography reveals that the left ventricle of a chronically hypertensive patient issignificantly hypertrophied. Using left ventricular pressure-volume loops, describe howend-diastolic pressure and volume and stroke volume will be altered by the hypertro-phy. Assume no change in heart rate, inotropy, or aortic pressure.

A hypertrophied ventricle is less compliant. This causes the end-diastolic pressure-volume curve to shift up and to the left, as shown in Figure 4-27. This shift will reducethe end-diastolic volume and increase the end-diastolic pressure at the end of ventricu-lar filling. The end-systolic volume will be normal unless there is a significant change ininotropy or aortic diastolic pressure. The width of the pressure-volume loop is nar-rower; therefore, the stroke volume is reduced.

CASE 4-2

LV Volume (ml)

LV P

ress

ure

(m

mH

g)

200

100

00 200100

ControlLoop

DecreasedCompliance

(hypertrophy)

Effects of left ventricular hypertrophy on the pressure-volume loop. Hypertrophy causes a reduction in ven-tricular compliance, which increases the slope of the end-diastolic pressure-volume relationship. This leads toan increase in end-diastolic pressure and a decrease in ventricular filling (end-diastolic volume). Reduced fill-ing leads to a decrease in stroke volume (Frank-Starling mechanism), which is shown as a decrease in thewidth of the pressure-volume loop. End-systolic volume does not change unless inotropy or afterload changes.LV, left ventricle.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

increase in aortic blood pressure because ofthe increase in cardiac output. For reasons de-scribed later in this chapter, this will lead to asmall increase in end-systolic volume; the neteffect, however, will still be an increase in thewidth of the pressure-volume loop (i.e., in-creased stroke volume). The normal ventricle,therefore, is capable of increasing its strokevolume to match an increase in venous return.The increase in the area within the pressure-volume loop, which represents the ventricularstroke work, will also be increased.

Effects of Preload Length on TensionDevelopment (Length-Tension Relationship)The mechanical or biophysical basis for theFrank-Starling mechanism can be describedby the length-tension relationship for cardiacmyocytes. The length-tension relationshipexamines how changes in the initial length ofa muscle (i.e., preload) affect the ability of themuscle to develop force (tension). To illus-trate this relationship, a piece of cardiac mus-cle (e.g., papillary muscle) is isolated andplaced within an in vitro bath containing anoxygenated, physiologic salt solution. One endof the muscle is attached to a force transducerto measure tension, and the other end is at-

tached to an immovable support rod (Fig. 4-11, left panel). The end that is attached tothe force transducer is movable so that the ini-tial length (preload) of the muscle can be fixedat a desired length. The muscle is then elec-trically stimulated to contract; however, thelength is not permitted to change and there-fore the contraction is isometric.

If the muscle is stimulated to contract at arelatively short initial length (low preload), acharacteristic increase in tension (termed “ac-tive” tension) will occur, lasting about 200m/sec (Fig. 4-11, right panel, curve a). Bystretching the muscle to a longer initial length,the passive tension will be increased prior tostimulation. The amount of passive tension de-pends on the elastic modulus (“stiffness”) ofthe tissue. The elastic modulus of a tissue is re-lated to the ability of a tissue to resist defor-mation; therefore, the higher the elastic mod-ulus, the “stiffer” the tissue. When the muscleis stimulated at the increased preload, therewill be a larger increase in active tension(curve b) than had occurred at the lower pre-load. If the preload is again increased, therewill be a further increase in active tension(curve c). Therefore, increases in preload leadto an increase in active tension. Not only is the

CARDIAC FUNCTION 75

LV Volume (ml)

LV P

ress

ure

(mm

Hg

)

200

100

00 200100

IncreasedVenousReturn

ControlLoop

↑EDV

↑SV

ESPVR

FIGURE 4-10 Effects of increasing venous return on left ventricular (LV) pressure-volume loops. This diagram showsthe acute response to an increase in venous return. It assumes no cardiac or systemic compensation and that aorticpressure remains unchanged. Increased venous return increases end-diastolic volume (EDV), but it normally does notchange end-systolic volume; therefore, stroke volume (SV) is increased. ESPVR, end-systolic pressure-volume rela-tionship.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

magnitude of active tension increased, but alsothe rate of active tension development (i.e.,the maximal slope with respect to time of thetension curve during contraction). The dura-tion of contraction and the time-to-peak ten-sion, however, are not changed.

If the results shown in Figure 4-11 areplotted as tension versus initial length (pre-load), a length-tension diagram is generated(Fig. 4-12). In the top panel, the passive ten-sion curve is the tension that is generated asthe muscle is stretched prior to contraction.Points a, b, and c on the passive curve corre-spond to the passive tensions and initial pre-load lengths for curves a, b, and c in Figure 4-11 prior to contraction. The total tensioncurve represents the maximal tension that oc-curs during contraction at different initial pre-loads. The total tension curve is the sum of thepassive tension and the additional tensiongenerated during contraction (active tension).The active tension, therefore, is the differencebetween the total and passive tension curves;it is shown in the bottom panel of Figure 4-12.The active tension diagram demonstrates thatas preload increases, there is an increase in ac-tive tension up to a maximal limit. The maxi-mal active tension in cardiac muscle corre-sponds to a sarcomere length of about 2.2microns. Cardiac muscle, unlike skeletal mus-cle, does not display a descending limb on theactive tension curve because the greater stiff-

ness of cardiac muscle normally prevents thesarcomeres from being stretched beyond 2.2microns.

This discussion described how changes inpreload affect the force generated by cardiacmuscle fibers during isometric contractions(i.e., with no change in length). Cardiac mus-cle fibers, however, normally shorten whenthey contract (i.e., undergo isotonic contrac-tions). If a strip of cardiac muscle in vitro is setat a given preload length and stimulated tocontract, it will shorten and then return to itsresting preload length (Fig. 4-13). If the initialpreload is increased and the muscle stimu-lated again, it will ordinarily shorten to thesame minimal length, albeit at a higher veloc-ity of shortening. This explains why, in Figure4-10, the increase in end-diastolic volume re-sulted in an increase in stroke volume with nochange in end-systolic volume.

The length-tension relationship, althoughusually used to describe the contraction of iso-lated muscles, can be applied to the wholeheart. By substituting ventricular volume forlength and ventricular pressure for tension,the length-tension relationship becomes apressure-volume relationship for the ventri-cle. This can be done because a quantitativerelationship exists between tension and pres-sure and between length and volume that isdetermined by the geometry of the ventricle.Figure 4-14 shows that as ventricular preload

76 CHAPTER 4

Ten

sio

n

Time

a

b

cStimulate

Passive

Active Total

For curve c

LMuscle

TensionTransducer

Fixed

Moveable

∆

FIGURE 4-11 Effects of increased preload on tension development by an isolated strip of cardiac muscle. The left panelshows how muscle length and tension are measured in vitro. The bottom of the muscle strip is fixed to an immovablerod, whereas the top of the muscle is connected to a tension transducer and a movable bar that can be used to ad-just initial muscle length (∆L). The right panel shows how increased preload (initial length) increases both passive andactive (developed) tension. The greater the preload, the greater the active tension generated by the muscle.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

volume is increased (i.e., end-diastolic volumeincreased), an increase in isovolumetric ven-tricular pressure development occurs duringventricular contraction, analogous to what isobserved with a single papillary muscle (seeFig. 4-12). This can be observed experimen-tally in the ventricle by occluding the aortaduring ventricular contraction and measuringthe peak systolic pressure generated by theventricle under this isovolumetric condition.If the ventricle were permitted to eject blood,

the increased pressure development resultingfrom increased preload would augment strokevolume, as depicted in Figure 4-10.

What mechanisms are responsible for theincrease in force generation with increasedpreload in the heart? In the past, it wasthought that changes in active tension causedby altered preload could be explained by achange in the number of actin and myosincross bridges formed (see Chapter 3).Although this can be a factor if sarcomerelength is increased beyond 2.2 � (the lengthof maximal force generation), the intact heartunder physiologic conditions operates at sar-comere lengths in the range of 1.8–2.2 � (i.e.,on the ascending limb of the length-tensionrelationship for the sarcomere). For variousstructural and mechanical reasons, the sar-comere length in cardiac myocytes does notnormally exceed 2.2 �. These observationshave led to the concept of length-dependentactivation. Experimental evidence supportsthree possible explanations. First, studies haveshown that increased sarcomere length sensi-tizes the regulatory protein troponin C to cal-cium without necessarily increasing intracel-lular release of calcium. This increasescalcium binding by troponin C, leading to anincrease in force generation as described inChapter 3. A second explanation is that fiberstretching alters calcium homeostasis withinthe cell so that increased calcium is availableto bind to troponin C. A third explanation isthat as a myocyte (and sarcomere) lengthens,the diameter must decrease because the vol-ume has to remain constant. It has been pro-posed that this would bring the actin andmyosin molecules closer to each other (de-creased lateral spacing), which would facili-tate their interactions.

It has traditionally been taught that theFrank-Starling mechanism does not result in achange in inotropy (intrinsic contractility) de-spite a change in force generation. However,we can no longer rigidly differentiate betweenthe mechanisms responsible for preload andinotropic effects on force generation becauseof what we now understand about length-dependent activation of the myofilaments.

CARDIAC FUNCTION 77

Ten

sio

nTe

nsi

on

Length

Length

PassiveTension

ActiveTension

TotalTension

c

c

b

b

a

a

FIGURE 4-12 Length-tension relationship for cardiacmuscle undergoing isometric contraction. The top panelshows that increasing the preload length from points ato c increases the passive tension. Furthermore, increas-ing the preload increases the total tension during con-traction as shown by arrows a, b, and c, which corre-spond to active tension changes depicted by curves a,b, and c in Figure 4-11. The length of the arrow is theactive tension, which is the difference between the to-tal and passive tensions. The bottom panel shows thatthe active tension increases to a maximum value as pre-load increases.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

Effects of Afterload on Stroke VolumeAfterload is the “load” against which theheart must contract to eject blood. A majorcomponent of the afterload for the left ventri-cle is the aortic pressure, or the pressure theventricle must overcome to eject blood. Thegreater the aortic pressure, the greater the af-terload on the left ventricle. For the right ven-tricle, the pulmonary artery pressure repre-sents the major afterload component.

Ventricular afterload, however, involvesfactors other than the pressure that the ven-tricle must develop to eject blood. One way to

estimate the afterload on the individual car-diac fibers within the ventricle is to examineventricular wall stress (�), which is propor-tional to the product of the intraventricularpressure (P) and ventricular radius (r), dividedby the wall thickness (h) (Equation 4-2). Thisrelationship for wall stress assumes that theventricle is a sphere. The determination of ac-tual wall stress is complex and must considernot only ventricular geometry, but also musclefiber orientation. Nonetheless, Equation 4-2helps to illustrate the factors that contributeto wall stress and therefore afterload on themuscle fibers.

� ∝

Wall stress can be thought of as the averagetension that individual muscle fibers withinthe ventricular wall must generate to shortenagainst the developed intraventricular pres-sure. At a given intraventricular pressure, wallstress is increased by an increase in radius(ventricular dilation). Therefore, afterload isincreased whenever intraventricular pressuresare increased during systole and by ventricu-lar dilation. On the other hand, a thickened,hypertrophied ventricle will have reducedwall stress and afterload on individual fibers.Ventricular wall hypertrophy can be thought

P � r

h

78 CHAPTER 4V

en

tric

ula

rP

ress

ure

Ventricular Volume

cb

a

Peak-SystolicPressure

End-DiastolicPressure

DevelopedPressure

FIGURE 4-14 Effects of increasing ventricular volume(preload) on ventricular pressure development.Increasing ventricular volume from a to c and then stim-ulating the ventricle to contract isovolumetrically in-creases the developed pressure and the peak-systolicpressure.

Eq. 4-2

Le

ng

th

Time

dL/dt

∆L

IncreasedPreload

IncreasedPreload

RestingLength

RestingLength

ContractedLength

∆ ↑∆L LMuscle

Load

A B

A

B

FIGURE 4-13 Effects of increased initial muscle length (increased preload) on muscle shortening (isotonic contrac-tions). The left panel shows a muscle lifting a load (afterload) at two different preload lengths (A and B). The rightpanel shows how increasing the preload leads to increased shortening (∆L) and increased velocity of shortening(dL/dt; change in length with respect to time). The muscle shortens to the same minimal length when preload is in-creased.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

of as an adaptive mechanism by which theventricle is able to offset the increase in wallstress that accompanies increased aortic pres-sure, aortic valve stenosis, or ventricular dila-tion.

Effects of Afterload on Frank-StarlingCurvesAn increase in afterload shifts the Frank-Starling curve down and to the right (Fig. 4-15). Therefore, at a given preload (LVEDPin Figure 4-15), an increase in afterload de-creases stroke volume. Conversely, decreasingafterload shifts the curves up and to the left,thereby increasing the stroke volume at anygiven preload. For reasons discussed later,changes in afterload result in a subsequentchange in preload so that as the Frank-Starling curve shifts, the operating point forthe curve shifts diagonally, as shown in Figure4-15. In the normal heart, changes in after-load do not have pronounced effects on strokevolume; however, the failing ventricle is verysensitive to changes in afterload.

Effects of Afterload on the Velocity of FiberShortening (Force-Velocity Relationship)The decrease in stroke volume that accompa-nies an increase in afterload is caused by im-

paired emptying of the ventricle. The basisfor this is found in the force-velocity rela-tionship of cardiac myocytes. The force-velocity relationship shows how afterload af-fects the velocity of shortening when musclefibers contract isotonically. To illustrate this, apapillary muscle is placed in an in vitro bathand a load is attached to one end (Fig. 4-16,left panel). When the muscle contracts, thefiber first generates tension isometrically(right panel, a to b) until the developed ten-sion exceeds the load imposed on the muscle.When this point is reached, the muscle fiberbegins to shorten and the tension remainsconstant and equal to the load that is beinglifted (b to c). The maximal velocity of short-ening occurs shortly after the muscle beginsto shorten. The muscle continues to shortenuntil the muscle begins to relax. When activetension falls below the load (point c), themuscle resumes its resting length (i.e., pre-load) (point c). Active tension continues tofall isometrically (c to d) until only the passivetension remains (point d).

If this experiment with the papillary mus-cle were repeated with increasing loads, a de-crease would occur in both the maximal ve-locity of fiber shortening (maximal slope ofline) and the degree of shortening, as shownin Figure 4-17. Plotting the maximal velocityof shortening against the load that the musclefiber must shorten against (i.e., the afterload)generates an inverse relationship between ve-locity of shortening and afterload (Fig. 4-18).In other words, the greater the afterload, theslower the velocity of shortening.

To further illustrate the force-velocity rela-tionship, consider the following example. If aman holds a 2-pound dumbbell at his sidewhile standing, and then contracts his bicepsmuscle at maximal effort, the weight will belifted at a relatively high velocity as the bicepsmuscle shortens. If the weight is increased to20 pounds, and the weight once again is liftedat maximal effort, the velocity will be muchslower. Higher weights further reduce the ve-locity until the weight can no longer be liftedand the contraction of the biceps muscle be-comes isometric. The x-intercept in the forcevelocity diagram (see Fig. 4-18) is the point at

CARDIAC FUNCTION 79

10

100

50

2000S

tro

ke V

olu

me

(ml)

LVEDP (mmHg)

B

AC

FIGURE 4-15 Effects of changes in afterload on Frank-Starling curves. An increase in afterload shifts the oper-ating point of the Frank-Starling curve from A to B,whereas a decrease in afterload shifts the operatingpoint from A to C. Therefore, increased afterload de-creases stroke volume and increases end-diastolic pres-sure (preload). The converse also is true.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

which the afterload is so great that the musclefiber cannot shorten. The x-intercept there-fore represents the maximal isometric force.The y-intercept represents an extrapolatedvalue for the maximal velocity (Vmax) thatwould be achieved if there was no afterload.The value is extrapolated because it cannot bemeasured experimentally (a muscle will notcontract in the absence of any load).

It is important to note that a cardiac musclefiber does not operate on a single force-velocity curve (Fig. 4-19). If preload is in-creased, a cardiac muscle fiber will have agreater velocity of shortening at a given after-

load. This occurs because the length-tensionrelationship requires that as the preload is in-creased, there is an increase in active tensiondevelopment. Once the fiber begins to shorten,an increased preload with an increase in ten-sion-generating capability causes a greatershortening velocity. In other words, increasingthe preload enables the muscle to contractfaster against a given afterload; this shifts theforce-velocity relationship to the right. Notethat increasing the preload increases the maxi-mal isometric force (x-intercept) as well as theshortening velocity at a given afterload.Changes in preload, however, do not alter Vmax.

80 CHAPTER 4

Length

Tension

Time

∆

∆

L

T

Preload

Resting

Maximal

Minimal

∆ LMuscle

Load

a

b c

d

FIGURE 4-16 Cardiac muscle isotonic contractions. The left panel shows how muscle length and tension are mea-sured in vitro. The lower end of the muscle is attached to a weight (load) that is lifted up from an immovable plat-form as the muscle develops tension and shortens (∆L). A bar attached to the top of the muscle can be moved toadjust initial muscle length (preload). The right panel shows changes in tension and length during contraction. Theperiods from a to b and from c to d represent periods of isometric contraction and relaxation, respectively. Muscleshortening (∆L) occurs between b and c, which occurs when the developed tension (∆T) exceeds the load.

DecreasingLength

Time

b

a c = increasing afterload

a

c

Preload

FIGURE 4-17 Effects of afterload on myocyte shorten-ing. Increased afterload (curves a to c) decreases the de-gree of muscle shortening and velocity of shortening ata given preload.

Afterload (Force)

Sho

rten

ing

Vel

ocity

Maximal IsometricForce

Vmax

FIGURE 4-18 Force-velocity relationship. Increased af-terload (which requires increased force generation) de-creases velocity of shortening by the muscle fiber. The x-intercept represents the maximal isometric force; they-intercept represents the maximal velocity of shorten-ing (Vmax) extrapolated to zero load.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

Therefore, an increase in preload on a cardiacmyocyte helps to offset the reduction in velocitythat occurs when afterload is increased.

Effects of Afterload on Pressure-VolumeLoopsChanges in afterload produce secondarychanges in preload, as shown in Figure 4-15.Therefore, afterload and preload are interde-pendent variables. This interdependence canbest be described using pressure-volume loops(Fig. 4-20). If afterload is increased by increas-ing aortic diastolic pressure, the ventricle hasto generate increased pressure before the aor-tic valve can open. The ejection velocity afterthe valve opens will be reduced because in-creased afterload decreases the velocity of car-diac fibers shortening, as described by theforce-velocity relationship. Because only a fi-nite period of time exists for electrical and me-chanical systole, less blood will be ejected (de-creased stroke volume) so that ventricularend-systolic volume increases as shown in thepressure-volume loop. The increased end-sys-tolic volume inside the ventricle will be addedto the venous return, thereby increasing end-diastolic volume. After several beats, a steadystate is achieved in which the increase in end-systolic volume is greater than the increase inend-diastolic volume so that the difference be-tween the two—the stroke volume—is de-creased (i.e., the width of the pressure-volumeloop is decreased). This increase in preloadsecondary to the increase in afterload activates

the Frank-Starling mechanism to partiallycompensate for the reduction in stroke volumecaused by the increase in afterload.

Effects of Inotropy on Stroke VolumeEffects of Inotropy on Length-TensionRelationshipVentricular stroke volume is altered both bychanges in preload and afterload, and bychanges in ventricular inotropy (sometimesreferred to as contractility). Changes in ino-tropy are caused by intrinsic cellular mecha-nisms that regulate the interaction betweenactin and myosin independent of changes insarcomere length. For example, if cardiac mus-cle is exposed to norepinephrine, it increasesactive tension development at any initial pre-load length as shown by the length-tension re-lationship (Fig. 4-21). This occurs because thenorepinephrine binds to 1-adrenoceptors, in-creasing calcium entry into the cell and cal-cium release by the sarcoplasmic reticulumduring contraction (see Chapter 3).

Effects of Inotropy on Force-VelocityRelationshipChanges in inotropy also alter the force-veloc-ity relationship. If the inotropic state of the

CARDIAC FUNCTION 81

Afterload (Force)

Sh

ort

en

ing

Ve

loci

ty

a b c

Increasing Preload a c

FIGURE 4-19 Effects of increasing preload (shift fromcurve a to c) on the force-velocity relationship. At agiven afterload, increasing the preload increases the ve-locity of shortening. Furthermore, increasing the pre-load shifts the x-intercept to the right, representing anincrease in isometric force generation.

LV Volume (ml)

0 200100

ControlLoop

ESV EDV

IncreasedAortic

Pressure

FIGURE 4-20 Effects of increased afterload (aortic pres-sure) on the steady-state left ventricular (LV) pressure-volume loop. Heart rate and inotropy are held constantin this illustration. Increased aortic pressure leads to anincrease in end-systolic volume (ESV), followed by a sec-ondary, but smaller increase in end-diastolic volume(EDV). The net effect is a narrower loop and thereforedecreased stroke volume.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

myocyte is increased, the force-velocity curvehas a parallel shift up and to the right, result-ing in an increase in both Vmax and maximalisometric force (Fig. 4-22). The increase in ve-locity at any given afterload results from theincreased inotropy enhancing force genera-tion by the actin and myosin filaments and in-creasing the rate of cross-bridge turnover. Theincrease in Vmax represents an increased in-trinsic capability of the muscle fiber to gener-ate force independent of load.

Effects of Inotropy on Pressure-VolumeLoopsThe increased velocity of fiber shortening thatoccurs with increased inotropy causes an in-creased rate of ventricular pressure develop-ment (dP/dt). This increases ejection velocityand stroke volume and reduces end-systolicvolume, as shown in Figure 4-23. When ino-tropy is increased, the end-systolic pressure-volume relationship is shifted to the left andbecomes steeper, because the ventricle cangenerate increased pressure at any given vol-ume. The end-systolic pressure-volume rela-tionship sometimes is used experimentally todefine the inotropic state of the ventricle. It is

analogous to the upward shift that occurs inthe total tension curve in the length-tensionrelationship (Fig. 4-21) when inotropy in-creases. Furthermore, the increased strokevolume leads to a reduction in ventricularend-diastolic volume because less end-systolicvolume is available to be added to the incom-ing venous return.

82 CHAPTER 4

IncreasedInotropy

Ten

sio

n

Length

PassiveTension

TotalTension

FIGURE 4-21 Effects of increased inotropy on thelength-tension relationship for cardiac muscle. In-creasing inotropy (for example, by stimulating the car-diac muscle with norepinephrine) shifts the total tension curve upward, which increases active tensiondevelopment (vertical arrows) at any given preloadlength.

Afterload (Force)

Sh

ort

en

ing

Ve

loci

ty

a b c

Increasing Inotropy a c

FIGURE 4-22 Effects of increasing inotropy (parallelshift from curve a to c) on the force-velocity relation-ship. Increased inotropy increases the velocity of short-ening at any given afterload, and increases Vmax (y-in-tercept). Furthermore, increased inotropy increasesmaximal isometric force (x-intercept).

LV Volume (ml)

0 200100

IncreasedInotropy

ControlLoop

ESV EDV

FIGURE 4-23 Effects of increasing inotropy on thesteady state of the left ventricular pressure-volumeloop. Heart rate and aortic pressure are held constant inthis illustration. Increased inotropy shifts the end-sys-tolic pressure-volume relationship (see Fig. 4-4) up andto the left, thereby decreasing end-systolic volume(ESV). A secondary, but smaller decrease in end-diastolicvolume (EDV) follows. The net effect is an increase instroke volume (EDV – ESV). LV, left ventricle.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

Effects of Inotropy on Frank-StarlingCurvesAn increase in inotropy causes the Frank-Starling curve to shift up and to the left (Fig.4-24). This leads to an increase in stroke vol-ume along with a reduction in ventricular pre-load. Conversely, a decrease in inotropy (asoccurs in systolic heart failure; see Chapter 9),shifts the relationship down and to the right,thereby decreasing stroke volume and in-creasing preload.

Changes in inotropy change the ejectionfraction, which is defined as the stroke vol-ume divided by the end-diastolic volume. Anormal ejection fraction is greater than 0.55(or 55%). Increasing inotropy increases ejec-tion fraction, whereas decreasing inotropy de-creases ejection fraction. Therefore, ejectionfraction often is used as a clinical index forevaluating the inotropic state of the heart. Inheart failure, for example, a decrease in in-otropy leads to a fall in stroke volume as wellas an increase in preload, thereby decreasingejection fraction sometimes to a value lessthan 20%. Treating a patient in heart failurewith an inotropic drug (e.g., -adrenoceptoragonist or digoxin) shifts the depressed Frank-Starling curve up and to the left, thereby in-

creasing stroke volume, decreasing preload,and increasing ejection fraction.

Changes in inotropic state are particularlyimportant during exercise (see Chapter 9).Increases in inotropic state help to maintainstroke volume at high heart rates. Increasedheart rate alone decreases stroke volume be-cause of reduced time for diastolic filling (de-creased end-diastolic volume). When ino-tropic state increases at the same time, thisdecreases end-systolic volume to help main-tain stroke volume.

Factors Influencing Inotropic StateSeveral factors influence inotropy (Fig. 4-25);the most important of these is the activity ofautonomic nerves. Sympathetic nerves, by re-leasing norepinephrine that binds to 1-adrenoceptors on myocytes, are prominent inventricular and atrial inotropic regulation (seeChapter 3). Parasympathetic nerves (vagal ef-ferents), which release acetylcholine thatbinds to muscarinic (M2) receptors on my-ocytes (see Chapter 3), have a significant neg-ative inotropic effect in the atria but only asmall effect in the ventricles. High levels ofcirculating epinephrine augment sympatheticadrenergic effects via 1-adrenoceptor activa-tion. In humans and some other mammalianhearts, an abrupt increase in afterload cancause a modest increase in inotropy (Anrepeffect) by a mechanism that is not fully un-derstood. In addition, an increase in heart ratecan cause a small positive inotropic effect(also termed the Bowditch effect, treppe, orfrequency-dependent activation). This latterphenomenon probably is due to an inability ofthe Na�/K�-ATPase to keep up with thesodium influx at higher frequency of actionpotentials at elevated heart rates, leading to anaccumulation of intracellular calcium via thesodium-calcium exchanger (see Chapter 2).Systolic failure that results from cardiomyopa-thy, ischemia, valve disease, arrhythmias, andother conditions is characterized by a loss ofintrinsic inotropy. In addition to these physio-logic and pathologic mechanisms, a variety ofinotropic drugs are used clinically to increaseinotropy in acute and chronic heart failure.These drugs include digoxin (inhibits sar-

CARDIAC FUNCTION 83

10

100

50

2000

LVEDP (mmHg)

Str

oke

Vol

ume

(ml)

B

AC

FIGURE 4-24 Effects of changes in inotropy on Frank-Starling curves. Decreased inotropy shifts the operatingpoint from A to B, which decreases stroke volume andincreases left ventricular end-diastolic pressure (LVEDP).Increased inotropy causes a shift from point A to C,which increases stroke volume and decreases LVEDP.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

colemmal Na�/K�-ATPase), -adrenoceptoragonists (e.g., dopamine, dobutamine, epi-nephrine, isoproterenol), and phosphodi-esterase inhibitors (e.g., milrinone).

Mechanisms of InotropyInotropy can be thought of as a length-inde-pendent activation of the contractile pro-teins. Any cellular mechanism that ultimately

84 CHAPTER 4

A 67-year-old male is diagnosed with left ventricular failure 4 months following an acutemyocardial infarction. One of the drugs he is given for treatment acts as a systemic arte-rial vasodilator. Using Frank-Starling curves and left ventricular pressure-volume loops,explain how decreasing afterload will improve left ventricular ejection fraction.

A systemic vasodilator reduces afterload on the left ventricle. This causes theStarling curve to shift up and to the left from its depressed state (because of the loss ofinotropy in failure) (left figure). This shift increases stroke volume and at the sametime reduces preload (end-diastolic pressure) from point A to B in left figure. Systemicvasodilation reduces aortic diastolic pressure, which enables the ventricle to ejectsooner, more rapidly, and to a smaller end-systolic volume (right figure). The reducedend-systolic volume leads to a compensatory decrease in end-diastolic volume; how-ever, the reduction in end-systolic volume will be greater than the reduction in end-diastolic volume so that stroke volume is increased. By increasing stroke volume and reducing the end-diastolic volume, the ejection fraction is increased.

CASE 4-3

10

100

50

2000S

tro

ke V

olu

me

(ml)

LVEDP (mmHg)

B

A

Non-failingHeart

FailingHeart

LV Volume (ml)

LV P

ress

ure

(m

mH

g)

200

100

00 200100

Heart Failure

Arterial Dilatorplus

HeartFailureLoop

Effects of an arterial vasodilator on stroke volumeand left ventricular end-diastolic pressure (LVEDP) inheart failure. In heart failure (specifically systolic fail-ure – see Chapter 9), the Frank-Starling curve shiftsdownward because of depressed inotropy. Arterialvasodilation, which reduces afterload on the ventri-cle, moves the operating point from A to B by shift-ing the Frank-Starling curve upward. This leads to anincrease in stroke volume and a decrease in LVEDP(preload).

Effects of an arterial vasodilator on left ventricularpressure-volume loops. Heart failure causes a down-ward shift (reduced slope) of the end-systolic pres-sure-volume relationship. This leads to an increase inend-systolic volume, a smaller compensatory in-crease in end-diastolic volume, and reduced strokevolume. Reducing arterial pressure decreases afterload on the ventricle, which leads to an increasein stroke volume. This decreases left ventricular end-systolic volume, and to a smaller extent, end-diastolic volume. The net effect is an increase instroke volume. LV, left ventricle.

Ch04_059-090_Klabunde 4/21/04 11:08 AM

alters myosin ATPase activity at a given sar-comere length alters force generation andtherefore can be considered an inotropicmechanism. Most of the signal transductionpathways that regulate inotropy involve Ca��

(see Chapter 3). Briefly, inotropic state can beenhanced by (1) increasing Ca�� influx acrossthe sarcolemma during the action potential(via L-type Ca�� channels); (2) increasing therelease of Ca�� by the sarcoplasmic reticu-lum; or (3) sensitizing troponin C to Ca��. Forexample, 1-adrenoceptor activation actingthrough Gs-proteins increases cAMP, whichactivates protein kinase-A. This enzyme canphosphorylate different intracellular sites toinfluence Ca�� entry, Ca�� release, and Ca��

affinity. Cardiac glycosides such as digoxin in-hibit the Na�/K�-ATPase, leading to an in-crease in intracellular Ca�� and an increase ininotropy.

MYOCARDIAL OXYGENCONSUMPTION

Changes in stroke volume, whether caused bychanges in preload, afterload, or inotropy, sig-nificantly alter the oxygen consumption of theheart. Changes in heart rate likewise affectmyocardial oxygen consumption. The con-tracting heart consumes a considerableamount of oxygen because of its need to re-generate the large amount of ATP hydrolyzedduring contraction and relaxation. Therefore,any change in myocardial function that affectseither the generation of force by myocytes or

their frequency of contraction will alter oxy-gen consumption. In addition, even in non-contracting cells, ATP utilized by ion pumpsand other transport functions requires oxygenfor the resynthesis of ATP.

How Myocardial OxygenConsumption is Determined

Oxygen consumption is defined as the volumeof oxygen consumed per min (e.g., mLO2/min) and is sometimes expressed per 100 gof tissue weight (mL O2/min per 100 g). Themyocardial oxygen consumption (MV� O2) canbe calculated by knowing the coronary bloodflow (CBF) and the arterial and venous oxy-gen contents (AO2 and VO2) according to thefollowing equation that uses the FickPrinciple:

MV�O2 � CBF � (AO2 � VO2)

Myocardial oxygen consumption, there-fore, is equal to the coronary blood flow mul-tiplied by the amount of oxygen extractedfrom the blood (the arterial-venous oxygendifference). The content of oxygen in blood isusually expressed as mL O2/100 mL blood (or,vol % O2). The oxygen content of arterialblood is normally about 20 mL O2/100 mLblood. To calculate the myocardial oxygenconsumption in the correct units, mL O2/100mL blood is converted to mL O2/mL blood;with this conversion, the arterial oxygen con-tent is 0.2 mL O2/mL blood. For example, ifCBF is 80 mL/min per 100 g, the AO2 is 0.2

CARDIAC FUNCTION 85

Catecholamines

Heart Rate(Bowditch Effect)Systolic

Failure

Afterload(Anrep Effect)

SympatheticActivationParasympathetic

Activation

_

_

Inotropic State(Contractility)

++

+ +

FIGURE 4-25 Factors regulating inotropy. (�), increased inotropy; (�), decreased inotropy.

Eq. 4-3

Ch04_059-090_Klabunde 4/21/04 11:08 AM

mL O2/mL blood and VO2 is 0.1 mL O2/mLblood, MV� O2 � 8 mL O2/min per 100 g. Thisvalue of myocardial oxygen consumption istypical for what is found in a heart contractingat resting heart rates against normal aorticpressures. During heavy exercise, myocardialoxygen consumption can increase to 70 mLO2/min per 100 g, or more. If contractions arearrested (e.g., by depolarization of the heartwith a high concentration of potassium chlo-ride), the myocardial oxygen consumption de-creases to about 2 mL O2/min per 100g. Thisvalue represents the energy costs of cellularfunctions not associated with contraction.Therefore, myocardial oxygen consumptionvaries considerably depending on the state ofmechanical activity.

Although myocardial oxygen consumptioncan be calculated as described above, gener-ally it is not feasible to measure coronaryblood flow and venous oxygen content exceptin experimental studies. Coronary blood flowcan be measured by placing flow probes oncoronary arteries or a thermodilution catheterwithin the coronary sinus. Arterial oxygencontent can be taken from a peripheral artery,but the venous oxygen content has to be ob-tained from the coronary sinus by inserting acatheter into the right atrium and then intothe coronary sinus.

Indirect indices of myocardial oxygen con-sumption have been developed to estimate

myocardial oxygen consumption when it is notfeasible to measure it. Although no index hasproven to be satisfactory over a wide range ofphysiologic conditions, one simple indexsometimes used in clinical studies is the pres-sure-rate product (also called the double-product). This index can be measured nonin-vasively by multiplying heart rate and systolicarterial pressure (mean arterial pressuresometimes is used instead of systolic arterialpressure). The pressure-rate product assumesthat the pressure generated by the ventricle isnot significantly different than the aortic pres-sure (i.e., there is no aortic valve stenosis).Experiments have shown that a reasonablecorrelation exists between changes in thepressure-rate product and myocardial oxygenconsumption. For example, if arterial pres-sure, heart rate, or both become elevated, oxy-gen consumption will increase.

Factors Influencing MyocardialOxygen Consumption

Part of the difficulty in finding a suitable indexof oxygen consumption is that several factorsdetermine myocyte oxygen consumption, in-cluding frequency of contraction, inotropicstate, afterload, and preload (Table 4-1). Forexample, doubling heart rate approximatelydoubles oxygen consumption, because myo-cytes are generating twice the number of ten-

86 CHAPTER 4

In an experimental study, administration of an inotropic drug is found to increase coro-nary blood flow (CBF) from 50 to 150 mL/min and increase the arterial-venous oxygendifference (AO2 – VO2) from 10 to 14 mL O2/100 mL blood. Calculate the percent in-crease in myocardial oxygen consumption (MV�O2) caused by infusion of this drug.

Myocardial oxygen consumption can be calculated from Equation 4-3, such that

MV�O2 � CBF � (AO2 � VO2)

The control oxygen consumption is 50 mL/min times the A-V oxygen difference of0.1 mL O2/mL blood, which equals 5 mL O2/min. Note that the arterial-venous oxygendifference must be converted from mL O2/100 mL blood to mL O2/mL blood. The experi-mental oxygen consumption is 150 mL/min times 0.14 mL O2/mL blood, which equals 21mL O2/min. This is a 320% increase in oxygen consumption ([(21 -5)/5] x 100).

PROBLEM 4-3

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sion cycles per minute. Increasing inotropy in-creases oxygen consumption because both therate of tension development and the magni-tude of tension are increased, and they bothare associated with increased ATP hydrolysisand oxygen consumption. An increase in af-terload likewise increases oxygen consump-tion because it increases the tension that mustbe developed by myocytes. Increasing strokevolume by increasing preload (end-diastolicvolume) also increases oxygen consumption.

Quantitatively, increased preload has lessimpact on oxygen consumption than does anincrease in afterload (e.g., aortic pressure). Tounderstand why, we need to examine the rela-tionship between wall stress, pressure, and ra-dius of the ventricle. As discussed earlier (seeEquation 4-2), ventricular wall stress (�) isproportional to the intraventricular pressure(P) multiplied by the ventricular internal ra-dius (r) and divided by the wall thickness (h).

� ∝

Wall stress is related to the tension an indi-vidual myocyte must develop during contrac-tion to generate a given ventricular pressure.At a given radius and wall thickness, a my-ocyte must generate increased contractileforce (i.e., wall stress) to develop a higherpressure. The contractile force must be in-creased even further to generate the same el-evated pressure if the ventricular radius is in-creased. For example, if the ventricle isrequired to generate 50% more pressure thannormal to eject blood because of elevated aor-

P � r

h

tic pressure, the wall stress that individualmyocytes must generate will be increased byapproximately 50%. This will increase the oxy-gen consumption of these myocytes by about50% because changes in oxygen consumptionare closely related to changes in wall stress. Asa second example, if the radius of the ventri-cle is increased by 50%, the wall stress neededby the myocytes to eject blood at a normalpressure will be increased by about 50%. Onthe other hand, if the ventricular end-diastolicvolume is increased by 50% and the pressureand wall thickness remain unchanged, thewall stress will be increased by only about14%. The reason for this is that a large changein ventricular volume (V) requires only a smallchange in radius (r). If we assume that theshape of the ventricle is a sphere, then

V � � � r3

By rearranging this relationship, we find that

r ∝ 3�V�

Substituting this into the wall stress equationresults in

� ∝

Although no single acceptable model for theshape of the ventricle exists because its shapechanges during contraction, a sphere serves asa convenient model for illustrating whychanges in volume have a relatively small af-fect on wall stress and oxygen consumption.Using this model, Equation 4-4 shows that in-creasing the end-diastolic volume by 50% (bya factor of 1.5) represents only a 14% (cuberoot of 1.5) increase in wall stress at a givenventricular pressure, whereas a 50% increasein pressure increases wall stress by 50%.Therefore, increasing pressure by a given per-centage increases wall stress about four timesmore than the same change in volume.

Relating the wall stress equation to oxygenconsumption helps to explain why increases inpressure generation have a much greater in-fluence on oxygen consumption than a similarpercentage increase in ventricular preload. Itis important, however, not to use the wall

P � 3�V�

h

43

CARDIAC FUNCTION 87

TABLE 4-1 FACTORS INCREASINGMYOCARDIAL OXYGENCONSUMPTION

↑ Heart Rate

↑ Inotropy

↑ Afterload

↑ Preload*

*Changes in preload affect oxygen consumptionmuch less than do changes in the other factors.

Eq. 4-4

Ch04_059-090_Klabunde 4/21/04 11:08 AM

stress equation to estimate oxygen demandsby the whole heart. The reason for this is thatwall stress estimates the tension required byindividual myocytes to generate pressure asthey contract. This wall stress, in large part,determines the oxygen consumption of indi-vidual myocytes, but oxygen consumption ofthe whole heart is the sum of the oxygen con-sumed by all of the myocytes. A hypertro-phied ventricle with a thicker wall, which hasreduced wall stress, may not have a reductionin overall oxygen consumption as suggested byEquation 4-4. In fact, because of its greatermuscle mass, oxygen consumption may be sig-nificantly increased in a hypertrophied heart,particularly if its efficiency is impaired by dis-ease. A less efficient heart performs less workper unit oxygen consumed (i.e., it generatesless pressure and stroke volume).

The concepts described above have impli-cations for treating patients with coronaryartery disease (CAD). For example, drugs thatdecrease afterload, heart rate, and inotropyare particularly effective in reducing myocar-dial oxygen consumption and relieving symp-toms of chest pain (i.e., angina), which resultsfrom inadequate oxygen delivery relative tothe oxygen demands of the myocardium.CAD patients are counseled to avoid activitiessuch as lifting heavy weights that lead to largeincreases in arterial blood pressure. In con-trast, CAD patients are often encouraged toparticipate in exercise programs such as walk-ing that utilize preload changes to augmentcardiac output by the Frank-Starling mecha-nism. It is important to minimize stressful sit-uations in these patients because stress causessympathetic activation of the heart and vascu-lature that increases heart rate, inotropy, andafterload, all of which lead to significant in-creases in oxygen demand by the heart.


• The cardiac cycle is divided into two gen-eral phases: diastole and systole. Diastolerefers to the period of time that the ventri-cles are undergoing relaxation and fillingwith blood from the atria. Ventricular filling

is primarily passive, although atrial contrac-tion has a variable effect on the final extentof ventricular filling (end-diastolic volume).Systole, or ventricular contraction, is initi-ated by electrical depolarization of the ven-tricles, which is represented by the QRScomplex of the electrocardiogram.Ventricular ejection begins when ventricu-lar pressure exceeds the pressure within theoutflow tract (aorta or pulmonary artery)and continues until ventricular relaxationcauses the ventricular pressures to fall suffi-ciently below the aortic and pulmonaryartery pressures to cause the aortic and pul-monic valves to close. The volume of bloodremaining in the ventricle at the end ofejection is the end-systolic volume.

• The first heart sound (S1) originates fromclosure of the atrioventricular valves (tri-cuspid and mitral) as the ventricles begin tocontract. The second heart sound (S2) re-sults from the closure of the pulmonic andaortic valves at the end of ventricular sys-tole. The third and fourth heart sounds (S3

and S4), when audible, occur during earlydiastole and atrial contraction, respectively.

• Ventricular stroke volume is the differencebetween the end-diastolic and end-systolicvolumes. Ventricular ejection fraction iscalculated as the stroke volume divided bythe end-diastolic volume. Ejection fractionis frequently used in a clinical setting to as-sess the inotropic state of the left ventricle.

• Cardiac output is the product of stroke vol-ume and heart rate. Normally, cardiac out-put is influenced more by changes in heartrate than by changes in stroke volume;however, impaired regulation of stroke vol-ume can have a significant adverse affecton cardiac output, as occurs during heartfailure.

• Ventricular preload is related to the extentof ventricular filling (end-diastolic volume)and the sarcomere length. Preload can beincreased by several factors: increasedblood volume, augmented venous return,decreased venous compliance (venous con-striction), atrial contraction force, and de-creased heart rate (increases filling time);indirectly, preload can be increased by a

88 CHAPTER 4

Ch04_059-090_Klabunde 4/21/04 11:08 AM

loss of ventricular inotropy or an increasein afterload.

• Increased preload increases the force ofcontraction. The length-tension diagram,in which an increase in preload increasesactive tension, shows this. Additionally, in-creased preload increases the velocity offiber shortening, as shown by a shift in theforce-velocity relationship to the right. Byitself, an increase in preload increasesstroke volume (Frank-Starling mecha-nism) without changing the end-systolicvolume.

• Ventricular afterload can be estimated byventricular wall stress, which is the productof ventricular pressure and ventricular ra-dius divided by the ventricular wall thick-ness. Therefore, left ventricular afterload(wall stress) is increased by elevated ven-tricular pressures during systole (e.g., asoccurs in hypertension) or when the ventri-cle is dilated (increased radius). Increasedwall thickness, as occurs in hypertrophy, re-duces the wall stress experienced by indi-vidual myocytes.

• Increased afterload decreases the velocityof fiber shortening during contraction, asshown by the force-velocity relationship. Inthe whole heart, this reduces stroke vol-ume and increases end-systolic volume at agiven preload and causes the Frank-Starling curve to shift downward. In addi-tion, increased afterload increases end-diastolic volume secondarily to the increasein end-systolic volume.

• Inotropy is the property of a cardiac myo-cyte that enables it to alter its tension development independent of changes inpreload length. Autonomic nerves and cir-culating catecholamines are importantmechanisms for regulating inotropy, al-though increases in afterload and heart ratecan augment inotropy. Loss of inotropy re-sults in heart failure.

• Increased inotropy enhances active tensiondevelopment by individual muscle fibersand increases ventricular pressure develop-ment, ejection velocity, and stroke volumeat a given preload and afterload. Increasedinotropy normally leads to a reduction in

preload secondary to the decrease in end-systolic volume.

• Myocardial oxygen consumption can becalculated using the Fick Principle, inwhich oxygen consumption equals theproduct of the coronary blood flow and thearteriovenous oxygen difference. Myo-cardial oxygen consumption is strongly in-fluenced by changes in arterial pressure,heart rate, and inotropy; it is less influ-enced by changes in stroke volume.

Review Questions

Please refer to the appendix for the answersto the review questions.For each question, choose the one best answer:

1. During the phase of rapid ventricularfilling,

a. S4 may sometimes be heard.b. The aortic valve is open.c. The mitral valve is open.d. Ventricular pressure is higher than

aortic pressure.

2. Right ventricular preload is increased bywhich of the following?

a. Decreased atrial contractilityb. Decreased blood volumec. Decreased heart rated. Decreased ventricular compliance

3. As the preload on a ventricular myocyteis increased,

a. Active tension development increases.b. Inotropy decreases.c. Sarcomere length decreases.d. Velocity of shortening decreases.

4. Left ventricular end-diastolic pressure isincreased by

a. Decreased afterload.b. Decreased venous return.c. Increased inotropy.d. Ventricular hypertrophy.

5. Ventricular stroke volume is reduced bya. Decreased inotropy.b. Increased venous return.c. Reduced afterload.d. Reduced heart rate.

CARDIAC FUNCTION 89

Ch04_059-090_Klabunde 4/28/04 10:18 AM

6. Left ventricular end-systolic volume isa. Decreased when aortic pressure is

suddenly increased.b. Greater than end-diastolic volume.c. Increased when inotropy is im-

paired.d. Reduced at increased preloads.

7. Myocardial inotropic state is enhanced bya. �1-adrenoceptor mediated increases

in cAMP.b. Decreasing heart rate.c. Inhibiting slow inward calcium

movement.d. Vagal activation.

8. Increasing the inotropic state of themyocardium will

a. Increase end-systolic volume.b. Increase the width of the pressure-

volume loop.c. Increase ventricular end-diastolic

volume.d. Shift the force-velocity relationship

to the left.

9. Increased afterload on the ventriclea. Decreases end-systolic volume.

b. Decreases the velocity of shortening.c. Increases stroke volume.d. Increases Vmax in the force-velocity

relationship.

10. If each of the following is increased by50%, which one would cause the smallestchange in myocardial oxygen consump-tion?

a. Heart rateb. Ventricular end-diastolic volumec. Mean arterial pressured. Ventricular radius

SUGGESTED READINGSBraunwald E, Ross J, Sonnenblick EH. Mechanisms of

Contraction of the Normal and Failing Heart. 2ndEd. Boston: Little, Brown & Co, 1976.

Covell JW, Ross J: Systolic and diastolic function (me-chanics) of the intact heart. In: Page E, Fozzard HA,Solaro RJ, eds. Handbook of Physiology, vol. 1.Bethesda: American Physiological Society,2002:741–785.

Fuchs F, Smith SH. Calcium, cross-bridges, and theFrank-Starling relationship. News Physiol Sci2001;16:5–10.

Katz AM. Physiology of the Heart. 3rd Ed. Philadelphia:Lippincott Williams & Wilkins, 2001.

Lilly LS. Pathophysiology of Heart Disease. 3rd Ed.Philadelphia: Lippincott Williams & Wilkins, 2003.

Opie LH. The Heart: Physiology from Cell toCirculation. 3rd Ed. Philadelphia: LippincottWilliams & Wilkins, 1998.

Sagawa K, Maughan L, Suga H, Sunagawa K. CardiacContraction and the Pressure-Volume Relationship.New York: Oxford University Press, 1988.

90 CHAPTER 4

Ch04_059-090_Klabunde 4/28/04 10:18 AM

CD-ROM MATERIALSLEARNING OBJECTIVESINTRODUCTIONANATOMY AND FUNCTION

Vascular NetworkDistribution of Pressures and

VolumesARTERIAL BLOOD PRESSURE

Aortic Pulse PressureMean Arterial PressureHemodynamics (Pressure, Flow and

Resistance)REGULATION OF SYSTEMIC VASCULAR

RESISTANCECalculation of Systemic Vascular

Resistance

Vascular ToneVENOUS BLOOD PRESSURE

Venous Blood Volume and Compliance

Mechanical Factors Affecting CentralVenous Pressure and Venous Return

VENOUS RETURN AND CARDIAC OUTPUTThe Balance between Venous Return

and Cardiac OutputSystemic Vascular Function CurvesCardiac Function CurvesInteractions between Cardiac and

Systemic Vascular Function CurvesSUMMARY OF IMPORTANT CONCEPTSREVIEW QUESTIONSSUGGESTED READINGS

c h a p t e r

5Vascular Function

Critical StenosisValsalva Maneuver

CD CONTENTS

LEARNING OBJECTIVES

Understanding the concepts presented in this chapter will enable the student to:1. Name the different types of vessels constituting the vascular network of the body and

describe the general function of each.2. Describe the factors that determine arterial pulse pressure.3. Describe how changes in cardiac output, systemic vascular resistance, and central venous

pressure affect mean arterial pressure.4. Describe in quantitative terms how changes in vessel radius, vessel length, blood viscos-

ity, and perfusion pressure affect blood flow.5. Calculate total resistance from series or parallel resistance networks.6. Explain why the pressure drop across small arteries and arterioles is much greater than

the pressure drop across other vessel types.7. Define vascular tone and list factors that alter vascular tone.8. Explain how each of the following affects central venous pressure: blood volume, venous

compliance, gravity, respiration, and muscle contraction.9. Define mean circulatory filling pressure and explain what determines its value.

10. Using cardiac and systemic function curves, explain how changes in blood volume, ve-nous compliance, vascular resistance, and cardiac performance influence the equilibriumbetween right atrial pressure and cardiac output.

91

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INTRODUCTION

The vascular system serves two basic func-tions: distribution and exchange. Distributionincludes transporting blood to and away fromorgans. The anatomical arrangement of thevasculature and physiologic control mecha-nisms that dilate or constrict blood vessels de-termine this transport. Changes in vessel di-ameters regulate blood pressure anddetermine the amount of blood flow to spe-cific organs and regions within organs. Thischapter focuses on vascular anatomy and thegeneral principles involved in the regulationof blood pressure and blood flow. Chapters 6and 7 describe these physiologic controlmechanisms in more detail. The exchangefunction is described in Chapter 8.

ANATOMY AND FUNCTION

Vascular Network

The left ventricle ejects blood into the aorta,which then distributes the blood flowthroughout the body using a network of arter-ial vessels. These vessels are illustrated inFigure 5-1. Table 5-1 summarizes the relativesizes and functions of different blood vessels.

The aorta, besides being the main vesselto distribute blood from the heart to the arte-rial system, dampens the pulsatile pressurethat results from the intermittent ejection ofblood from the left ventricle. The dampeningis a function of the aortic compliance, which isdiscussed in more detail later in this chapter.Large arteries branching off the aorta (e.g.,carotid, mesenteric, and renal arteries) dis-

92 CHAPTER 5

Aorta

LargeArtery

Arteriole

Capillaries

Venule

VenaCava

Vein

SmallArtery

FIGURE 5-1 Major types of blood vessels found within the circulation.

TABLE 5-1 SIZE AND FUNCTION OF DIFFERENT TYPES OF BLOOD VESSELS INTHE SYSTEMIC CIRCULATION

VESSEL TYPE DIAMETER (MM) FUNCTION

Aorta 25 Pulse dampening and distribution

Large arteries 1.0–4.0 Distribution

Small arteries 0.2–1.0 Distribution and resistance

Arterioles 0.01–0.20 Resistance (pressure/flow regulation)

Capillaries 0.006–0.010 Exchange

Venules 0.01–0.20 Exchange, collection, and capacitance

Veins 0.2–5.0 Capacitance function (blood volume)

Vena cava 35 Collection

Ch05_091-116_Klabunde 4/21/04 11:21 AM

tribute the blood flow to specific organs or re-gions of the body. These large arteries, al-though capable of constricting and dilating,serve no significant role in the regulation ofpressure and blood flow under normal physio-logic conditions. Once the distributing arteryreaches the organ to which it supplies blood, itbranches into smaller arteries that distrib-ute blood flow within the organ. These smallerarteries continue branching into smaller andsmaller vessels. Once they reach diameters ofless 200 �m, they are termed arterioles. Noclear demarcation between small arteries andarterioles exists; therefore, no consensus hasbeen reached regarding the point at which asmall artery becomes an arteriole. Many in-vestigators speak of different branching or-ders of arterial vessels within a tissue or organ.Most would agree that arterioles have only afew layers of vascular smooth muscle and are,in general, less than 200 �m in diameter.

Together, the small arteries and arteriolesrepresent the primary resistance vessels thatregulate arterial blood pressure and bloodflow within organs. Resistance vessels arehighly innervated by autonomic nerves (par-ticularly sympathetic adrenergic), and theyconstrict or dilate in response to changes innerve activity. The resistance vessels are richlyendowed with receptors that bind circulatinghormones (e.g., catecholamines, angiotensinII), which can alter vessel diameter (seeChapters 3 and 6). They also respond to vari-ous substances (e.g., adenosine, potassiumion, and nitric oxide) produced by the tissuesurrounding the vessel or by the vascular en-dothelium.

As arterioles become smaller in diameter(�10 �m), they lose their smooth muscle.Vessels that have no smooth muscle and arecomposed of only endothelial cells and a base-ment membrane are termed capillaries.Although they are the smallest vessels withinthe circulation, they have the greatest cross-sectional area because they are so numerous.Because the total blood flow of capillaries isthe same as the flow within the aorta leavingthe heart, and because the capillary cross-sectional area is about 1000 times greater thanthe aorta, the mean velocity of blood flowing

within capillaries (0.05 cm/sec) is about onethousand-fold less than the velocity in theaorta (50 cm/sec). The reason for this is thatflow (F) is the product of mean velocity (V)times cross-sectional area (A) (F � V·A).When this expression is rearranged, we findthat the mean velocity is inversely propor-tional to cross-sectional area (V � F/A).

Capillaries have the greatest surface areafor exchange. Endothelium, oxygen, carbondioxide, water, electrolytes, proteins, meta-bolic substrates and by-products, and circulat-ing hormones are exchanged across the capil-lary between the plasma and the tissueinterstitium surrounding it (see Chapter 8).Capillaries, therefore, are the primary ex-change vessels within the body.

When capillaries join together, they formpost-capillary venules, which serve as ex-change vessels for fluid and macromoleculesbecause of their high permeability. As post-capillary venules converge and form largervenules, smooth muscle reappears. These ves-sels, like the resistance vessels, are capable ofdilating and constricting. Changes in venulardiameter regulate capillary pressure and ve-nous blood volume.

Venules converge to form larger veins.Together, venules and veins are the primarycapacitance vessels of the body, i.e., the sitewhere most of the blood volume is found andregional blood volume is regulated. Con-striction of veins decreases venous blood vol-ume and increases venous pressure, which canalter cardiac output by affecting right atrialand ventricular preload. The final venous ves-sels are the inferior and superior vena cavae,which carry the blood back to the right atriumof the heart.

Distribution of Pressures and Volumes

Blood pressure is highest in the aorta and pro-gressively decreases as the blood flows furtheraway from the heart (Fig. 5-2). The mean aor-tic pressure is about 95 mm Hg in a normaladult. The mean blood pressure does not fallmuch as the blood flows down the aorta andthrough large distributing arteries. The reason

VASCULAR FUNCTION 93

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for this is that the aorta and large arteries haverelatively little resistance to flow, and there-fore little loss of pressure energy occurs alongtheir lengths. It is not until the blood reachesthe small arteries and arterioles (the primaryresistance vessels) that there is a large fall inmean arterial blood pressure. Approximately50% to 70% of the pressure drop within thevasculature occurs within the resistance ves-sels. The reason for this is that small arteriesand arterioles, as a group, have the highest re-sistance to flow and therefore produce thegreatest pressure drop along their length. Bythe time blood reaches the capillaries themean blood pressure may be 25–30 mm Hg,depending on the organ. It is important thatthe capillary pressure is relatively low; other-wise, large amounts of fluid would leakthrough the capillaries (and post-capillaryvenules), causing tissue edema (see Chapter8). The pressure falls further as blood travelsthrough veins back to the heart. Pressurewithin the thoracic vena cava near the rightatrium is very close to zero, although it fluctu-ates by a few millimeters of mercury (mm Hg)during the cardiac cycle and because of respi-ratory activity.

The greatest volume (60% to 80%) ofblood within the circulation resides within thevenous vasculature. This is why veins are re-

ferred to as capacitance vessels. The relativevolume of blood between the arterial and venous sides of the circulation can vary con-siderably depending on total blood volume,intravascular pressures, and vascular compli-ance. The latter varies depending on the stateof venous contraction, which is primarily reg-ulated by sympathetic nerves innervating theveins.

ARTERIAL BLOOD PRESSURE

Ejection of blood into the aorta by the leftventricle results in a characteristic aortic pres-sure pulse (Fig. 5-3). The peak pressure of theaortic pulse is termed the systolic pressure,and the lowest pressure in the aorta, which is

94 CHAPTER 5

MeanPressure(mmHg)

PercentTotal

Volume

or

FIGURE 5-2 Distribution of pressures and volumes in the systemic circulation. The greatest pressure drop occursacross small arteries and arterioles; most of the blood volume is found within the veins and venules.

Pdiastolic

Pdiastolic

Psystolic

Psystolic

Pmean

Pulse Pressure =

FIGURE 5-3 Pressure pulse within the aorta. The pulsepressure is the difference between the maximal pressure(systolic) and the minimal pressure (diastolic). The meanpressure is approximately equal to the diastolic pressureplus one-third the pulse pressure.

Ch05_091-116_Klabunde 4/21/04 11:21 AM

found just before the ventricle ejects bloodinto the aorta (see Fig. 4-2), is termed the di-astolic pressure. The difference betweenthe systolic and diastolic pressures is the aor-tic pulse pressure. If, for example, the sys-tolic pressure is 130 mm Hg and the diastolicpressure is 85 mm Hg, then the pulse pres-sure is 45 mm Hg. Therefore, any factor thataffects either systolic or diastolic pressures af-fects pulse pressure.

As blood flows down the aorta and into dis-tributing arteries, characteristic changes takeplace in the shape of the pressure wave contour.As the pressure pulse moves away from theheart, the systolic pressure rises, and the dias-tolic pressure falls. Although it is not clear whythe pressure pulse changes shape, it probably isrelated to a number of factors including (1) de-creased compliance of distal arteries and (2) re-flective waves, particularly from arterial branchpoints, which summate with the pulse wavetraveling down the aorta and arteries. In addi-tion, mean arterial pressure declines as thepressure pulse travels down distributing arteriesowing to the resistance of the arteries; however,the reduction in mean pressure is small (just afew mm Hg) because the distributing arterieshave a relatively low resistance. Therefore, thevalues measured for arterial pressure differ de-pending on the site of measurement. When thearterial pressure is measured using a sphygmo-manometer (i.e., blood pressure cuff) on theupper arm, the pressure measurement repre-sents the pressure within the brachial artery.The measured pressures, however, are not iden-tical with the systolic and diastolic pressuresfound in the aorta or the pressures measured inother distributing arteries.

Aortic Pulse Pressure

The compliance of the aorta and the ventricu-lar stroke volume determines pulse pressure.Compliance is defined by the relationshipbetween volume and pressure, in which com-pliance equals the slope of that relationship,or the change in volume (�V) divided by thechange in pressure (�P) at a given pressure(see Compliance from Chapter 4 on CD). Thecompliance of a blood vessel is determined in

large part by the relative proportion of elastinfibers versus smooth muscle and collagen inthe vessel wall (see Fig. 3-7). Elastin fibers of-fer the least resistance to stretch, whereas col-lagen offers the greatest resistance. A vesselsuch as the aorta that has a greater proportionof elastin fibers versus smooth muscle and col-lagen has a relatively low resistance to stretchand therefore has the greatest compliance.

The relatively high compliance of the aortadampens the pulsatile output of the left ventri-cle, thereby reducing the pulse pressure. If theaorta were a rigid tube, the pulse pressurewould be very high. However, as blood isejected into the aorta, the walls of the aorta ex-pand to accommodate the increase in bloodvolume contained within the aorta because theaorta is compliant. As the aorta expands, theincrease in pressure is determined by changein aortic volume divided by the compliance ofthe aorta at that particular range of volumes.The more compliant the aorta, the smaller thepressure change (i.e., pulse pressure) at anygiven change in aortic volume (Fig. 5-4).

A change in compliance affects only pulsepressure and not the mean pressure, which re-mains unchanged as long as cardiac outputand systemic vascular resistance do notchange. In contrast, a change in stroke volumechanges mean aortic pressure in addition topulse pressure if the cardiac output changes.For example, if stroke volume and cardiacoutput are increased by an increase in in-otropy, both pulse pressure and mean arterialpressure increase. If, however, cardiac outputis not changed when stroke volume changes(e.g., if a decrease in heart rate accompaniesthe increase in stroke volume), then only thepulse pressure changes—the mean aorticpressure does not change.

No single value for aortic compliance existsbecause the relationship between volume andpressure is not linear. At higher volumes andpressures, the slope of the relationship de-creases and compliance decreases. Therefore,at very high mean arterial pressures, the re-duced compliance results in an increase inpulse pressure at a given stroke volume. Ageand arteriosclerotic disease also decrease aor-tic compliance, which increases aortic pulse


Ch05_091-116_Klabunde 4/21/04 11:21 AM

pressure (see Fig. 5-4). It is common for el-derly people to have aortic pulse pressures of60 mm Hg or more, whereas younger adultshave aortic pulse pressures of about 40-45mm Hg at resting heart rates.

In summary, aortic pulse pressure is deter-mined by ventricular stroke volume and aorticcompliance (Fig. 5-5). Any factor that changesstroke volume (e.g., ventricular preload, after-load and inotropy; heart rate) or aortic compli-ance (e.g., age, arteriosclerosis, hypertension)alters aortic pulse pressure. Beat-to-beatchanges in pulse pressure occur owing tochanges in stroke volume. In contrast, chronic,long-term increases in pulse pressure are dueto decreased aortic compliance.

Mean Arterial Pressure

Because of the shape of the aortic pressurepulse, the value for the mean pressure (geo-metric mean) is less than the arithmetic aver-age of the systolic and diastolic pressures asshown in Figure 5-3. At normal resting heartrates, mean aortic (or arterial) pressure (MAP)can be estimated from the diastolic (Pdias) andsystolic (Psys) pressures by Equation 5-1:

MAP � Pdias � 1⁄3 (Psys � Pdias)

For example, if systolic pressure is 120 mmHg and diastolic pressure is 80 mm Hg, the

mean arterial pressure will be approximately93 mm Hg. At high heart rates, however,mean arterial pressure is more closely approx-imated by the arithmetic average of systolicand diastolic pressure because the shape of

96 CHAPTER 5

40 404080 8080120 120120160 160160

Aortic Pressure(mmHg)



↑∆V

↑PP ↑PPPPAor

tic V

olum

e

∆V∆V

NormalDecreasedCompliance

FIGURE 5-4 Effects of stroke volume and aortic compliance on aortic pulse pressure. At a given aortic compliance,increasing the stroke volume (�V) into the aorta increases the pulse pressure (PP). At a given stroke volume, de-creasing the aortic compliance (decreased slope of �V/�P) increases the pulse pressure.

Aortic PulsePressure

AgeArteriosclerosisHypertension

Inotropy Heart Rate

AfterloadPreload

StrokeVolume

AorticCompliance

FIGURE 5-5 Factors affecting aortic pulse pressure.Pulse pressure is increased by those factors that increasestroke volume or decrease aortic compliance.

Eq. 5-1

Ch05_091-116_Klabunde 4/21/04 11:21 AM

the arterial pressure pulse changes (it be-comes narrower) as the period of diastoleshortens more than does systole. Therefore, todetermine mean arterial pressure accurately,analog electronic circuitry or digital tech-niques are used. In clinical practice (e.g., dur-ing routine blood pressure measurement us-ing a sphygmomanometer), only systolic anddiastolic arterial pressures are measured.Mean arterial pressure, however, is neededwhenever hemodynamic information is re-quired to assess systemic vascular function.

No single value exists for normal mean ar-terial pressure. In infant children, the meanarterial pressure may be only 70 mm Hg,whereas in older adults, mean arterial pres-sure may be 100 mm Hg. With increasing age,the systolic pressure generally rises more thandiastolic pressure; therefore, the pulse pres-sure increases with age. Small differences ex-ist between men and women, with womenhaving slightly lower pressures at equivalentages. In adults, arterial pressure is considerednormal when the systolic pressure is less than120 mm Hg (but > 90 mm Hg) and the dia-stolic pressure is less than 80 mm Hg (but > 60 mm Hg), which represents a normalmean pressure of less than 95 mm Hg.Abnormally low and elevated arterial pres-sures are discussed in Chapter 9.

What factors determine mean arterial pres-sure? As blood is pumped into the resistancenetwork of the systemic circulation, pressureis generated within the arterial vasculature.The mean arterial pressure (MAP) is deter-mined by the cardiac output (CO), systemicvascular resistance (SVR), and central venouspressure (CVP) as shown in Equation 5-2,which is based on the relationship betweenflow, pressure, and resistance as described inthe next section.

MAP � (CO • SVR) � CVP

Therefore, changes in cardiac output, sys-temic vascular resistance or central venouspressure affect mean arterial pressure. If car-diac output and systemic vascular resistancechange reciprocally and proportionately, MAPwill not change. For example, if cardiac out-put is reduced by one-half and systemic vas-

cular resistance is doubled, mean arterialpressure will remain unchanged.

Figure 5-6, which is based upon Equation5-2, shows that as cardiac output is increased,a linear increase occurs in arterial pressure(assuming that resistance and venous pressureremain constant). An increase in resistance(increased slope of the line) results in agreater arterial pressure for any given cardiacoutput. Conversely, a decrease in resistanceresults in a lower arterial pressure for anygiven cardiac output.

Cardiac output, systemic vascular resistance,and venous pressure are constantly changing,and they are interdependent (i.e., changing onevariable can change each of the other variables).For example, increasing systemic vascular resis-tance increases the afterload on the heart,which decreases cardiac output and central ve-nous pressure, as described in more detail laterin this chapter. Furthermore, extrinsic controlmechanisms acting on the heart and circulationcan affect these variables. If, for example, car-diac output suddenly falls by 20% (as can occurwhen standing), mean arterial pressure will not decrease by 20% because the body compen-sates by increasing systemic vascular resistancethrough baroreceptor mechanisms to maintainconstant pressure (see Chapter 6).


Cardiac Output

Me

an

Art

eri

al P

ress

ure

CVP

↓SVR

↑SVR

FIGURE 5-6 The relationship between cardiac output(CO), systemic vascular resistance (SVR), mean arterialpressure (MAP), and central venous pressure (CVP).Increasing SVR increases MAP at any given cardiac out-put, whereas decreasing SVR decreases MAP at a givencardiac output. This figure is based on Equation 5-2, inwhich MAP � (CO x SVR) � CVP.

Eq. 5-2

Ch05_091-116_Klabunde 4/21/04 11:21 AM

Hemodynamics (Pressure, Flow, and Resistance)

The term hemodynamics describes thephysical factors governing blood flow withinthe circulatory system. Blood flow through anorgan is determined by the pressure gradient(�P) driving the flow divided by the resistance(R) to flow (Equation 5-3). The pressure gra-dient (or perfusion pressure) driving flowthrough an organ is the arterial minus the ve-nous pressure. For an individual blood vessel,the pressure gradient is the pressure differ-ence between two defined points along thevessel. Equation 5-3 is a hydrodynamic formof Ohm’s Law, where current (I) equals thevoltage difference (�V) divided by resistance(R).

F �

By rearranging Equation 5-3, we see that thedriving pressure across an organ or along thelength of a vessel is determined by the prod-uct of the flow and resistance (Equation 5-4).

�P � F � R

Equation 5-4 serves as the basis for Equation5-2 in which cardiac output is substituted forflow, systemic vascular resistance is substi-tuted for resistance, and mean arterial pres-sure minus central venous pressure is substi-tuted for the pressure gradient. Thesecomponents are then rearranged to solve formean arterial pressure.

Blood flow through organs (as well asthrough the entire systemic circulation) is de-termined largely by changes in resistance be-cause arterial and venous pressures are nor-mally maintained within a narrow range byvarious feedback mechanisms. Therefore, it isimportant to understand what determines re-sistance in individual vessels and within vascu-lar networks.

Effects of Vessel Length, Radius, and BloodViscosity on Resistance to Blood FlowThree factors determine the resistance (R) toblood flow within a single vessel: vessel length(L), blood viscosity () and diameter (or ra-

�PR

dius, r) of the vessel. These are described byEquation 5-5 as follows:

R ∝

Resistance is directly proportional to vessellength. Therefore, a vessel that is twice as longas another vessel with the same radius willhave twice the resistance to flow. In the body,individual vessel lengths do not change appre-ciably; therefore, changes in vessel lengthhave only a minimal effect on resistance.

Resistance to flow is directly related to theviscosity of the blood. For example, if viscosityincreases two-fold, the resistance to flow in-creases two-fold. At normal body tempera-tures, the viscosity of plasma is about 1.8 timesthe viscosity of water. The viscosity of wholeblood is about three to four times the viscosityof water owing to the presence of red cells andproteins. Blood viscosity normally does notchange much; however, it can be significantlyaltered by changes in hematocrit and temper-ature and by low flow states. Hematocrit is thevolume of red blood cells expressed as a per-centage of a given volume of whole blood. Ifhematocrit increases from a normal value of40% to an elevated value of 60% (this istermed polycythemia), the blood viscosity ap-proximately doubles. Decreasing blood tem-perature increases viscosity by about 2% perdegree Centigrade. The flow rate of blood alsoaffects viscosity. At very low flow states in themicrocirculation—as occurs during circula-tory shock—the blood viscosity can increaseseveral-fold. This occurs because at low flowstates, cell-to-cell and protein-to-cell adhesiveinteractions increase, which can cause eryth-rocytes to adhere to one another and increasethe blood viscosity.

Vessel radius is the most important factordetermining resistance to flow. Because radiusand resistance are inversely related, an in-crease in radius reduces resistance. Further-more, a change in radius alters resistance in-versely to the fourth power of the radius. Forexample, a two-fold increase in radius de-creases resistance sixteen-fold! Therefore,vessel resistance is exquisitely sensitive tochanges in radius. Because changes in radius

� L

r4

98 CHAPTER 5

Eq. 5-3

Eq. 5-5

Eq. 5-4

Ch05_091-116_Klabunde 4/21/04 11:21 AM

and diameter are directly proportional, diam-eter can be substituted for radius in Equation5-5.

If the expression for resistance (Equation5-5) is combined with the equation describingthe relationship between flow, pressure, andresistance (F��P/R; Equation 5-3), the fol-lowing relationship is obtained:

F ∝ �

This relationship (Poiseuille’s equation)was first described by the French physicianPoiseuille (1846). The full equation contains πin the numerator, and the number 8 in the de-nominator (a constant of integration).Equation 5-6 describes how flow is related toperfusion pressure, radius, length, and viscos-ity. In the body, however, flow does not con-form precisely to this relationship because theequation assumes the following: (1) the ves-sels are long, straight, rigid tubes; (2) theblood behaves as a Newtonian fluid in whichviscosity is constant and independent of flow;and (3) the blood is flowing under steady lam-inar flow conditions. Despite these assump-tions, which clearly are not achieved in vivo,the relationship is important because it de-scribes the dominant influence of vessel ra-dius on resistance and flow, and therefore pro-vides a conceptual framework to understandhow physiologic and pathologic changes inblood vessels and blood viscosity affect pres-sure and flow.

The relationship between flow and radius(Equation 5-6) for a single vessel is shown

�P � r4

� L

graphically in Figure 5-7. In this analysis,laminar flow conditions are assumed, and dri-ving pressure, viscosity, and vessel length areheld constant. As vessel radius decreasesfrom a relative value of 1.0, a dramatic fall inflow occurs because flow is directly related toradius to the fourth power. For example,when radius is one-half normal (0.5 relativeradius), flow is decreased sixteen-fold.Therefore, the new flow is only about 6% of the original flow. This figure dramaticallyillustrates how very small changes in vesselradius can have profound effects on flow (and on perfusion pressure if this were thedependent variable and flow were held con-stant).

Series and Parallel Arrangement of the VasculatureIt is crucial that Poiseuille’s equation shouldbe applied only to single vessels. If, for exam-ple, a single arteriole within the kidney wereconstricted by 50%, although the resistance ofthat single vessel would increase sixteen-fold,the vascular resistance for the entire renal cir-culation would not increase sixteen-fold. Thechange in overall renal resistance would beimmeasurable. This is because the single arte-riole is one of many resistance vessels within acomplex network of vessels, and therefore itconstitutes only a small fraction of the resis-tance for the whole organ. To help understandthis complex arrangement of vessel architec-ture, it is necessary to examine the vascularcomponents in terms of series and parallel el-ements.


An isolated, cannulated arteriole is perfused with an oxygenated physiologic salt solu-tion at a constant flow, and the pressure gradient across the two ends of the arterioleis initially 2 mm Hg. If the application of a drug constricts the vessel diameter by 50%,what will be the new pressure gradient across the arteriole?

Under constant flow conditions, �P � �R (from Equation 5-4). Furthermore, R � 1/r4

(from Equation 5-5). Therefore, �P � 1/r4. Using this relationship, we find that decreas-ing diameter (or radius, which is proportional to diameter) by 50% (to 1/2 its originalradius) increases �P by a factor of 16 (reciprocal of 1/2 to the fourth power). Therefore,the new pressure gradient along the length of vessel will be 32 mm Hg (2 mm Hg x 16).

PROBLEM 5-1

Eq. 5-6

Ch05_091-116_Klabunde 4/21/04 11:21 AM

The parallel arrangement of organs andtheir circulations (see Fig. 1-2) is importantbecause parallel vessels decrease total vascu-lar resistance. When there is a parallelarrangement of resistances, the reciprocal ofthe total resistance is equal to the sum of thereciprocals of the individual resistances. Forexample, the total resistance (RT) of three par-allel resistances (R1, R2, R3) would be:

� � �

or, solving for RT,

RT �

Two important principles emerge fromEquation 5-7. First, the total resistance of anetwork of parallel resistances is less than theresistance of the single lowest resistance;therefore, parallel vessels greatly reduce resis-tance. For example, assume that R1 � 5, R2 �10, and R3 � 20. When the equation is solved,RT � 2.86, a value that is less than the lowestindividual resistance. The resistance calcula-tion for parallel networks explains why capil-laries constitute a relatively small fraction ofthe total vascular resistance of an organ or mi-crovascular network. Although capillarieshave the highest resistance of individual ves-

1

R1

1

� R1

2

� R1

3

1R3

1R2

1R1

1RT

sels because of their small diameter, they alsoform a large network of parallel vessels. Thisreduces their resistance as a group of vessels.The second principle is that when many par-allel vessels exist, changing the resistance of asmall number of these vessels will have littleeffect on total resistance.

Within an organ, the vascular arrangementis a combination of series and parallel ele-ments. In Figure 5-8, the artery, arterioles,capillaries, venules, and vein are in series witheach other. All of the blood that flows throughthe artery likewise flows through each of theother vascular segments. Within each of theseries segments, many parallel componentsmay exist (e.g., several parallel capillaries mayarise from a single arteriole). Each vascularsegment will have a resistance value that is de-termined by vessel length, radius, and numberof parallel vessels.

For an in-series resistance network, the to-tal resistance (RT) equals the sum of the indi-vidual segmental resistances. The total resis-tance for the model depicted in Figure 5-8 is:

RT � RA � Ra � Rc � Rv � RV

(A � artery; a � arterioles; c � capillary; v � venules; V � vein)

The resistance of each segment relative tothe total resistance of all the segments deter-mines how changing the resistance of one seg-

100 CHAPTER 5

Relative Radius

Rel

ativ

e F

low F ∝ r4

00

0.2

0.2

0.4

0.4

0.6

0.6

0.8

0.8

1.0

1.0

FIGURE 5-7 The effects of changes of vessel radius on flow through a single vessel. This quantitative relationship isderived from Poiseuille’s equation (Equation 5-6). Decreasing vessel radius (r) dramatically increases resistance and de-creases flow (F) at constant perfusion pressure because flow is proportional to radius to the fourth power.

Eq. 5-7

Eq. 5-8

Ch05_091-116_Klabunde 4/21/04 11:21 AM

ment affects total resistance. To illustrate thisprinciple, assign a relative resistance value toeach of the five resistance segments in thismodel. The relative resistances are similar towhat is observed in a typical vascular bed.

Assume RA � 1, Ra � 70, Rc � 20, Rv � 8, RV � 1;

Therefore, RT � 1 � 70 �20 �8 � 1� 100

If RA were to increase four-fold (to a value of4), RT would increase to 104, a 4% increase.In contrast, if Ra were to increase four-fold(to a value of 280), the RT would increase to310, a 210% increase. In this model, RA rep-resents a large artery distributing blood flowto an organ, and Ra represents the small ar-teries and arterioles, which are the primary

site of vascular resistance. Therefore, thisempirical example demonstrates thatchanges in large artery resistance have littleeffect on total resistance, whereas changes insmall artery and arteriolar resistancesgreatly affect total resistance. This is whysmall arteries and arterioles are the principalvessels regulating organ blood flow and sys-temic vascular resistance.

The above analysis explains why the radiusof a large, distributing artery must be de-creased by more than 60% or 70% to have asignificant effect on organ blood flow. This isreferred to as a “critical” stenosis (see CriticalStenosis on CD). The concept of a criticalstenosis can be confusing because Poiseuille’sequation indicates that resistance to flow is in-versely related to radius to the fourth power.


A parent arteriole branches into two smaller arterioles. In relative terms, the resistanceof the parent arteriole is 1, and the resistance of each daughter vessel is 4. What is thecombined resistance of the parent vessel and its branches?

In this problem, the two smaller daughter arterioles (RD) are parallel with each otherand in series with the parent arteriole (RP). Therefore, the total resistance (RT) can befound by the following equation:

RT � RP �

Substituting the relative resistances given in this problem, we obtain:

RT � 1 � � 31

14

� 14

1

R1

D

� R1

D

PROBLEM 5-2

Artery Arterioles Capillaries Venules Vein

FIGURE 5-8 Model of the circulation within an organ showing the series arrangement of multiple segments of par-allel vessels.

Ch05_091-116_Klabunde 4/21/04 11:21 AM

Therefore, a 50% reduction in radius shouldincrease resistance sixteen-fold (a 1,500% in-crease). Indeed, within that single vessel seg-ment, resistance will increase sixteen-fold;however, total resistance will increase only byabout 15% if the large artery resistance is nor-mally 1% of the total resistance.

REGULATION OF SYSTEMICVASCULAR RESISTANCE

Systemic vascular resistance, which issometimes called total peripheral resistance(TPR), is the resistance to blood flow offeredby all of the systemic vasculature, excludingthe pulmonary vasculature. Mechanisms thatcause generalized vasoconstriction will in-crease systemic vascular resistance, andmechanisms that cause vasodilation will de-crease systemic vascular resistance. The in-crease in systemic vascular resistance in re-sponse to sympathetic stimulation, forexample, depends on the degree of sympa-thetic activation, the responsiveness of thevasculature, the number of vascular beds in-volved, and the relative series and parallelarrangement of these vascular beds to eachother. Systemic vascular resistance primarily is

determined by changes in vascular diameters,although changes in blood viscosity also affectsystemic vascular resistance.

Calculation of Systemic VascularResistance

Systemic vascular resistance (SVR) can be cal-culated if cardiac output (CO), mean arterialpressure (MAP), and central venous pressure(CVP) are known. This calculation is done byrearranging Equation 5-2 as follows:

SVR � (MAP

C�

OCVP)

Although systemic vascular resistance canbe calculated from mean arterial pressure andcardiac output, its value is not determined byeither of these variables (although its valuechanges depending upon the pressure – seebelow). Systemic vascular resistance is deter-mined by vascular diameters, length, anatom-ical arrangement of vessels, and blood viscos-ity. Because vessels are compliant, increasingintravascular pressure expands the vessels,thereby causing a small reduction in resis-tance. Nonetheless, the decrease in systemicvascular resistance that occurs when pressure

102 CHAPTER 5

A patient was found to have S-T segment depression in his electrocardiogram duringan exercise stress test, suggesting the presence of coronary artery disease. A follow-upcoronary angiogram revealed that the diameter of the left main coronary artery (seeChapter 7, Figure 7-6) was reduced by 50%. If this vessel normally contributes to 1% ofthe total coronary vascular resistance under resting flow conditions, how much will thisreduction in diameter increase total coronary vascular resistance? Express your answeras a percentage increase.

The total coronary resistance (RT) equals the sum of the series resistance elements.Therefore, the left main coronary artery resistance (RL) would be in series with the re-mainder of the resistance elements (RX), so that RT � RL � RX. Normally, RL � 0.01(RT)and RX � 0.99(RT) because RL is 1% of RT, and therefore RT � 0.01(RT) � 0.99(RT) � 1(RT).Decreasing the vessel diameter by 50% increases RL by a factor of 16 because R �1/r4.Therefore, the resistance of the stenotic vessel will be 16 times its normal resistance, sothat RL � 16(0.01)RT, or RL � 0.16(RT). We can now say that RT � 0.16(RT) � 0.99(RT).Therefore, RT � 1.15(RT), which means that total coronary resistance increases by only15% [(1.15/1) x 100] when the resistance of the left main coronary artery increases1,500% (16-fold increase).

CASE 5-1

Eq. 5-9

Ch05_091-116_Klabunde 4/21/04 11:21 AM

increases is not owing to the pressure directlybut rather is caused by passive increases invessel diameter. Mathematically, systemic vas-cular resistance is the dependent (calculated)variable in Equation 5-9; however, physiologi-cally, systemic vascular resistance and cardiacoutput are the independent variables nor-mally, and mean arterial pressure is the de-pendent variable; that is, mean arterial pres-sure changes in response to changes in cardiacoutput and systemic vascular resistance.

When calculating systemic vascular resis-tance, it is customary to use the units of mmHg/mL • min�1 (peripheral resistance units,PRU) or the units of dynes • sec/cm5 (in whichpressure is expressed in dynes/cm2 instead ofmm Hg; 1 mm Hg � 1,330 dynes/cm2) and flowis expressed in cm3/sec). When calculating resis-tance in PRU, pressure has the units of mm Hgand cardiac output is expressed in mL/min.

Vascular Tone

Under normal physiologic conditions, changesin the diameter of precapillary resistance ves-sels (small arteries and arterioles) represent

the most important mechanism for regulatingsystemic vascular resistance. Resistance ves-sels are normally in a partially constrictedstate that is referred to as the vascular toneof the vessel. This tone is generated bysmooth muscle contraction within the wall ofthe blood vessel. From this partially con-stricted state, a vessel can constrict furtherand thereby increase resistance, or it can di-late by smooth muscle relaxation and therebydecrease resistance. Venous vessels likewisepossess a level of vascular tone.

Extrinsic and intrinsic mechanisms deter-mine the degree of smooth muscle activation(Fig. 5-9). Extrinsic mechanisms, such as sym-pathetic nerves and circulating hormones,originate outside of the organ or tissue.Intrinsic mechanisms originate from withinthe blood vessel or the tissue surrounding thevessel. Examples of intrinsic mechanisms in-clude endothelial-derived factors, smoothmuscle myogenic tone, locally produced hor-mones, and tissue metabolites. Some of theseextrinsic and intrinsic factors promote vaso-constriction (e.g., sympathetic nerves and an-giotensin II, endothelin-1), whereas others


Infusion of a drug is found to increase cardiac output by 30% and decrease mean arte-rial pressure by 10%. By what percentage does this drug change systemic vascular resis-tance? Is this drug a vasodilator or vasoconstrictor? Assume that central venous pres-sure is 0 mm Hg and does not change.

From Equation 5-9, we know that

SVR � (MAP

C�

OCVP)

Because central venous pressure (CVP) is zero, this equation simplifies to:

SVR � MCAO

P

In this problem, CO is increased by 30% and MAP is decreased by 10%:

SVR � 01.9.3

MCAO

P � 0.69

Therefore, SVR is decreased by 31% (0.69 SVR is the equivalent of a 31% decrease),and the drug is a vasodilator. Note: In solving this problem, MAP and CO cannot bemultiplied by their percentage change.

PROBLEM 5-3

Ch05_091-116_Klabunde 4/21/04 11:21 AM

promote smooth muscle relaxation and vascu-lar dilation (e.g., endothelial-derived nitric ox-ide and tissue metabolites such as adenosineand hydrogen ion). Therefore, at any giventime, vasoconstrictor and vasodilator influ-ences are competing to determine the vascu-lar tone. The extrinsic and intrinsic mecha-nisms regulating vascular tone are describedin more detail in Chapters 2, 6, and 7.

In general, the vasoconstrictor mechanismsare important for maintaining systemic vascu-lar resistance and arterial pressure, whereasvasodilator mechanisms regulate blood flowwithin organs. For example, if the body needsto maintain arterial blood pressure when aperson stands up, vasoconstrictor mechanisms(primarily sympathetic adrenergic) are acti-vated to constrict resistance vessels and in-crease systemic vascular resistance. If an or-gan requires more blood flow and oxygendelivery (e.g., exercising muscle), vasodilatormechanisms will predominate and overridevasoconstrictor influences. Therefore, thecompetition between vasoconstrictor and va-sodilator influences can be thought of as com-petition between maintenance of arterialblood pressure and organ perfusion.

VENOUS BLOOD PRESSURE

Venous pressure is a general term that repre-sents the average blood pressure within thevenous compartment. A more specific term,central venous pressure, describes theblood pressure in the thoracic vena cava nearthe right atrium. This pressure is importantbecause it determines the filling pressure ofthe right ventricle, and thereby determinesventricular stroke volume through the Frank-Starling mechanism as discussed in Chapter 4.

Venous Blood Volume and Compliance

Several factors influence central venous pres-sure: cardiac output, respiratory activity, con-traction of skeletal muscles (particularly legand abdominal muscles), sympathetic vaso-constrictor tone, and gravitational forces. Allof these factors ultimately change central ve-nous pressure (�PV) by changing either ve-nous blood volume (�VV) or venous compli-ance (CV) as described by Equation 5-10.

�PV ∝ �

CV

V

V

Equation 5-10 is a rearrangement of theequation used to define compliance, in whichcompliance (in this case venous compliance)equals a change in venous volume divided bythe change in venous pressure that occurswith the change in volume (see Compliancein Chapter 4 on the CD). Therefore, an in-crease in venous volume increases venouspressure by an amount determined by thecompliance of the veins. Furthermore, a de-crease in venous compliance, as occurs dur-ing sympathetic activation of veins, increasesvenous pressure.

The relationship described by Equation 5-10 can be depicted graphically as shown inFigure 5-10, in which venous blood volume isplotted against venous blood pressure. Thedifferent curves represent different states ofvenous tone, and the slope of a tangent line atany point on the curve represents the compli-ance. Looking at a single curve, it is evident

104 CHAPTER 5

Arteriole TissueMetabolites

LocalHormones

Myogenic

EndothelialFactors

Neural

Humoral

Extrinsic Intrinsic

Constriction Dilation

FIGURE 5-9 Vascular tone. The state of vessel tone isdetermined by the balance between constrictor anddilator influences.

Eq. 5-10

Ch05_091-116_Klabunde 4/21/04 11:21 AM

that an increase in venous volume will in-crease venous pressure. The amount by whichthe pressure increases for a given change involume depends on the slope of the relation-ship between the volume and pressure (i.e.,the compliance). As with arterial vessels (seeFig. 5-4), the relationship between venousvolume and pressure is not linear (see Fig. 5-10). The slope of the compliance curve(�V/�P) is greater at low pressures and vol-umes than at higher pressures and volumes.The reason for this is that at very low pres-sures, a large vein collapses. As the pressureincreases, the collapsed vein assumes a morecylindrical shape with a circular cross-section.Until a cylindrical shape is attained, the wallsof the vein are not stretched appreciably.Therefore, small changes in pressure can re-sult in a large change in volume by changes invessel geometry rather than by stretching thevessel wall. At higher pressures, when the veinis cylindrical in shape, increased pressure canincrease the volume only by stretching the

vessel wall, which is resisted by the structureand composition of the wall (particularly bycollagen, smooth muscle, and elastin compo-nents). Therefore, at higher volumes andpressures, the change in volume for a givenchange in pressure (i.e., compliance) is less.

The smooth muscle within veins is ordinar-ily under some degree of tonic contraction.Like arteries and arterioles, a major factor de-termining venous smooth muscle contractionis sympathetic adrenergic stimulation, whichoccurs under basal conditions. Changes insympathetic activity can increase or decreasethe contraction of venous smooth muscle,thereby altering venous tone. When this oc-curs, a change in the volume-pressure rela-tionship (or compliance curve) occurs, as de-picted in Figure 5-10. For example, increasedsympathetic activation will shift the compli-ance curve down and to the right, decreasingits slope (compliance) at any given volume(from point A to B in Fig. 5-10). This right-ward diagonal shift in the venous compliancecurve results in a decrease in venous volumeand an increase in venous pressure. Drugsthat reduce venous tone (e.g., nitrodilators)will decrease venous pressure while increas-ing venous volume by shifting the compliancecurve to the left.

The previous discussion emphasized thatvenous pressure can be altered by changes invenous blood volume or in venous compli-ance. These changes can be brought about bythe factors or conditions summarized in Table5-2. Central venous pressure is increased by:

1. A decrease in cardiac output. This can re-sult from decreased heart rate (e.g., brady-cardia associated with atrioventricular [AV]nodal block) or stroke volume (e.g., in ven-tricular failure), which results in bloodbacking up into the venous circulation (in-creased venous volume) as less blood ispumped into the arterial circulation. Theresultant increase in thoracic blood volumeincreases central venous pressure.

2. An increase in total blood volume. This oc-curs in renal failure or with activation ofthe renin-angiotensin-aldosterone system


Vol

ume

Pressure

IncreasedTone

A

B

Shape of vein at different pressures

FIGURE 5-10 Compliance curves for a vein. Venouscompliance (the slope of line tangent to a point on thecurve) is very high at low pressures because veins col-lapse. As pressure increases, the vein assumes a morecircular cross-section and its walls become stretched;this reduces compliance (decreases slope). Point A is thecontrol pressure and volume. Point B is the pressure andvolume resulting from increased tone (decreased com-pliance) brought about, for example, by sympatheticstimulation of the vein.

Ch05_091-116_Klabunde 4/21/04 11:21 AM

(see Chapter 6) and leads to an increase invenous pressure.

3. Venous constriction (reduced venous com-pliance). Whether elicited by sympatheticactivation or by circulating vasoconstrictorsubstances (e.g., catecholamines, an-giotensin II), venous constriction reducesvenous compliance, thereby increasingcentral venous pressure.

4. A shift in blood volume into the thoracicvenous compartment. This shift occurswhen a person changes from standing to asupine or sitting position and results fromthe effects of gravity.

5. Arterial dilation. This occurs during with-drawal of sympathetic tone or when arterialvasodilator drugs increase blood flow fromthe arterial into the venous compartments,thereby increasing venous volume and cen-tral venous pressure.

6. A forceful expiration, particularly against ahigh resistance (as occurs with a Valsalvamaneuver). This expiration causes externalcompression of the thoracic vena cava asintrapleural pressure rises.

7. Muscle contraction. Rhythmic muscularcontraction, particularly of the limbs andabdomen, compresses the veins (which de-creases their functional compliance) andforces blood into the thoracic compart-ment.

Mechanical Factors AffectingCentral Venous Pressure andVenous Return

Several of the factors affecting central venouspressure can be classified as mechanical (orphysical) factors. These include gravitationaleffects, respiratory activity, and skeletal mus-cle contraction. Gravity passively alters centralvenous pressure and volume, and respiratoryactivity and muscle contraction actively pro-mote or impede the return of blood into thecentral venous compartment, thereby alteringcentral venous pressure and volume.

GravityGravity exerts significant effects on venous re-turn. When a person changes from supine to astanding posture, gravity acts on the vascularvolume, causing blood to accumulate in thelower extremities. Because venous compli-ance is much higher than arterial compliance,most of the blood volume accumulates inveins, leading to venous distension and an el-evation in venous pressure in the dependentlimbs. The shift in blood volume causes cen-tral venous volume and pressure to fall. Thisreduces right ventricular filling pressure (pre-load) and stroke volume by the Frank-Starlingmechanism. Left ventricular stroke volumesubsequently falls because of reduced pul-

106 CHAPTER 5

TABLE 5-2 FACTORS INCREASING CENTRAL VENOUS PRESSURE (CVP),EITHER BY DECREASING VENOUS COMPLIANCE OR BYINCREASING VENOUS BLOOD VOLUME

CVP INCREASED BY CHANGE IN:

Decreased cardiac output Volume

Increased blood volume Volume

Venous constriction Compliance

Changing from standing to supine body posture Volume

Arterial dilation Volume

Forced expiration (e.g., Valsalva) Compliance

Muscle contraction (abdominal and limb) Volume & Compliance

Ch05_091-116_Klabunde 4/21/04 11:21 AM

monary venous return to the left ventricle; thereduced stroke volume causes cardiac outputand arterial blood pressure to decrease. If sys-temic arterial pressure falls by more than 20mm Hg upon standing, this is termed ortho-static or postural hypotension. When thisoccurs, cerebral perfusion may fall and a per-son may become “light headed” and experi-ence a transient loss of consciousness (syn-cope). Normally, baroreceptor reflexes (seeChapter 6) are activated to restore arterialpressure by causing peripheral vasoconstric-tion and cardiac stimulation (increased heartrate and inotropy).

The effects of changes in posture on hydro-static pressures are illustrated Figure 5-11. Inthis model, mean aortic pressure (MAP) andcentral venous pressure (CVP) are shown asreservoirs. The vertical height between thesetwo reservoirs represents the systemic perfu-

sion pressure. Cardiac output constantly refillsthe aortic reservoir as it empties into the sys-temic circulation. In a horizontal configuration(Figure 11, Diagram A), mean capillary hydro-static pressure (PC) is some value betweenMAP and CVP, typically about 25 mm Hg. Ifthe horizontal tube (i.e., the vasculature) is ori-entated vertically (Diagram B), PC increasesbecause of hydrostatic forces. If the vasculatureis rigid (Diagram B), there is no volume shiftbetween the arterial and venous reservoirs, andMAP and CVP remain unchanged (as does car-diac output). However, if the vasculature ishighly compliant (as it actually is), the in-creased hydrostatic forces increase trans-mural pressure (intravascular minus extravas-cular pressure; i.e., the distending pressure)across the vessel walls and expand the vessels,particularly the highly compliant veins(Diagram C). The blood for this venous expan-


Heart

Heart

(A) Supine

(B) Upright (C) Upright

CVP

CVPCVP

MAP

MAP

MAP

CO

CO CO

PC

PC PC

∆P

∆P ∆P

Heart

FIGURE 5-11 Effects of gravity on central venous pressure (CVP), cardiac output (CO), and mean arterial pressure(MAP). Diagram A, supine position. Diagram B: an upright position with rigid vessel results in elevated capillary pres-sure (PC) owing to hydrostatic forces, but no change in CVP, CO, MAP, or systemic perfusion pressure (�P). DiagramC: upright position with compliant vessels; elevated PC from hydrostatic pressure owing to gravity distends blood ves-sels (particularly veins) and increases vascular volume (especially in lower limbs), leading to a fall in CVP, MAP, �P, andCO.

Ch05_091-116_Klabunde 4/21/04 11:21 AM

sion comes from the venous and arterial reser-voirs, thereby decreasing CVP and MAP. Thedecrease in CVP decreases cardiac preload anddecrease cardiac output by the Frank-Starlingmechanism. The decreased cardiac output re-sults in a fall in MAP (decreased reservoirheight). The net effect is reductions in bothMAP and CVP, although quantitatively, the fallin MAP is 10 to 20 times greater than the fall inCVP for reasons explained later in this chapter.

Upright posture not only shifts venousblood volume from the thoracic compartmentto the dependent limbs, but it also results in alarge elevation in capillary pressure in the de-pendent limbs. When a person is lying down,there is no appreciable hydrostatic pressuredifference between the level of the heart andfeet. The mean aortic pressure may be 95 mmHg, the mean capillary pressure in the feetmay be about 20 mm Hg, and the central ve-nous pressure near the right atrium may benear 0 mm Hg. When the person stands up-right, if no baroreceptor or myogenic reflexesoperate, the mean aortic and central venouspressures will fall quite significantly. A hydro-static column equal to the vertical distancefrom the heart to the feet will increase capil-lary pressure in the feet. If the distance fromthe heart to the feet is 120 cm, the hydrostaticpressure exerted on the capillaries in the feetwill be 120 cmH20, which is the equivalent of88 mm Hg (mercury is 13.6 times denser thanwater). Theoretically, this hydrostatic pressureadded to the normal capillary pressure will in-crease the capillary pressure in the feet to 108mm Hg! Without the activation of importantcompensatory mechanisms, this would rapidlylead to significant edema in the feet and de-pendent limbs (see Chapter 8) and loss of in-travascular blood volume.

The changes depicted in Figure 5-11,Diagram C, are rapidly compensated in a nor-mal individual by myogenic vasoconstrictormechanisms, sympathetic-mediated vasocon-striction, venous valve functioning, musclepump activity, and the abdominothoracicpump. When these mechanisms are operat-ing, capillary and venous pressures in the feetwill be elevated by only 10–20 mm Hg, meanaortic pressure will be maintained, and central

venous pressure will be only slightly reduced.Because of these compensatory mechanisms,a person who is standing has a higher systemicvascular resistance (primarily owing to sympa-thetic activation of resistance vessels), de-creased venous compliance (owing to sympa-thetic activation of veins), decreased strokevolume and cardiac output (owing to de-creased ventricular preload), and increasedheart rate (baroreceptor-mediated tachycar-dia). The net effect of these changes is main-tenance of normal mean aortic pressure.

Respiratory Activity (Abdominothoracic or Respiratory Pump) Venous return to the right atrium from the ab-dominal vena cava is determined by the pres-sure difference between the abdominal venacava and the right atrial pressure, as well as bythe resistance to flow, which is primarily de-termined by the diameter of the thoracic venacava. Therefore, increasing right atrial pres-sure impedes venous return, whereas lower-ing right atrial pressure facilitates venous re-turn. These changes in venous returnsignificantly influence stroke volume throughthe Frank-Starling mechanism.

Pressures in the right atrium and thoracicvena cava depend on intrapleural pressure.This pressure is measured in the space be-tween the thoracic wall and the lungs and isgenerally negative (subatmospheric). Duringinspiration, the chest wall expands and the di-aphragm descends (red arrows on chest walland diaphragm in Figure 5-12). This causesthe intrapleural pressure (Ppl) to become morenegative, causing expansion of the lungs, atrialand ventricular chambers, and vena cava(smaller red arrows). This expansion decreasesthe pressures within the vessels and cardiacchambers. As right atrial pressure falls duringinspiration, the pressure gradient for venousreturn to the heart is increased. During expira-tion the opposite occurs, although the net ef-fect of respiration is that the increased rate anddepth of ventilation facilitates venous returnand ventricular stroke volume.

Although it may appear paradoxical, the fallin right atrial pressure during inspiration is as-sociated with an increase in right atrial and

108 CHAPTER 5

Ch05_091-116_Klabunde 4/21/04 11:21 AM

ventricular preloads and right ventricularstroke volume. This occurs because the fall inintrapleural pressure causes the transmuralpressure to increase across the chamber walls,thereby increasing the chamber volume,which increases sarcomere length and myo-cyte preload. For example, if intrapleuralpressure is normally –4 mm Hg at end-expira-tion and right atrial pressure is 0 mm Hg, thetransmural pressure (the pressure that dis-tends the atrial chamber) is 4 mm Hg. Duringinspiration, if intrapleural pressure decreasesto –8 mm Hg and atrial pressure decreases to–2 mm Hg, the transmural pressure across theatrial chamber increases from 4 mm Hg to 6mm Hg, thereby expanding the chamber. Atthe same time, because blood pressure withinthe atrium is diminished, this leads to an in-crease in venous return to the right atriumfrom the abdominal vena cava. Similar in-creases in right ventricular transmural pres-sure and preload occur during inspiration.The increase in sarcomere length during in-spiration augments right ventricular strokevolume by the Frank-Starling mechanism. Inaddition, changes in intrapleural pressure dur-ing inspiration influence the left atrium andventricle; however, the expanding lungs andpulmonary vasculature act as a capacitancereservoir (pulmonary blood volume increases)so that the left ventricular filling is not en-hanced during inspiration. During expiration,

however, blood is forced from the pulmonaryvasculature into the left atrium and ventricle,thereby increasing left ventricular filling andstroke volume. Expiration, in contrast, de-creases right atrial and ventricular filling. Thenet effect of respiration is that increasing therate and depth of respiration increases venousreturn and cardiac output.

If a person exhales forcefully against aclosed glottis (Valsalva maneuver), the largeincrease in intrapleural pressure impedes ve-nous return to the right atrium (see ValsalvaManeuver on CD). This occurs because thelarge increase in intrapleural pressure can col-lapse the thoracic vena cava, which dramati-cally increases resistance to venous return.Because of the accompanying decrease intransmural pressure across the ventricularchamber walls, ventricular volume decreasesdespite the large increase in the pressurewithin the chamber. Decreased chamber vol-ume (i.e., decreased preload) leads to a fall inventricular stroke volume by the Frank-Starling mechanism. Similar changes can oc-cur when a person strains while having abowel movement, or when a person lifts aheavy weight while holding their breath.

Skeletal Muscle PumpVeins, particularly in extremities, contain one-way valves that permit blood flow toward theheart and prevent retrograde flow. Deep veins


-4

-8

0

-2

VenousReturn

Inspiration Expiration

FIGURE 5-12 Effects of respiration on venous return. Left panel: During inspiration, intrapleural pressure (Ppl) de-creases as the chest wall expands and the diaphragm descends (large red arrows). This increases the transmural pres-sure across the superior and inferior vena cava (SVC and IVC), right atrium (RA), and right ventricle (RV), which causesthem to expand. This facilitates venous return and leads to an increase in atrial and ventricular preloads. Right panel:During inspiration, Ppl and right atrial pressure (PRA) become more negative, which increases venous return. Duringexpiration, Ppl and PRA become less negative and venous return falls. Numeric values for Ppl and PRA are expressed asmm Hg.

Ch05_091-116_Klabunde 4/21/04 11:21 AM

in the lower limbs are surrounded by largegroups of muscle that compress the veinswhen the muscles contract. This compressionincreases the pressure within the veins, whichcloses upstream valves and opens downstreamvalves, thereby functioning as a pumpingmechanism (Fig. 5-13). This pumping mecha-nism plays a significant role in facilitating ve-nous return during exercise. The musclepump also helps to counteract gravitationalforces when a person stands up by facilitatingvenous return and lowering venous and capil-lary pressures in the feet and lower limbs.When the venous valves become incompe-tent, as occurs when veins become enlarged(varicose veins), muscle pumping becomes in-effective. Besides the loss of muscle pumpingin aiding venous return, blood volume andpressure increase in the veins of the depen-dent limbs, which increases capillary pressureand may cause edema (see Chapter 8).

VENOUS RETURN AND CARDIACOUTPUT

The Balance between VenousReturn and Cardiac Output

Venous return is the flow of blood back to theheart. Previous sections described how the ve-nous return to the right atrium from the ab-dominal vena cava is determined by the pres-sure gradient between the abdominal vena

cava and the right atrium, divided by the re-sistance of the vena cava. However, that analy-sis looks at only a short segment of the venoussystem and does not show what factors deter-mine venous return from the capillaries.Venous return is determined by the differencebetween the mean capillary and right atrialpressures divided by the resistance of all thepost-capillary vessels. If we consider venousreturn as being all the systemic flow returningto the heart, venous return is determined bythe difference between the mean aortic andright atrial pressures divided by the systemicvascular resistance. Under steady-state condi-tions, this venous return equals cardiac outputwhen averaged over time because the cardio-vascular system is essentially a closed system.(The cardiovascular system, strictly speaking,is not a closed system because fluid is lostthrough the kidneys and by evaporationthrough the skin, and fluid enters the circula-tion through the gastrointestinal tract.Nevertheless, a balance is maintained be-tween fluid entering and leaving the circula-tion during steady-state conditions. There-fore, think of cardiac output and venousreturn as being equal.)

Systemic Vascular Function Curves

Blood flow through the entire systemic circu-lation, whether viewed as the flow leaving theheart (cardiac output) or returning to theheart (venous return), depends on both car-diac and systemic vascular function. As de-scribed in more detail below, cardiac outputunder normal physiologic conditions dependson systemic vascular function. Cardiac outputis limited to a large extent by the prevailingstate of systemic vascular function. Therefore,it is important to understand how changes insystemic vascular function affect cardiac out-put and venous return (or total systemic bloodflow because cardiac output and venous re-turn are equal under steady-state conditions).

The best way to show how systemic vascu-lar function affects systemic blood flow is byuse of systemic vascular and cardiac functioncurves. Credit for the conceptual understand-ing of the relationship between cardiac output

110 CHAPTER 5

Relaxed ContractedFIGURE 5-13 Rhythmic contraction of skeletal musclecompresses veins, particularly in the lower limbs, andpropels blood toward the heart through a system ofone-way valves.

Ch05_091-116_Klabunde 4/21/04 11:21 AM

and systemic vascular function goes to ArthurGuyton and colleagues, who conducted exten-sive experiments in the 1950s and 1960s. Todevelop the concept of systemic vascular func-tion curves, we must understand the relation-ship between cardiac output, mean aortic, andright atrial pressures. Figure 5-14 shows thatat a cardiac output of 5 L/min, the right atrialpressure is near zero and mean aortic pressureis about 95 mm Hg. If cardiac output is re-duced experimentally, right atrial pressure in-creases and mean aortic pressure decreases.The fall in aortic pressure reflects the rela-tionship between mean aortic pressure, car-diac output, and systemic vascular resistance(see Equation 5-2). As cardiac output is re-duced to zero, right atrial pressure continuesto rise and mean aortic pressure continues tofall, until both pressures are equivalent, whichoccurs when systemic blood flow ceases. Thepressure at zero systemic flow, which is calledthe mean circulatory filling pressure, isabout 7 mm Hg. This value is found experi-mentally when baroreceptor reflexes areblocked; otherwise the value for mean circula-tory filling pressure is higher because of vas-cular smooth muscle contraction and de-creased vascular compliance owing tosympathetic activation.

The reason right atrial pressure increasesin response to a decrease in cardiac output isthat less blood per unit time is translocated bythe heart from the venous to the arterial vas-cular compartment. This leads to a reductionin arterial blood volume and an increase in ve-nous blood volume, which increases rightatrial pressure. When the heart is completelystopped and there is no flow in the systemiccirculation, the intravascular pressure foundthroughout the entire vasculature is a functionof total blood volume and vascular compli-ance.

The magnitude of the relative changes inaortic and right atrial pressures from a normalcardiac output to zero cardiac output is deter-mined by the ratio of venous to arterial com-pliances. If venous compliance (CV) equals thechange in venous volume (�VV) divided by thechange in venous pressure (�PV), and arterialcompliance (CA) equals the change in arterialvolume (�VA) divided by the change in arte-rial pressure (�PA), the ratio of venous to ar-terial compliance (CV/CA) can be expressed bythe following equation:

CC

A

V �

When the heart is stopped, the decrease inarterial blood volume (�VA) equals the in-crease in venous blood volume (�VV).Because �VA equals �VV, Equation 5-11 canbe simplified to the following relationship:

CC

A

V ∝

�

�

PP

A

V

Equation 5-12 shows that the ratio of ve-nous to arterial compliance is proportional tothe ratio of the changes in arterial to venouspressures when the heart is stopped. This ra-tio is usually in the range of 10–20. If, for ex-ample, the ratio of venous to arterial compli-ance is 15, there is a 1 mm Hg increase inright atrial pressure for every 15 mm Hg de-crease in mean aortic pressure.

If the right atrial pressure curve fromFigure 5-14 is plotted as cardiac output versusright atrial pressure (i.e., reversing the axis),

�VV/�PV�VA/�PA


MeanAortic

Pressure

RightAtrial

Pressure

50

0

50

100

Pre

ssu

re (

mm

Hg

)

Pmc

FIGURE 5-14 Effects of cardiac output on mean aorticand right atrial pressures. Decreasing cardiac output tozero results in a rise in right atrial pressure and a fall inaortic pressure. Both pressures equilibrate at the meancirculatory filling pressure (Pmc).

Eq. 5-11

Eq. 5-12

Ch05_091-116_Klabunde 4/21/04 11:21 AM

the relationship shown in Figure 5-15 (blackcurve in both panels) is observed. This curveis called the systemic vascular functioncurve. This relationship can be thought of aseither the effects of cardiac output on rightatrial pressure (cardiac output being the inde-pendent variable) or the effect of right atrialpressure on venous return (right atrial pres-sure being the independent variable). Whenviewed from the latter perspective, systemicvascular function curves are sometimes calledvenous return curves.

The value of the x-intercept in Figure 5-15is the mean circulatory filling pressure, or thepressure throughout the vascular system whenthere is no blood flow. This value depends onthe vascular compliance and blood volume(Fig. 5-15, Panel A). Increased blood volumeor decreased venous compliance causes a par-allel shift of the vascular function curve to theright, which increases mean circulatory fillingpressure. Decreased blood volume or in-creased venous compliance causes a parallelshift to the left and a decrease in the mean cir-culatory filling pressure.

Decreased systemic vascular resistance in-creases the slope without appreciably chang-ing mean circulatory filling pressure (Fig. 5-15, Panel B). Increased systemic vascularresistance decreases the slope while keepingthe same mean circulatory filling pressure.

Therefore, at a given cardiac output, a de-crease in systemic vascular resistance in-creases right atrial pressure, whereas an in-crease in systemic vascular resistancedecreases right atrial pressure. These changescan be difficult to conceptualize, but the fol-lowing explanation might help to clarify.When the small resistance vessels dilate, sys-temic vascular resistance decreases. If the car-diac output remains constant, arterial pres-sure and arterial blood volume must decrease.Arterial blood volume shifts over to the ve-nous side of the circulation, and the increasein venous volume increases the right atrialpressure. Changes in systemic vascular resis-tance have little effect on mean circulatoryfilling pressure because the rather smallchanges in arterial diameter required to pro-duce large changes in resistance have little af-fect on overall vascular compliance, which isoverwhelmingly determined by venous com-pliance.

Cardiac Function Curves

According to the Frank-Starling relationship,an increase in right atrial pressure increasescardiac output. This relationship can be de-picted using the same axis as used in systemicfunction curves in which cardiac output (de-pendent variable) is plotted against right atrial

112 CHAPTER 5

↑Vol

5

10

Ca

rdia

c O

utp

ut

(L/m

in)

Pmc PmcP (mmHg)RA PRA (mmHg)10

000

↓Vol

↓SVR

↑SVR

↓Cv

↑Cv

A B

10

FIGURE 5-15 Systemic function curves. Panel A shows the effects of changes in cardiac output on right atrial pres-sure (PRA) and mean circulatory filling pressures (Pmc) at different blood volumes (Vol) and venous compliances (Cv).Panel B shows how changes in systemic vascular resistance (SVR) affect the systemic function curves.

Ch05_091-116_Klabunde 4/21/04 11:21 AM

pressure (independent variable) (Fig. 5-16). These curves are similar to the Frank-Starling curves shown in Figure 4-9. There isno single cardiac function curve, but rather afamily of curves that depends on the inotropicstate and afterload (see Chapter 4). Changesin heart rate also shift the cardiac functioncurve because cardiac output, not stroke vol-ume as in Figure 4-9, is the dependent vari-able. With a “normal” function curve, the car-diac output is about 5 L/min at a right atrialpressure of about 0 mm Hg. If cardiac perfor-mance is enhanced by increasing heart rate orinotropy or by decreasing afterload, it shiftsthe cardiac function curve up and to the left.At the same right atrial pressure of 0 mm Hg,the cardiac output will increase. Conversely, adepressed cardiac function curve, as occurswith decreased heart rate or inotropy or withincreased afterload, will decrease the cardiacoutput at any given right atrial pressure.However, the magnitude by which cardiacoutput changes when cardiac performance isaltered is determined in large part by the stateof systemic vascular function. Therefore, it isnecessary to examine both cardiac and systemvascular function at the same time.

Interactions between Cardiac andSystemic Vascular Function Curves

By themselves, systemic vascular function andcardiac function curves provide an incompletepicture of overall cardiovascular dynamics;however, when coupled together, these curvescan offer a new understanding as to the waycardiac and vascular function are coupled.

When the cardiac function and vascularfunction curves are superimposed (Fig.5-17), a unique intercept between a given car-diac and a given vascular function curve (pointA) exists. This intercept is the equilibriumpoint that defines the relationship betweencardiac and vascular function. The heart func-tions at this equilibrium until one or bothcurves shift. For example, if the sympatheticnerves to the heart are stimulated to increaseheart rate and inotropy, only a small increasein cardiac output will occur, accompanied by asmall decrease in right atrial pressure (pointB). If at the same time the venous complianceis decreased by sympathetic activation of ve-nous vasculature, cardiac output will begreatly augmented (point C). If the decreasein venous compliance is accompanied by a de-crease in systemic vascular resistance, cardiacoutput would be further enhanced (point D).These changes in venous compliance and sys-temic vascular resistance, which occur duringexercise, permit the cardiac output to in-crease. This example shows that for cardiacoutput to increase significantly during cardiacstimulation, there must be some alteration invascular function so that venous return is aug-mented and right atrial pressure (ventricularfilling) is maintained. Therefore, in the normalheart, cardiac output is limited by factors thatdetermine vascular function.

In pathologic conditions such as heart fail-ure, cardiac function limits venous return. Inheart failure, ventricular inotropy is lost; totalblood volume is increased; and afterload is in-creased (see Chapter 9). The former two leadto an increase in atrial and ventricular pres-sures and volumes (increased preload), whichenables the Frank-Starling mechanism to par-tially compensate for the loss of inotropy. Thesechanges during heart failure can be


0 100

5

10

P (mmHg)RA

CardiacOutput(L/min)

Normal

Depressed

Enhanced

FIGURE 5-16 Cardiac function curves. Cardiac output isplotted as a function of right atrial pressure (PRA); nor-mal (solid black), enhanced (red) and depressed (red)curves are shown. Cardiac performance, measured ascardiac output, is enhanced (curves shift up and to theleft) by an increase in heart rate and inotropy and a de-crease in afterload.

Ch05_091-116_Klabunde 4/21/04 11:21 AM

depicted using cardiac and systemic functioncurves as shown in Figure 5-18. In this figure,point A represents the operating point in a nor-mal heart, and point B indicates where a heartmight operate when it is in failure in the ab-sence of systemic compensation—cardiac out-put would be greatly reduced and right atrialpressure would be elevated. Compensatory in-creases in blood volume and systemic vascularresistance, along with reduced venous compli-

ance, shift the systemic function to the rightand decrease the slope. The new, combined in-tercept (point C) represents a partial compen-sation in the cardiac output at the expense of alarge increase in right atrial pressure. The in-creased atrial pressure helps to support ven-tricular preload and stroke volume through theFrank-Starling mechanism.

In summary, total blood flow through thesystemic circulation (cardiac output or venous

114 CHAPTER 5

V

0 100

5

10

15

P (mmHg)RA

CardiacOutput(L/min) A

B

C

D

↓CV

↓C &↓SVR

CardiacStimulation Normal

CardiacFunction

FIGURE 5-17 Combined cardiac and systemic function curves: effects of exercise. Cardiac output is plotted againstright atrial pressure (PRA) to show the effects of altering both cardiac and systemic function. Point A represents thenormal operating point described by the intercept between the normal cardiac and systemic function curves. Cardiacstimulation alone changes the intercept from point A to B. Cardiac stimulation coupled with decreased venous com-pliance (CV) (or increased venous volume) shifts the operating intercept to point C. If systemic vascular resistance (SVR)also decreases, which is similar to what occurs during exercise, the new intercept becomes point D.

0 100

5

10

P (mmHg)RA

Ca

rdu

ac

Ou

tpu

t (L

/min

)

A

B

C

CardiacFailure

20 30

↑↓

↑

VolCv

SVR

FIGURE 5-18 Combined cardiac and systemic function curves: effects of chronic heart failure. The normal operatingintercept (point A) is shifted to point B when cardiac function alone is depressed by loss of inotropy. Compensatoryincreases in total blood volume (Vol) and systemic vascular resistance (SVR), along with reduced venous compliance(CV), shifts the systemic function to the right and decreases the slope. The new combined intercept (point C) repre-sents partial compensation in cardiac output at the expense of a large increase in right atrial pressure (PRA).

Ch05_091-116_Klabunde 4/21/04 11:21 AM

return) depends on both cardiac and systemicvascular function. Cardiac stimulation in anormal heart has only a modest effect on car-diac output; however, if systemic function isadditionally altered by decreasing venouscompliance and systemic vascular resistance,the cardiac output is able to increase. Withoutchanges in systemic function, cardiac output islimited by the return of blood to the heart andventricular filling.


• Regulation of arterial pressure and organblood flow is primarily the function of thesmall arteries and arterioles. Capillaries arethe principal site for exchange becausethey have the greatest surface area.Furthermore, capillaries have the lowestvelocity of flow because they have thegreatest cross-sectional area. Most of theblood volume is found in the venous circu-lation, which serves a capacitance function(it acts as a blood reservoir) within thebody.

• Aortic pulse pressure is primarily deter-mined by ventricular stroke volume andaortic compliance.

• Mean arterial pressure is determined bythe product of cardiac output and systemicvascular resistance, plus central venouspressure.

• Vascular resistance is inversely related tothe vessel radius to the fourth power, and itis directly related to vessel length andblood viscosity. Vessel radius is the mostimportant factor for regulating resistance.

• The parallel arrangement of vascular bedsin the body reduces overall resistance.Furthermore, because of this arrangement,a resistance change in one vascular bed hasminimal influence on pressure and flow inother vascular beds.

• The resistance of a single vessel or group ofvessels is the perfusion pressure divided bythe blood flow.

• Changes in large artery resistance have lit-tle effect on total resistance of a vascularbed, whereas changes in small artery and

arteriolar resistances greatly affect total re-sistance. The reason for this is that the re-sistance of a large artery is normally only asmall percentage of the total resistance of avascular bed.

• Arterial and venous vessels are normally ina partially constricted state (i.e., they pos-sess vascular tone), which is determined bythe net effect of vasoconstrictor and va-sodilator influences acting upon the vessel.

• Central venous pressure is important be-cause it determines the preload on theheart. Central venous pressure is altered bychanges in venous blood volume and ve-nous compliance. Gravity, respiratory activ-ity, and the pumping action of rhythmicallycontracting skeletal muscle have importantinfluences on central venous pressure.

• Cardiac output is strongly influenced bychanges in systemic vascular function asdescribed by cardiac and systemic vascularfunction curves. In the normal heart, car-diac output is limited by factors that deter-mine vascular function.

Review Questions

Please refer to the appendix for the answersto the review questions.For each question, choose the one best answer:

1. Concerning different types of blood ves-sels in a vascular network,

a. Arterioles have the highest individ-ual resistance, and therefore, as agroup of vessels, have the greatestpressure drop.

b. Capillaries as a group of vessels con-stitute the greatest resistance to flowwithin an organ.

c. Capillaries and venules are the pri-mary site for fluid exchange.

d. Large arteries are the most impor-tant vessels for blood flow and pres-sure regulation.

2. Arterial pulse pressurea. Decreases at high heart rates if

stroke volume decreases.


Ch05_091-116_Klabunde 4/28/04 10:19 AM

b. Decreases when cardiac inotropy isincreased.

c. Increases when aortic compliance isincreased with age.

d. Is the perfusion pressure for the sys-temic circulation.

3. A patient who has coronary artery dis-ease is treated with a drug that reducesheart rate by 10% without changingstroke volume. Furthermore, the drug isfound to decrease mean arterial pressureby 10%. Assume that central venouspressure remains at 0 mmHg. This drug

a. Decreases systemic vascular resis-tance by 10%.

b. Does not alter cardiac output.c. Does not alter systemic vascular re-

sistance.d. Reduces pressure by dilating the

systemic vasculature.

4. Which of the following will increaseblood flow to the greatest extent in a sin-gle isolated blood vessel?

a. Decreasing the blood temperatureby 10°C

b. Increasing perfusion pressure by100%

c. Increasing blood viscosity by 100%d. Increasing the vessel diameter by

50%

5. If cardiac output is 4500 mL/min, meanarterial pressure is 94 mm Hg, and rightatrial pressure is 4 mm Hg, systemic vas-cular resistance (in peripheral resistanceunits, PRU; mm Hg/ml • min-1) is:

a. 0.02b. 20c. 50d. 4.05 � 105

6. If the renal artery supplying blood flowto the kidney has its internal diameterreduced by 50%, the blood flow to thekidney will decrease by what amount?Assume that renal artery resistance is 1%of total renal resistance and that there isno autoregulation.

a. 50%b. Less than 20%c. 8-foldd. 16-fold

8. Central venous pressure is increased bya. Forcefully exhaling against a closed

glottis.b. Increasing cardiac output.c. Increasing venous compliance.d. Standing.

8. Venous return to the right atrium isa. Decreased as cardiac output in-

creases.b. Decreased by sympathetic activation

of veins.c. Increased during a forced expiration

against a closed glottis.d. Increased during inspiration.

9. Mean circulatory filling pressure is in-creased by

a. Decreased venous compliance.b. Increased systemic vascular resis-

tance.c. Decreased blood volume.d. Increased cardiac output.

10. In a normal heart, cardiac output andright atrial pressure are both increasedby

a. Decreased blood volume.b. Decreased systemic vascular resis-

tance.c. Increased heart rate.d. Increased venous compliance.

SUGGESTED READINGSBerne RM, Levy MN. Cardiovascular Physiology. 8th

Ed. Philadelphia: Mosby, 2001.Guyton AC, Jones CE, Coleman TG. Circulatory

Physiology: Cardiac Output and its Regulation. 2ndEd. Philadelphia: W.B. Saunders, 1973.

Mulvany MJ. Small artery remodeling and significance inthe development of hypertension. News Physiol Sci2002;17:105–109.

Rhoades RA, Tanner GA. Medical Physiology. 2nd Ed.Philadelphia: Lippincott Williams & Wilkins, 2003.

116 CHAPTER 5

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LEARNING OBJECTIVESINTRODUCTIONAUTONOMIC NEURAL CONTROL

Autonomic Innervation of the Heartand Vasculature

Baroreceptor Feedback Regulationof Arterial Pressure

ChemoreceptorsOther Autonomic Reflexes Affecting

the Heart and Circulation

HUMORAL CONTROLCirculating CatecholaminesRenin-Angiotensin-Aldosterone

SystemAtrial Natriuretic PeptideVasopressin (Antidiuretic Hormone)

SUMMARY OF NEUROHUMORALMECHANISMS


c h a p t e r

6Neurohumoral Control of the Heart and Circulation

LEARNING OBJECTIVES

Understanding the concepts presented in this chapter will enable the student to:1. Describe the roles of the following regions of the brain in the autonomic regulation of car-

diac and vascular function: medullary “cardiovascular centers,” hypothalamus, and cortex.2. Describe the origin and distribution of sympathetic and parasympathetic nerves to the

heart and circulation.3. Know the location and function of alpha- and beta-adrenoceptors and muscarinic receptors

in the heart and blood vessels.4. Describe the effects of sympathetic and parasympathetic stimulation on the heart and cir-

culation.5. Describe the location and afferent connections from the carotid sinus, aortic arch, and car-

diopulmonary baroreceptors to the medulla oblongata.6. Describe how carotid sinus baroreceptors respond to changes in arterial pressure (mean

pressure and pulse pressure), and explain how changes in baroreceptor activity affect sym-pathetic and parasympathetic outflow to the heart and circulation.

7. Describe (a) the location of peripheral and central chemoreceptors; (b) the way they re-spond to hypoxemia, hypercapnia, and acidosis; and (c) the effects of their stimulation onautonomic control of the heart and circulation.

8. List the factors that stimulate the release of catecholamines, renin, atrial natriuretic pep-tide, and vasopressin.

9. Describe how sympathetic nerves, circulating catecholamines, angiotensin II, aldosterone,atrial natriuretic peptide, and vasopressin interact to regulate arterial blood pressure.

117

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INTRODUCTION

Autonomic nerves and circulating hormonesserve as important mechanisms for regulatingcardiac and vascular function. These mecha-nisms are controlled by sensors that monitorblood pressure (baroreceptors), blood volume(volume receptors), blood chemistry(chemoreceptors), and plasma osmolarity (os-moreceptors). Peripheral sensors such asbaroreceptors are found in arteries, veins, andcardiac chambers. They have afferent nervefibers that travel to the central nervous sys-tem, where their activity is monitored andcompared against a “set point” for arterialpressure. Deviations from the set point resultin selective activation or deactivation of neu-rohumoral efferent control systems. Sensorslocated within the central nervous system(e.g., central chemoreceptors and osmorecep-tors) also interact with regions within thebrain that control neurohumoral status. Thesensors work together with the neurohumoralmechanisms to ensure that arterial bloodpressure is adequate for perfusing organs.Although the following sections describe sev-eral individual neurohumoral mechanisms,note that all of these mechanisms interact to-gether to ensure cardiovascular homeostasis.

AUTONOMIC NEURAL CONTROL

Autonomic Innervation of the Heartand Vasculature

Autonomic regulation of cardiovascular func-tion is controlled by the central nervous sys-tem. The medulla oblongata located withinthe brainstem, the hypothalamus, and the cor-tical regions work to regulate autonomic func-tion (Figs. 6-1 and 6-2). Regions within themedulla contain the cell bodies for theparasympathetic (vagal) and sympathetic ef-ferent nerves. The hypothalamus plays anintegrative role by modulating medullary neu-ronal activity, for example, during exercise orwhen the body needs to adjust blood flow tothe skin to regulate body temperature. Highercenters, including the cortex, connect withthe hypothalamus and medulla. The highercenters can alter cardiovascular function dur-

ing times of emotional stress (e.g., caused byfear and anxiety).

The central nervous system receives sen-sory (afferent) input from peripheral sensorsand from sensors within the brain. Afferentfibers from peripheral baroreceptors andchemoreceptors, as well as respiratory stretchreceptors, enter the medulla at the nucleustractus solitarius (NTS) (see Fig. 6-2).Inhibitory interneurons from cells within theNTS project to other medullary regions con-taining cell bodies of sympathetic nerves. Inaddition, excitatory interneurons from theNTS project to medullary regions containingcells bodies of parasympathetic (vagal) nerves.The NTS also sends fibers to the hypothala-mus. Sensors within the hypothalamus thatmonitor blood temperature (thermorecep-tors) send fibers to medullary regions to mod-ulate sympathetic outflow to the cutaneouscirculation.

Parasympathetic InnervationThe parasympathetic vagal fibers innervatingthe heart originate from cell bodies located

118 CHAPTER 6

SpinalCord

Hypothalamus

Pons

Medulla

CerebralCortex

FIGURE 6-1 Regions of the central nervous system in-volved in cardiovascular regulation. The primary site ofcardiovascular regulation resides in the medulla; the hy-pothalamus serves as an integrative region for coordi-nating cardiovascular responses. Higher centers such asthe cortex influence cardiovascular function.

Ch06_117-140_Klabunde 4/21/04 11:26 AM

within the medulla of the brainstem (see Figs.6-1 and 6-2). These cell bodies are found incollections of neurons called the dorsal vagalnucleus and nucleus ambiguous. Electricalstimulation of these nuclei produces bradycar-dia; therefore, these regions of the medullaare sometimes referred to as the “cardioin-hibitory center.” Under normal resting condi-tions, these neurons are tonically active,thereby producing what is termed “vagaltone” on the heart, resulting in resting heartrates significantly below the intrinsic firingrate of the sinoatrial pacemaker. Afferentnerves, particularly from peripheral barore-ceptors that enter the medulla through theNTS, modulate the activity of these vagal neu-rons. Excitatory interneurons from the NTS,which normally are excited by tonic barore-

ceptor activity, stimulate vagal activity. In ad-dition, efferent fibers from the hypothalamusmodulate the vagal neurons.

Efferent vagal fibers (also referred to aspreganglionic fibers) exit the medulla as thetenth cranial nerve and travel to the heartwithin the left and right vagus nerves.Branches from these nerves innervate specificregions within the heart such as the sinoatrialand atrioventricular nodes, conduction path-ways, myocytes, and the coronary vasculature.The preganglionic efferent fibers synapsewithin or near the target tissue and form smallganglia, from which short postganglionicfibers innervate specific tissue sites.Activation of these postganglionic fiberscauses the release of the neurotransmitteracetylcholine. This neurotransmitter binds to

NEUROHUMORAL CONTROL OF THE HEART AND CIRCULATION 119

Higher Centers

Hypothalamus

VagalSymp

–

––

+

+

ReceptorAfferents

HeartBlood Vessels

Medulla

NTS+

FIGURE 6-2 Schematic representation of autonomic sympathetic (Symp) and vagal interconnections within the cen-tral nervous system. Receptor afferent nerve fibers (e.g., from baroreceptors) enter the medulla at the nucleus trac-tus solitarius (NTS), which projects inhibitory interneurons to the sympathetic neurons and excitatory fibers to the va-gal neurons. The medulla receives input from the hypothalamus and higher brain centers. Sympathetic activation (�)of blood vessels and the heart causes smooth muscle contraction (vasoconstriction), increased heart rate (positivechronotropy), increased conduction velocity within the heart (positive dromotropy), and increased contractility (posi-tive inotropy). Vagal activation of the heart decreases (�) chronotropy, dromotropy, and inotropy.

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muscarinic receptors (M2), which decreaseschronotropy, dromotropy, and inotropy (moreso in the atria than in the ventricles), and di-lates the coronary vasculature (Table 6-1 andFigure 6-3).

The right vagus is usually the primary vagalbranch that innervates the sinoatrial (SA)node, whereas the left vagus primarily inner-vates the atrioventricular (AV) node and theventricular conduction system. This can be

120 CHAPTER 6

TABLE 6-1 EFFECTS OF SYMPATHETIC AND PARASYMPATHETICSTIMULATION ON CARDIAC AND VASCULAR FUNCTION

SYMPATHETIC PARASYMPATHETIC

Heart

Chronotropy (rate) + + + – – –

Inotropy (contractility) + + + – 1

Dromotropy (conduction velocity) + + – – –

Vessels (Vasoconstriction)

Resistance (arteries, arterioles) + + + – 2

Capacitance (veins, venules) + + + 0

Relative magnitude of responses (�, increase; �, decrease; 0, no response) indicated by number of � or � signs. 1 More pronounced in atria than ventricles.2 Vasodilator effects only in specific organs such as genitalia.

Inotropy

Chronotropy

Dromotropy

SympatheticNerve Terminal

ACh

NE NENEVasoconstriction

Vasodilation

ParasympatheticNerve Terminal

α1

M2 M2

M2

α2α2

α2

α1

β1

β2

β2 β2__

_ _

Blood VesselHeart

FIGURE 6-3 Adrenergic and muscarinic receptors in the heart and blood vessels. Norepinephrine (NE) released fromsympathetic nerve terminals binds to postjunctional adrenoceptors in the heart (subtype affinity to NE: �1>>�2 and�1) to produce positive inotropy, chronotropy, and dromotropy. In blood vessels, NE binds to postjunctional adreno-ceptors (subtype affinity to NE: �1>>�2 and �2). NE binding to postjunctional �-adrenoceptors causes vasoconstric-tion, whereas binding to �2-adrenoceptors causes vasodilation. In both cardiac and vascular tissue, prejunctional �2-adrenoceptors inhibit NE release, and prejunctional �2-adrenoceptors enhance NE release. Parasympathetic (vagal)nerves in the heart release acetylcholine (ACh), which binds to prejunctional muscarinic receptors (M2) to inhibit NErelease. ACh also binds to postjunctional M2 receptors to decrease inotropy, chronotropy, and dromotropy. In a fewspecific organs (e.g., genitalia), ACh released by parasympathetic nerves binds to vascular M2 receptors to produceendothelial-dependent vasodilation.

Ch06_117-140_Klabunde 4/21/04 11:26 AM

demonstrated experimentally by electricallystimulating the right vagus nerve, whichcauses bradycardia (or SA nodal arrest) withlittle change in AV nodal conduction, as evi-denced by a relatively small increase in the P-R interval of the electrocardiogram. Left vagalstimulation, in contrast, usually results in apronounced AV nodal block (see Chapter 2),with relatively little decrease in heart rate.However, these responses to vagal stimulationcan be markedly different between individu-als because of crossover of the left and rightvagal efferents.

Some efferent parasympathetic fibers in-nervate blood vessels in specific organs inwhich they directly or indirectly cause vasodi-lation. Direct vasodilation by parasympatheticactivation in some tissues (e.g., genitalia erec-tile tissue) is achieved through the release ofacetylcholine, which binds to muscarinic re-ceptors on the vascular endothelium to causevasodilation through the subsequent forma-tion of nitric oxide (see Chapter 3).Parasympathetic stimulation causes indirectvasodilation in some organs (e.g., gastroin-testinal circulation) by stimulating non-vascu-lar tissue to produce vasodilator substancessuch as bradykinin, which then binds to vas-cular receptors to cause vasodilation. Notethat any existing parasympathetic nerves pri-marily serve to regulate blood flow within spe-cific organs rather than to play a significantrole in the regulation of systemic vascular re-sistance and arterial blood pressure.

Sympathetic InnervationThe sympathetic adrenergic control of theheart and vasculature originates from neuronsfound within the medulla. These neurons arenot organized into distinct nuclei, but insteadmake up a less defined but highly complex sys-tem of interconnected neurons. Electricalstimulation of certain regions within themedulla produce tachycardia and systemicvasoconstriction; therefore, terms such as“cardiostimulatory centers” and “pressor” and“vasoconstrictor centers” are sometimes usedto describe these neuronal networks.Sympathetic neurons have spontaneous actionpotential activity, which results in tonic stimu-

lation of the heart and vasculature. Therefore,acute sympathetic denervation of the heartand systemic blood vessel usually results inbradycardia and systemic vasodilation. At lowresting heart rates, the effects of sympatheticdenervation on the heart rate are relativelysmall because the heart is under a high levelof vagal tone. In contrast, sympathetic tone isrelatively high in most organ circulations;therefore, sudden removal of sympathetictone produces significant vasodilation and hy-potension.

Parasympathetic activity within themedulla normally inhibits sympathetic activ-ity, and vice versa. Therefore, reciprocal acti-vation of the medullary centers controlling va-gal and sympathetic outflow generally occurs.An example of this reciprocity occurs when aperson stands up and arterial blood pressurefalls. Baroreceptor reflexes cause themedullary centers to increase sympatheticoutflow to stimulate the heart (increase heartrate and inotropy) and to constrict the sys-temic vasculature. These cardiac and vascularresponses help to restore normal arterial pres-sure. As sympathetic fibers are being acti-vated, parasympathetic activity is decreased.This is important because without removal ofvagal influences on the heart, the ability of en-hanced sympathetic activity to increase heartrate is impaired.

Regions within the hypothalamus can inte-grate and coordinate cardiovascular responsesby providing input to medullary centers.Studies have shown that electrical stimulationof specific hypothalamic regions produces au-tonomic responses that mimic those that oc-cur during exercise, or the flight-or-fight re-sponse. These coordinated responses includesympathetic-mediated tachycardia, increasedinotropy, catecholamine release, and systemicvasoconstriction.

Input from higher cortical regions can alterautonomic function as well. For example, sud-den fear or emotion can sometimes cause va-gal activation leading to bradycardia, with-drawal of sympathetic vascular tone, andfainting (vasovagal syncope). Fear and anxi-ety can lead to sympathetic activation thatcauses tachycardia, increased inotropy, and


Ch06_117-140_Klabunde 4/21/04 11:26 AM

hypertension. Chronic sympathetic activationinduced by long-term emotional stress can re-sult in sustained hypertension, cardiac hyper-trophy, and arrhythmias.

Axons from sympathetic neurons (alsotermed preganglionic fibers) leave themedulla, travel down the spinal cord, and exitat specific thoracolumbar levels (T1–L2).These fibers then synapse within sympatheticparavertebral ganglia (cervical, stellate,and thoracolumbar sympathetic chain) lo-cated on either side of the spinal cord, or theysynapse within prevertebral ganglia locatedwithin the abdomen (celiac, superior mesen-

teric, and inferior mesenteric ganglia) (Fig. 6-4). Postganglionic sympathetic fibers travelto target organs where they innervate arteriesand veins; capillaries are not innervated. Smallbranches of these efferent nerves are found inthe adventitia (outer) layer of blood vessels.Varicosities, which are small enlargementsalong the sympathetic nerve fibers, providethe site of neurotransmitter release.

Postganglionic sympathetic fibers travelingto the heart innervate the sinoatrial and atrio-ventricular nodes, conduction system, andcardiac myocytes, as well as the coronary vas-culature. Sympathetic activation increases

122 CHAPTER 6

Heart

BloodVessels

Cervical

Thoracic

Lumbar

T1

T12

ParavertebralGanglia

PrevertebralGanglia

Cranial Nerve X(vagus) A

B

C

D

FIGURE 6-4 Organization of sympathetic and vagal innervation of the heart and circulation. The tenth cranial nerve(vagus; parasympathetic) arises from the brainstem. Preganglionic fibers (solid red line, A) travel to the heart, wherethey synapse with cell bodies of short postganglionic fibers that innervate the heart. Preganglionic sympathetic nerves(solid black lines) arise from thoracic (T1–T12) and lumbar segments of the spinal cord. Some of these fibers (B) en-ter the paravertebral ganglia (sympathetic chain) on both sides of the spinal cord, and travel within the ganglia tosynapse above (B) or below their entry level, or at their level of entry (C). Postganglionic fibers (dotted black lines)from the cervical ganglia primarily innervate the heart, whereas those from thoracic ganglia travel to blood vesselsand to the heart. Preganglionic fibers from lower thoracic and upper lumbar segments generally synapse in prever-tebral ganglia (D), from which postganglionic fibers travel to blood vessels.

Ch06_117-140_Klabunde 4/21/04 11:26 AM

chronotropy, dromotropy, and inotropy (seeTable 6-1). These effects are mediated pri-marily by norepinephrine binding to �1-adrenoceptors on the heart (see Figure 6-3).There are also post-junction �2-adrenoceptorsin the heart; however, they are normally lessimportant than �1-adrenoceptors. Prejunctional�2-adrenoceptors facilitate norepinephrinerelease, whereas prejunctional �2-adrenocep-tors inhibit norepinephrine release.

Sympathetic activation constricts both re-sistance and capacitance vessels, thereby in-creasing systemic vascular resistance (and ar-terial blood pressure) and decreasing venouscapacitance (which increases venous pres-sure) (see Table 6-1). Norepinephrine re-leased by sympathetic adrenergic nerves pref-erentially binds �1-adrenoceptors to causesmooth muscle contraction and vasoconstric-tion (see Figure 6-3). Similar responses occurwhen norepinephrine binds to postjunctional�2-adrenoreceptors located primarily on smallarteries and arterioles, although postjunc-tional �1-adrenoceptors are generally themore important �-adrenoceptor subtype. Inaddition, norepinephrine can bind to prejunc-tional �2-adrenoreceptors, which acts as anegative feedback mechanism for modulatingnorepinephrine release.

Blood vessels possess postjunctional �2-adrenoceptors. Activation of postjunctional �2-adrenoceptors by norepinephrine (and, moreimportantly, by circulating epinephrine)causes vasodilation in the absence of opposing�-adrenoceptor mediated vasoconstriction. Toobserve this �2-adrenoceptor induced vasodi-lation experimentally, one can stimulate vascu-lar sympathetic nerves in the presence of com-plete �-adrenoceptor blockade. Normally, thissmall �2-receptor mediated vasodilator effectof norepinephrine is completely overwhelmedby simultaneous �-adrenoceptor activation,leading to vasoconstriction.

Sympathetic activation of resistance vesselssignificantly contributes to the vascular tone inmany organs. This can be demonstrated byabruptly removing sympathetic influences(e.g., by blocking �-adrenoceptors with drugs).When this is done, blood flow increases, theamount of which depends upon the degree of

sympathetic tone and the strength of local au-toregulatory mechanisms that will attempt tomaintain constant blood flow (see Chapter 7).For example, if �-adrenoceptors in the fore-arm circulation are blocked pharmacologically,blood flow increases two- or three-fold. Overtime, however, intrinsic autoregulatory mecha-nisms restore normal tone and blood flow.

As described further in Chapter 7, the vas-cular response to sympathetic activation dif-fers among organs. For example, skeletal mus-cle, cutaneous, gastrointestinal, and renalcirculations are strongly influenced by sympa-thetic activity. In contrast, the coronary andcerebral circulations have only weak re-sponses to sympathetic stimulation. Sym-pathetic stimulation of the heart producesonly transient coronary vasoconstriction,which is followed by vasodilation produced bymetabolic factors associated with increasedcardiac mechanical activity. Therefore, gener-alized sympathetic activation of the circula-tion increases arterial pressure and reducesorgan perfusion throughout the body exceptin the heart and brain.

Baroreceptor Feedback Regulationof Arterial Pressure

As described above, sympathetic nerves playan important role in regulating systemic vas-cular resistance and cardiac function, andtherefore arterial blood pressure. But, howdoes the body control the systemic vascularresistance and cardiac output to establish andmaintain an arterial blood pressure to ensureadequate organ perfusion?

Arterial blood pressure is regulatedthrough negative feedback systems incorpo-rating pressure sensors (i.e., baroreceptors)found in strategic locations within the cardio-vascular system. Arterial baroreceptors arefound in the carotid sinus (at the bifurcationof external and internal carotids) and in theaortic arch (Fig. 6-5). The sinus nerve (nerveof Hering), a branch of the glossopharyngealnerve (cranial nerve IX), innervates thecarotid sinus. Afferent fibers from the carotidsinus travel in the glossopharyngeal nerve upto the brainstem, where they synapse at the


Ch06_117-140_Klabunde 4/21/04 11:26 AM

nucleus tractus solitarius. The nucleus tractussolitarius modulates the activity of “cardiovas-cular centers” within the medulla. The aorticarch baroreceptors are innervated by the aor-tic nerve, which then combines with the vagus

nerve (cranial nerve X) before traveling to thenucleus tractus solitarius.

The arterial baroreceptors respond to thestretching of the vessel walls produced by in-creases in arterial blood pressure (Figure 6-6).Increased arterial pressure increases the firingrate of individual receptors and nerves. Eachindividual receptor has its own threshold andsensitivity to changes in pressure; therefore,additional receptors are recruited as pressureincreases. Overall, the receptors of the carotidsinus respond to pressures ranging from about60–180 mm Hg. Therefore, if arterial bloodpressure decreases from normal, it lowers thefiring rate of the carotid sinus baroreceptors;conversely, increased arterial pressure in-creases receptor firing.

Baroreceptors are sensitive to the rate ofpressure change and to a steady or mean pres-sure. At a given mean arterial pressure, de-creasing the arterial pulse pressure decreasesfiring rate. This is important during conditionssuch as hemorrhagic shock in which pulsepressure (as well as mean pressure) decreasesbecause of the decline in stroke volumecaused by decreased ventricular preload andincreased heart rate. Therefore, reducedpulse pressure reinforces the baroreceptor re-flex when mean arterial pressure falls. Thecurve representing the frequency of barore-ceptor firing in Figure 6-6 is the integrated re-ceptor firing at a given pulse pressure. At re-duce pulse pressures, the curve shifts to the

124 CHAPTER 6

L. InternalCarotid

R. InternalCarotid

R. ExternalCarotid

L. ExternalCarotid

Aortic ArchReceptors

CarotidSinus

Receptors

Vagus Nerve(Cranial Nerve X)

Glossopharyngeal Nerve(Cranial Nerve IX)

AscendingAorta

Sinus Nerve

FIGURE 6-5 Location and innervation of arterial barore-ceptors. Carotid sinus receptors are located on the in-ternal carotid artery just above the junction with the ex-ternal carotid artery. These receptors are innervated bythe sinus nerve of Hering, which joins the glossopha-ryngeal nerve (cranial nerve IX) before traveling up tothe medulla. Afferent nerves from the aortic arch re-ceptors join the vagus nerve (cranial nerve X), whichthen travel to the medulla. R, right; L, left.

0100 200

50

100

Mean Arterial Pressure(mmHg)

IntegratedReceptor

Firing Rate(% max)

Arterial Pressure Pulse

ReceptorFiring

Carotid Sinus

Mean

MaximalSensitivity

ReducePulse

Pressure

NormalPulse

Pressure

FIGURE 6-6 Effects of arterial pressure on integrated carotid sinus firing rate. Left panel: The threshold for receptoractivation occurs at mean arterial pressures of about 60 mm Hg; maximal firing occurs at about 180 mm Hg. Maximalreceptor sensitivity occurs at normal mean arterial pressures. The receptor firing-response curve shifts to the rightwith decreased pulse pressures; therefore, a decrease in pulse pressure at a given mean pressure decreases firing.Right panel: Single receptor firing in response to pulsatile pressure. Receptors fire more rapidly when arterial pressureis rapidly increasing during cardiac systole.

Ch06_117-140_Klabunde 4/21/04 11:26 AM

right, thereby decreasing the firing at anygiven mean arterial pressure.

Maximal carotid sinus sensitivity (the pointof greatest slope of the response curve inFigure 6-6) occurs near the “set point” of nor-mal mean arterial pressures (approximately 95mm Hg in adults). Therefore, small deviationsfrom this set point elicit large changes inbaroreceptor firing frequency. This set point,and the entire receptor response curve, is notfixed. Chronic shifts in this curve can occurduring hypertension, heart failure, and otherdisease states. In hypertension, for example,the curve shifts to the right, thereby reducingthe firing rate at any given mean arterial pres-sure. This resetting of the baroreceptor re-sponse can occur at the level of the receptorsthemselves as well as in the brainstem. In ar-teriosclerosis, the carotid arteries at the regionof the carotid sinus become less compliant,and therefore they stretch less in response tochanges in arterial blood pressure—this de-creases their sensitivity. During exercise,medullary and hypothalamic control centerscan modulate autonomic efferent responses ata given level of baroreceptor firing, therebyresetting arterial pressure to a higher level.

Receptors located within the aortic archfunction similarly to carotid sinus receptors;however, they have a higher threshold pres-sure for firing and are less sensitive than thecarotid sinus receptors. Therefore, the aorticarch baroreceptors serve as secondary barore-ceptors, with the carotid sinus receptors nor-mally being the dominant arterial barorecep-tor.

To understand how the baroreceptor reflexoperates, consider the events that occur in re-sponse to a decrease in arterial pressure(mean, pulse, or both) when a person sud-denly stands up (Figure 6-7). When uprightposture is suddenly assumed from the supineposition, gravity causes venous blood poolingbelow the heart, particularly in the legs (seeChapter 5). This decreases venous return,central venous pressure, and ventricular pre-load, leading to a fall in cardiac output and ar-terial blood pressure. Decreased stretching ofbaroreceptors results in decreased barorecep-tor firing. The “cardiovascular center” within

the medulla responds by increasing sympa-thetic outflow, which increases systemic vas-cular resistance (vasoconstriction) and cardiacoutput (increased heart rate and inotropy).Decreased parasympathetic outflow from themedulla contributes to the elevation in heartrate.

Note that baroreceptor firing normally ex-erts a tonic inhibitory influence on sympa-thetic outflow from the medulla. Therefore,hypotension and decreased baroreceptor fir-ing disinhibits sympathetic outflow (i.e., it in-creases sympathetic activity) from themedullary centers. The combined effects onsystemic vascular resistance and cardiac out-put increases arterial blood pressure back to-ward its set point.

The carotid sinus reflex can be activated byrubbing the neck over the carotid sinus (i.e.,carotid sinus massage). This mechanicalstimulation of the receptors increases their fir-ing, which leads to decreased sympathetic andincreased parasympathetic outflow from themedulla. This action is sometimes used toabort certain types of arrhythmias by activat-ing the vagus efferents to the heart.

In addition to arterial baroreceptors,stretch receptors are located at the venoatrialjunctions of the heart (cardiopulmonary re-ceptors) and respond to atrial filling and con-traction. These tonically active receptors are


CNS

SVR

CO

DecreasedArterial

Pressure

DecreasedReceptor

Firing

Sympathetic↑

Parasympathetic↓

+

+ +

+

FIGURE 6-7 Baroreceptor feedback loop. A sudden de-crease in arterial pressure, as occurs when a person sud-denly stands up from a supine position, decreasesbaroreceptor firing, activating sympathetic nerves andinhibiting parasympathetic (vagal) nerves. This changein autonomic balance increases (�) cardiac output (CO)and systemic vascular resistance (SVR), which helps torestore normal arterial pressure. CNS, central nervoussystem.

Ch06_117-140_Klabunde 4/21/04 11:26 AM

innervated by myelinated vagal afferents.Increased stretch caused by an increase in ve-nous return can sometimes increase heart ratevia medullary center activation of sympatheticefferent activity to the SA node. This re-sponse, which is called the Bainbridge re-flex, increases heart rate when the initialheart rate is low.

An increase in blood volume and venouspressure stimulates other types of cardiopul-monary receptors to decrease antidiuretichormone (ADH, vasopressin) release by theposterior pituitary. Decreased circulatingADH causes diuresis, which leads to a fall inblood volume and venous pressure. If bloodvolume is lost as a result of dehydration or he-morrhage, these receptors will increase ADHrelease so that the kidneys excrete less water.

Unmyelinated vagal afferents are foundthroughout the atria and ventricles. Receptorsassociated with these vagal afferents respondto stretch such that the firing rate of these re-ceptors is enhanced with increased atrial andventricular pressures. The effects of these re-

ceptors on sympathetic and vagal outflow aresimilar to on the arterial baroreceptors.Depending upon the circumstances, however,these receptors can either oppose or reinforcearterial baroreceptor function. In heart fail-ure, atrial and ventricular filling pressures areincreased, whereas arterial pressure is de-creased. Under this condition, increased firingby the atrioventricular receptors opposes thedecreased firing by arterial baroreceptors.During hemorrhage, cardiac chamber pres-sures and arterial pressures are both reduced.This causes the atrioventricular receptors andthe arterial baroreceptors to decrease their fir-ing rates and therefore reinforce each other.

Chemoreceptors

Chemoreceptors are specialized cells locatedon arteries (peripheral chemoreceptors) andwithin the medulla (central chemoreceptors)that monitor pO2, pCO2, and H� concentra-tion. Their primary function is to regulate res-piratory activity to maintain arterial blood

126 CHAPTER 6

How do the carotid sinus baroreceptors respond to occlusion of both common carotidarteries? What are the cardiovascular responses to bilateral carotid occlusion? Howwould these responses be altered by bilateral vagotomy? How would these responsesbe altered by the pharmacologic blockade of �1-adrenoceptors?

The common carotid arteries are below the carotid sinus baroreceptors. Therefore,occlusion of both carotid arteries reduces pressure within the carotid sinuses. This de-creases their firing, leading to increased sympathetic and decreased vagal outflowfrom the medullary cardiovascular centers. This action results in systemic vasoconstric-tion (increased systemic vascular resistance and decreased venous compliance) and car-diac stimulation (increased heart rate and inotropy). These cardiovascular adjustmentswill cause arterial pressure to rise.

Bilateral vagotomy enhances the response described above because as arterial pres-sure rises during carotid occlusion, the aortic arch baroreceptors, which are innervatedby the vagus nerve, increase their firing. This partially counteracts the effects of de-creased carotid sinus firing. Bilateral vagotomy removes this influence of the aorticarch baroreceptors.

Blockade of �1-adrenoceptors would prevent the sympathetic-mediated increases inheart rate and inotropy (although some withdrawal of vagal tone may still result in asmall tachycardia). The pressor response would still occur because of systemic vasocon-striction (�1-adrenoceptor mediated); however, it would be blunted significantly be-cause cardiac stimulation would be blocked.

PROBLEM 6-1

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pO2, pCO2, and pH within a narrow physio-logic range. Chemoreceptor activity, however,affects cardiovascular function either directlyby influencing medullary cardiovascular cen-ters or indirectly through altered pulmonarystretch receptor activity. Impaired respiratorygas exchange, hypoxic environments, cerebralischemia, and circulatory shock, for example,increase chemoreceptor activity, leading toenhanced sympathetic outflow to the heartand vasculature by activating pressor regionswithin the medulla.

The peripheral chemoreceptors arefound in two locations. Small carotid bodiesare associated with the external carotid arter-ies near their bifurcation with the internalcarotids. Afferent nerve fibers from thecarotid body receptors join with the sinusnerve before entering the glossopharyngealnerve to synapse in the medulla. The carotidbodies increase their firing in response to a fallin arterial pO2 (hypoxemia) or to an increasein arterial pCO2 (hypercapnia) and hydrogenion concentration (acidosis). The thresholdpO2 for activation is about 80 mm Hg (normalarterial pO2 is about 95 mm Hg). Any eleva-tion of pCO2 above its normal value of 40 mmHg, or a decrease in pH below 7.4, also in-creases receptor firing. In addition, carotidbody firing can be stimulated by reducedcarotid body perfusion, as occurs during hy-potension associated with circulatory shock.This response to reduced perfusion can occurwithout changes in arterial pO2, pCO2, andpH. The mechanism may involve cellular hypoxia resulting from inadequate oxygen de-livery to the carotid bodies (i.e., “stagnanthypoxia”). Another set of peripheral chemore-ceptors, the aortic bodies, are located on theaortic arch, and they function similarly to thecarotid bodies. Their afferent connections tothe medulla travel with the vagus nerve.

Central chemoreceptors are found inthe medulla regions that control cardiovascu-lar and respiratory activity. These receptorsincrease their firing in response to hyper-capnia and acidosis but not directly in re-sponse to hypoxia. Carbon dioxide diffusingfrom the blood into the cerebrospinal fluidforms hydrogen ion by the bicarbonate buffer

system, and it is the hydrogen ion rather thanthe carbon dioxide that stimulates receptorfiring.

If a subject breathes a gas mixture contain-ing 10% instead of 21% oxygen, chemorecep-tor activation (primarily peripheral) increasesrespiratory activity and stimulates sympatheticactivity to the heart and systemic vasculature,causing arterial blood pressure to increase. If,however, respiratory rate and depth are not al-lowed to change, the sympathetic-mediatedpressor response is accompanied by bradycar-dia resulting from vagal activation of theheart. This demonstrates that the tachycardianormally found during hypoxemia is sec-ondary to respiratory stimulation and activa-tion of pulmonary stretch receptors.Cardiovascular responses to hypercapnia andacidosis likewise depend in part upon respira-tory responses.

Other Autonomic Reflexes Affectingthe Heart and Circulation

In addition to the baroreceptor and chemore-ceptor reflexes already described, severalother reflexes affect cardiovascular function(Table 6-2). An increase in intracranial pres-sure, which can occur following hemorrhagicstroke or brain trauma, elicits a strong, sympa-thetic-mediated pressor response (Cushingreflex), often accompanied by baroreceptor-mediated bradycardia. It is thought that thehigh intracranial pressure produces brain is-chemia that stimulates medullary centers.Another sympathetic reflex involving the brainoccurs when cerebral perfusion falls owing tosevere hypotension (a mean arterial pressureless than 60 mm Hg), producing cerebral ischemia. This can be thought of as a final ef-fort by the body to restore perfusion pressureto the brain by causing intense constriction ofthe systemic circulation. Mean arterial pres-sure can rise to well over 200 mm Hg duringsevere cerebral ischemia.

Pain also affects cardiovascular function.For example, chest pain associated with coro-nary ischemia (anginal pain) or myocardial in-farction in the anterior left ventricle can causegeneralized sympathetic activation, leading to


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128 CHAPTER 6

TABLE 6-2 REFLEXES AFFECTING THE HEART AND CIRCULATION THROUGHCHANGES IN SYMPATHETIC AND PARASYMPATHETIC ACTIVITY

RECEPTOR RECEPTOR SYMPATHETIC PARASYMPA-

REFLEX TYPE LOCATION STIMULUS ACTIVITY THETIC ACTIVITY

Arterial Baroreceptor

Bainbridge

Cardiac

Peripheral Chemo-receptor

Central Chemo-receptors

Cushing Reflex

Cerebral Ischemia

Bezold-Jarisch Reflex

Pain

Deep Pain

Vasovagal Reflex

Pulmonary Stretch Reflex

Muscle and Joint Reflex

Diving Reflex

Temperature Reflex

Mechanoreceptors sense deformation or stretch; chemoreceptors respond to chemical stimuli; nociceptors respondto pain caused by mechanical, thermal, or chemical stimuli; proprioceptors sense position and movement; and ther-moreceptors respond to either cold or warm temperatures. The vasovagal reflex can be triggered by several differ-ent stimuli such as pain or strong emotion. 1Decreased parasympathetic activity to heart contributes to the increasein heart rate seen when respiration is augmented. If respiration is held constant, parasympathetic activity is in-creased, leading to bradycardia. 2Brain ischemia caused by high intracranial pressure and reduced cerebral perfusionstimulates chemoreceptors via increased hydrogen ion concentration. 3Cardiac ischemic pain, as well as other originsof pain, can trigger this reflex. 4Deep pain arising from viscera and muscle elicits this reflex.

Mechano-receptor

Mechano-receptor

Mechano-receptor

Chemo-receptor

Chemo-receptor

Chemo-receptor 2

Chemo-receptor

Chemo-receptor

Nociceptor

Nociceptor

Various

Proprio-ceptor

Proprio-ceptor,Chemo-receptor

Thermo-receptor

Thermo-receptor

InternalCarotids andAortic Arch

VenoatrialJunctions

Atria andVentricles

Carotid andAorticBodies

Medulla

Brain

Brain

Ventricles and coro-nary arteries

Various 3

Various 4

Various

Airways,RespiratoryMuscles

Muscles

Face

Skin, Hypo-thalamus

IncreasedArterialPressure

IncreasedVenous Return

IncreasedChamberPressure

Hypoxia,Hypercapnia,Acidosis

Hypercapnia,Acidosis

IntracranialPressure

Ischemia

Chemical,Ischemia

Pain

Pain

StrongEmotion, Pain

Lung Inflation

MuscleMovement

WaterSubmersion

Increased &DecreasedTemperature

Decreased

Increased

Decreased

Increased

Increased

Increased

Increased

Decreased

Increased

Decreased

Decreased

Decreased

Increased

Increased

Increased orDecreased

Increased

Decreased

Increased

Decreased 1

Decreased

Increased

Decreased

Increased

Decreased

Increased

Increased

Decreased

Decreased

Increased

Insignificant

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elevated arterial pressure and tachycardia andto sweating (diaphoresis). If cardiac outputdecreases significantly because of the is-chemic injury, arterial pressure may fall de-spite the enhanced sympathetic activity. Deeppain produced by trauma or visceral disten-sion can produce hypotension (i.e., circulatoryshock) caused by enhanced parasympatheticand decreased sympathetic activity. Anotherexample of a pain reflex is the cold pressorresponse. If a person’s hand is submergedinto ice-cold water, arterial pressure increasesas a result of sympathetic activation.

Stimulation of specific types of chemore-ceptors within the heart and coronary arteriescan produce bradycardia and hypotension me-diated by vagus nerve afferents and efferents(Bezold-Jarisch reflex). This reflex is some-times stimulated when dye is injected intocoronary arteries during coronary arteriogra-phy. Ischemia within the inferoposterior wallof the left ventricle can likewise produce thisreflex.

Lung inflation activates pulmonarystretch receptors (located in the airways andrespiratory muscles) that inhibit medullarysympathetic centers and cause arterial pres-sure to fall; heart rate increases reflexively.These receptors contribute to the normalcyclical changes in heart rate and arterialpressure associated with respiratory activity.

Limb muscles and tendons also possess re-ceptors that sense tension and length changes(muscle and joint stretch receptors).Passive or active movement of joints can stim-ulate sympathetic activity to the heart and cir-culation and help to reinforce cardiovascularresponses to exercise.

The diving reflex is observed in man, al-though this reflex is far more developed in an-imals such as seals and ducks. When a persondives under water, the heart rate slows (vagalmediated) and systemic blood flow is reducedowing to peripheral vasoconstriction (sympa-thetic mediated). This response reduces oxy-gen consumption by the body and myo-cardium while preserving coronary andcerebral blood flow. Breath holding enhancesthis reflex. Thermoreceptors located on theface respond to the cool water and relay this

information to the brainstem through afferentfacial nerves.

Finally, changes in environmental temper-ature sensed by cold and warm thermore-ceptors in the skin can lead to reflex changesin cutaneous blood flow and sweating.Similarly, changes in core temperature,sensed by thermoreceptors located in the hy-pothalamus, produce changes in sympatheticactivity to the skin circulation. For example, adecrease in either skin surface temperature orhypothalamic blood temperature leads to cu-taneous vasoconstriction.

HUMORAL CONTROL

In addition to autonomic nerves, many circu-lating factors (humoral substances) exist thataffect cardiac and vascular function. Some ofthese humoral factors directly influence theheart and blood vessels, whereas others indi-rectly alter cardiovascular function throughchanges in blood volume. Major humoral fac-tors include circulating catecholamines, therenin-angiotensin-aldosterone system, atrialnatriuretic peptide, and antidiuretic hormone(vasopressin). Although not addressed in thischapter, note that many other hormones andcirculating substances (e.g., thyroxine, estro-gen, insulin, and growth hormone) have director indirect cardiovascular effects.

Circulating Catecholamines

Circulating catecholamines originate fromtwo sources. The adrenal medulla releasescatecholamines (80% epinephrine, 20% nor-epinephrine) when preganglionic sympatheticnerves innervating this tissue are activated.This occurs during times of stress (e.g., exer-cise, heart failure, blood loss, emotional stress,excitement, or pain). Sympathetic nerves in-nervating blood vessels are another source ofcirculating catecholamines, principally norep-inephrine. Normally, most of the norepineph-rine released by sympathetic nerves is takenback up by the nerves and metabolized (someis taken up by extraneuronal tissues). A smallamount of released norepinephrine, however,diffuses into the blood and circulates through-


Ch06_117-140_Klabunde 4/21/04 11:26 AM

out the body. At times of high levels of sym-pathetic nerve activation, the amount of nor-epinephrine spilling over into the blood canincrease dramatically.

Circulating epinephrine has several directcardiovascular actions that depend upon therelative distribution of adrenergic receptors indifferent organs and the relative affinities ofthe different receptors for epinephrine.Epinephrine binds to �1, �2, �1, and �2

adrenoceptors; however, the affinity of epi-nephrine for �-adrenoceptors is much greaterthan for �-adrenoceptors. The relative recep-tor affinities explain why, at low plasma con-centrations, epinephrine binds preferentially

to �-adrenoceptors. Therefore, at low to mod-erate circulating levels of epinephrine, heartrate, inotropy, and dromotropy are stimulated(primarily �1-adrenoceptor mediated). Epi-nephrine at low concentrations binds to �2-adrenoceptors located on small arteries andarterioles (particularly in skeletal muscle) andcauses vasodilation.

If a low dose of epinephrine is injected in-travenously while systemic hemodynamics aremonitored, heart rate (and cardiac output)will increase, systemic vascular resistance willfall, but mean arterial pressure will changevery little (Fig. 6-8; Table 6-3). At high plasmaconcentrations, the cardiovascular actions of

130 CHAPTER 6

FIGURE 6-8 Effects of intravenous administration of a low dose of epinephrine on arterial pressure and heart rate. Alow dose of epinephrine increases heart rate and arterial pulse pressure (it increases systolic and decreases diastolicpressure) with little change in mean arterial pressure. These changes occur because low concentrations of epineph-rine preferentially bind to cardiac �1-adrenoceptors (produces cardiac stimulation) and vascular �2-adrenoceptors(produces systemic vasodilation). Mean pressure does not change very much because the increase in cardiac outputis offset by the decrease in systemic vascular resistance.

TABLE 6-3 DIRECT EFFECTS OF LOW PLASMA CONCENTRATIONS OFEPINEPHRINE (EPI) AND NOREPINEPHRINE (NOREPI) ON CARDIACAND VASCULAR FUNCTION

EPI NOREPI

Cardiac

Heart Rate � � 1

Inotropy � �

Dromotropy � �

Vasculature

Resistance �/� 2 �

Capacitance � �

�, increases; –, decreases. 1 Decreases heart rate invivo owing to baroreceptor reflexes. 2 Some vascularbeds constrict, whereas others dilate.

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epinephrine are different because epineph-rine binds to �-adrenoceptors as well as to �-adrenoceptors. Increasing concentrations ofepinephrine result in further cardiac stimula-tion along with �-adrenoceptor mediated acti-vation of vascular smooth muscle leading tovasoconstriction. This increases arterial bloodpressure (pressor response) owing to both anincrease in cardiac output and an increase insystemic vascular resistance.

Circulating norepinephrine affects theheart and systemic vasculature by binding to�1, �2, �1, and �2 adrenoceptors; however, theaffinity of norepinephrine for �2 and �2-adrenoceptors is relatively weak. Therefore,the predominant affects of norepinephrineare mediated through �1 and �1-adrenocep-tors. If norepinephrine is injected intra-venously, it causes an increase in mean arter-ial blood pressure (systemic vasoconstriction)and pulse pressure (owing to increased strokevolume) and a paradoxical decrease in heartrate after an initial transient increase in heartrate (Fig. 6-9; Table 6-3). The transient in-

crease in heart rate is due to norepinephrinebinding to �1-adrenoceptors in the sinoatrialnode, whereas the secondary bradycardia isdue to a baroreceptor reflex (vagal-mediated),which is in response to the increase in arterialpressure.

High levels of circulating catecholamines,caused by a catecholamine-secreting adrenaltumor (pheochromocytoma), causes tachy-cardia, arrhythmias, and severe hypertension(systolic arterial pressures can exceed 200 mmHg).

Other actions of circulating catecholaminesinclude (1) stimulation of renin release withsubsequent elevation of angiotensin II (AII)and aldosterone, and (2) cardiac and vascularsmooth muscle hypertrophy and remodeling.These actions of catecholamines, in addition tothe hemodynamic and cardiac actions alreadydescribed, make them a frequent therapeutictarget for the treatment of hypertension, heartfailure, coronary artery disease, and arrhyth-mias. This has led to the development and useof many different types of � and �-adrenocep-


How would the changes in arterial pressure and heart rate shown in Figure 6-8 be dif-ferent if �1-adrenoceptors were blocked before the administration of low-dose epi-nephrine?

�1-adrenoceptor activation is responsible for the tachycardia and increased cardiacoutput produced by epinephrine. Blocking �1-adrenoceptors would abolish this re-sponse. Epinephrine also binds to vascular �2-adrenoceptors to cause vasodilation;therefore arterial pressure would fall during epinephrine infusion in the presence of�1-adrenoceptor blockade because the decrease in systemic vascular resistance wouldnot be offset by an increase in cardiac output.

PROBLEM 6-2

How would the norepinephrine-induced changes in arterial pressure and heart rateshown in Figure 6-9 be different in the presence of bilateral cervical vagotomy?

Bilateral cervical vagotomy would prevent vagal slowing of the heart and denervatethe aortic arch baroreceptors. Heart rate (and inotropy) would increase owing to nor-epinephrine binding to �1-adrenoceptors on the heart that is now unopposed by thevagus. This, along with aortic arch denervation, would enhance the pressor response ofnorepinephrine.

PROBLEM 6-3

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tor antagonists to modulate the effects of cir-culating catecholamines as well as the norepi-nephrine released by sympathetic nerves.

Renin-Angiotensin-AldosteroneSystem

The renin-angiotensin-aldosterone systemplays an important role in regulating blood vol-ume, cardiac and vascular function, and arterialblood pressure. Although the pathways forrenin and angiotensin formation have beenfound in a number of tissues, the most impor-tant site for renin formation and subsequentformation of circulating angiotensin is the kid-ney. Sympathetic stimulation of the kidneys(via �1-adrenoceptors), renal artery hypoten-sion, and decreased sodium delivery to the dis-tal tubules (usually caused by reducedglomerular filtration rate secondary to reducedrenal perfusion) stimulate the release of renininto the circulation. The renin is formed within,and released from, juxtaglomerular cells as-sociated with afferent and efferent arterioles ofrenal glomeruli, which are adjacent to the mac-ula densa cells of distal tubule segments thatsense sodium chloride concentrations in thedistal tubule. Together, these components arereferred to as the juxtaglomerular apparatus.

Renin is an enzyme that acts upon an-giotensinogen, a circulating substrate syn-

thesized and released by the liver, which un-dergoes proteolytic cleavage to form the de-capeptide angiotensin I. Vascular endothe-lium, particularly in the lungs, has an enzyme,angiotensin-converting enzyme (ACE),that cleaves off two amino acids to form theoctapeptide, angiotensin II.

Angiotensin II has several important func-tions that are mediated by specific angiotensinII receptors (AT1) (Figure 6-10). It

1. Constricts resistance vessels, thereby in-creasing systemic vascular resistance andarterial pressure.

2. Facilitates norepinephrine release fromsympathetic nerve endings and inhibitsnorepinephrine re-uptake by nerve end-ings, thereby enhancing sympatheticadrenergic affects.

3. Acts upon the adrenal cortex to release al-dosterone, which in turn acts upon the kid-neys to increase sodium and fluid reten-tion, thereby increasing blood volume.

4. Stimulates the release of vasopressin fromthe posterior pituitary, which acts upon thekidneys to increase fluid retention andblood volume.

5. Stimulates thirst centers within the brain,which can lead to an increase in blood vol-ume.

6. Stimulates cardiac and vascular hypertrophy.

132 CHAPTER 6

60

80

100

140

180

100

120

60

FIGURE 6-9 Effects of intravenous administration of a moderate dose of norepinephrine on arterial pressure andheart rate. Norepinephrine increases mean arterial pressure and arterial pulse pressure; heart rate transiently increases(�1-adrenoceptor stimulation), then decreases owing to baroreceptor reflex activation of vagal efferents to the heart.Mean arterial pressure rises because norepinephrine binds to vascular �1-adrenoceptors, which increases systemicvascular resistance.

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Angiotensin II is continuously producedunder basal conditions, and this productioncan change under different physiologic condi-tions. For example, when a person exercises,circulating levels of angiotensin II increase.An increase in renin release during exerciseprobably results from sympathetic stimulationof the kidneys. Changes in body posture like-wise alter circulating AII levels, which are in-creased when a person stands. As with exer-cise, this results from sympathetic activation.Dehydration and loss of blood volume (hypo-volemia) stimulate renin release and an-giotensin II formation in response to renalartery hypotension, decreased glomerular fil-tration rate, and sympathetic activation.

Several cardiovascular disease states are as-sociated with changes in circulating an-giotensin II. For example, secondary hyper-tension caused by renal artery stenosis isassociated with increased renin release andcirculating angiotensin II. Primary hyperal-dosteronism, caused by an adrenal tumorthat secretes large amounts of aldosterone, in-creases arterial pressure through its effects onrenal sodium retention. This increases blood

volume, cardiac output, and arterial pressure.In this condition, renin release and circulatingangiotensin II levels are usually depressed be-cause of the hypertension. In heart failure,circulating angiotensin II increases in re-sponse to sympathetic activation and de-creased renal perfusion. Therapeutic manipu-lation of the renin-angiotensin-aldosteronesystem has become important in treating hy-pertension and heart failure. ACE inhibitorsand AT1 receptor blockers effectively decreasearterial pressure, ventricular afterload, bloodvolume, and hence ventricular preload, andthey inhibit and reverse cardiac and vascularremodeling that occurs during chronic hyper-tension and heart failure.

Note that local, tissue-produced an-giotensin may play a significant role in cardio-vascular pathophysiology. Many tissues andorgans, including the heart and blood vessels,can produce renin and angiotensin II, whichhave actions directly within the tissue. Thismay explain why ACE inhibitors can reducearterial pressure and cause cardiac and vascu-lar remodeling (e.g., diminish hypertrophy)even in individuals who do not have elevated


Renin

AII

ArterialPressure

Aldosterone

↑Renal

Sodium & FluidRetention

AngiotensinogenSympatheticStimulation

Hypotension

SodiumDelivery ACE

SystemicVasoconstriction

BloodVolume

AIKidney

CardiacOutput

Cardiac &Vascular

Hypertrophy

AdrenalCortex

↓

↑↑

Thirst

FIGURE 6-10 Formation of angiotensin II and its effects on renal, vascular, and cardiac function. Renin is released bythe kidneys in response to sympathetic stimulation, hypotension, and decreased sodium delivery to distal tubules.Renin acts upon angiotensinogen to form angiotensin I (AI), which is converted to angiotensin II (AII) by angiotensin-converting enzyme (ACE). AII has several important actions: it stimulates aldosterone release, which increases renalsodium reabsorption; directly stimulates renal sodium reabsorption; stimulates thirst; produces systemic vasocon-striction; and causes cardiac and vascular smooth muscle hypertrophy. The overall systemic effect of increased AII isincreased blood volume, venous pressure, and arterial pressure.

Ch06_117-140_Klabunde 4/21/04 11:26 AM

circulating levels of angiotensin II. In hyper-tension and heart failure, for example, tissueACE activity is often elevated, and this may bethe primary target for the pharmacologic ac-tions of ACE inhibitors.

Atrial Natriuretic Peptide

Atrial natriuretic peptide (ANP) is a 28-aminoacid peptide that is synthesized, stored, andreleased by atrial myocytes in response toatrial distension, angiotensin II stimulation,endothelin, and sympathetic stimulation (�-adrenoceptor mediated). Therefore, elevatedlevels of ANP are found during conditionssuch as hypervolemia and congestive heartfailure, both of which cause atrial distension.

ANP is involved in the long-term regula-tion of sodium and water balance, blood vol-ume, and arterial pressure (Figure 6-11).Most of its actions are the opposite of angiotensin II, and therefore ANP is acounter-regulatory system for the renin-angiotensin-aldosterone system. ANP de-creases aldosterone release by the adrenalcortex; increases glomerular filtration rate;

produces natriuresis and diuresis (potassiumsparing); and decreases renin release, therebydecreasing angiotensin II. These actions re-duce blood volume, which leads to a fall incentral venous pressure, cardiac output, andarterial blood pressure. Chronic elevations ofANP appear to decrease arterial blood pres-sure primarily by decreasing systemic vascularresistance.

The mechanism of systemic vasodilationmay involve ANP receptor-mediated eleva-tions in vascular smooth muscle cGMP (ANPactivates particulate guanylyl cyclase). ANPalso attenuates sympathetic vascular tone.This latter mechanism may involve ANP act-ing upon sites within the central nervous sys-tem as well as through inhibition of norepi-nephrine release by sympathetic nerveterminals.

A new class of drugs that are neutral en-dopeptidase (NEP) inhibitors may be usefulin treating heart failure. By inhibiting NEP,the enzyme responsible for the degradation ofANP, these drugs elevate plasma levels ofANP. NEP inhibition is effective in somemodels of heart failure when combined with

134 CHAPTER 6

↓Aldosterone

↓Angiotensin II

↓ ReninRelease

NatriuresisDiuresis

↑GFR

↓

↓ CO

↓

↓ SVR

DegradationAtrial distensionSympathetic stimulationAngiotensin IIEndothelin

NEP

BloodVolume

CVP

↓

ANP

ArterialPressure

FIGURE 6-11 Formation and cardiovascular/renal actions of atrial natriuretic peptide (ANP). ANP, which is releasedfrom cardiac atrial tissue in response to atrial distension, sympathetic stimulation, increased angiotensin II, and en-dothelin, functions as a counter-regulatory mechanism for the renin-angiotensin-aldosterone system. ANP decreasesrenin release, angiotensin II and aldosterone formation, blood volume, central venous pressure, and arterial pressure.NEP, neutral endopeptidase; GFR, glomerular filtration rate; CVP, central venous pressure; CO, cardiac output; SVR,systemic vascular resistance.

Ch06_117-140_Klabunde 4/21/04 11:26 AM

an ACE inhibitor. The reason for this is thatNEP inhibition, by elevating ANP, reinforcesthe effects of ACE inhibition.

Brain-type natriuretic peptide (BNP), a 32-amino acid peptide hormone related to ANP,is synthesized and released by the ventricles inresponse to pressure and volume overload,particularly during heart failure. BNP appearsto have actions that are similar to those ofANP. Recently, circulating BNP has beenshown to be a sensitive biomarker for heartfailure.

Vasopressin (Antidiuretic Hormone)

Vasopressin (arginine vasopressin, AVP; anti-diuretic hormone, ADH) is a nonapeptidehormone released from the posterior pituitary(Figure 6-12). AVP has two principal sites ofaction: the kidneys and blood vessels. Themost important physiologic action of AVP isthat it increases water reabsorption by the kidneys by increasing water permeability inthe collecting duct, thereby permitting theformation of concentrated urine. This is the


A 56-year old male patient is found to have an arterial pressure of 190/115 mm Hg.Two years earlier he was normotensive. Diagnostic tests reveal bilateral renal arterystenosis. Describe the mechanisms by which this condition elevates arterial pressure.

Bilateral renal artery stenosis reduces the pressure within the afferent arterioles,which causes release of renin. This, in turn, increases circulating angiotensin II, whichstimulates aldosterone release. Activation of the renin-angiotensin-aldosterone systemcauses sodium and fluid retention by the kidneys and an increase in blood volume,which increases cardiac output. Increased vasopressin (stimulated by angiotensin II)contributes to the increase in blood volume. Increased angiotensin II increases systemicvascular resistance by binding to vascular AT1 receptors and by enhancement of sympa-thetic activity. These changes in cardiac output and systemic vascular resistance lead toa hypertensive state.

CASE 6-1

Angiotensin IIHyperosmolarityDecreased atrial receptor firingSympathetic stimulation

Vasoconstriction

Pituitary

Renal FluidReabsorption

IncreasedBlood Volume

IncreasedArterial Pressure

Vasopressin

FIGURE 6-12 Cardiovascular and renal effects of arginine vasopressin (AVP). AVP release from the posterior pituitaryis stimulated by angiotensin II, hyperosmolarity, decreased atrial receptor firing (usually in response to hypovolemia),and sympathetic activation. The primary action of AVP is on the kidney to increase water reabsorption (antidiureticeffect), which increases blood volume and arterial pressure. AVP also has direct vasoconstrictor actions at high con-centrations.

Ch06_117-140_Klabunde 4/21/04 11:26 AM

antidiuretic property of AVP, and it leads to anincrease in blood volume and arterial bloodpressure. This hormone also constricts arterialblood vessels; however, the normal physio-logic concentrations of AVP are below its va-soactive range. Studies have shown, neverthe-less, that in severe hypovolemic shock, whenAVP release is very high, AVP contributes tothe compensatory increase in systemic vascu-lar resistance.

Several mechanisms regulate the releaseof AVP. Specialized stretch receptors withinthe atrial walls and large veins (cardiopul-monary baroreceptors) entering the atria de-crease their firing rate when atrial pressurefalls (as occurs with hypovolemia). Afferentsfrom these receptors synapse within the hy-pothalamus, which is the site of AVP synthe-sis. AVP is transported from the hypothala-mus via axons to the posterior pituitary, fromwhere it is secreted into the circulation. Atrialreceptor firing normally inhibits the releaseof AVP. With hypovolemia and decreasedcentral venous pressure, the decreased firingof atrial stretch receptors leads to an increasein AVP release. AVP release is also stimulatedby enhanced sympathetic activity accompany-ing decreased arterial baroreceptor activityduring hypotension. An important mecha-nism regulating AVP release involves hypo-thalamic osmoreceptors, which sense extra-cellular osmolarity. When osmolarity rises, asoccurs during dehydration, AVP release isstimulated. Finally, angiotensin II receptorslocated within the hypothalamus regulateAVP release; an increase in angiotensin IIstimulates AVP release.

Heart failure causes a paradoxical increasein AVP. The increased blood volume and atrialpressure associated with heart failure suggestthat AVP secretion should be inhibited, but itis not. It may be that sympathetic and renin-angiotensin system activation in heart failureoverride the volume and low pressure cardio-vascular receptors (as well as the osmoregula-tion of AVP) and cause the increase in AVP se-cretion. This increase in AVP during heartfailure may contribute to the increased sys-temic vascular resistance and to renal reten-tion of fluid.

In summary, the importance of AVP in car-diovascular regulation is primarily through itseffects on volume regulation, which in turn af-fects ventricular preload and cardiac outputthrough the Frank-Starling relationship.Increased AVP, by increasing blood volume,increases cardiac output and arterial pressure.The vasoconstrictor effects of AVP are proba-bly important only when AVP levels are veryhigh, as occurs during severe hypovolemia.

INTEGRATION OF NEUROHUMORALMECHANISMS

Autonomic and humoral influences are neces-sary to maintain a normal arterial blood pres-sure under the different conditions in whichthe human body functions. Neurohumoralmechanisms enable the body to adjust tochanges in body posture, physical activity, orenvironmental conditions. The neurohumoralmechanisms act through changes in systemicvascular resistance, venous compliance, bloodvolume, and cardiac function, and throughthese actions they can effectively regulate ar-terial blood pressure (Table 6-4). Althougheach mechanism has independent cardiovas-cular actions, it is important to understandthat each mechanism also has complex inter-actions with other control mechanisms thatserve to reinforce or inhibit the actions of theother control mechanisms. For example, acti-vation of sympathetic nerves either directly orindirectly increases circulating angiotensin II,aldosterone, adrenal catecholamines, andarginine vasopressin, which act together to in-crease blood volume, cardiac output, and ar-terial pressure. These humoral changes areaccompanied by an increase in ANP, whichacts as a counter-regulatory system to limit theeffects of the other neurohumoral mecha-nisms.

Finally, it is important to note that someneurohumoral effects are rapid (e.g., auto-nomic nerves and catecholamine effects oncardiac output and pressure), whereas othersmay take several hours or days becausechanges in blood volume must occur beforealterations in cardiac output and arterial pres-sure can be fully expressed.

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• Autonomic regulation of the heart and vas-culature is primarily controlled by specialregions within the medulla oblongata of thebrainstem that contain the cell bodies ofsympathetic and parasympathetic (vagal)efferent nerves.

• The hypothalamus plays an integrative roleby modulating medullary neuronal activity(e.g., during exercise).

• Sensory information from peripheralbaroreceptors (e.g., carotid sinus barore-ceptors) synapse within the medulla at thenucleus tractus solitarius, which modulatesthe activity of the sympathetic and vagalneurons within the medulla.

• Preganglionic parasympathetic efferentnerves exit the medulla as the tenth cranialnerve and travel to the heart within the leftand right vagus nerves. Preganglionic fiberssynapse within ganglia located within theheart; short postganglionic fibers innervatethe myocardial tissue. Preganglionic sym-pathetic efferent nerves exit from thespinal cord and synapse within paraverte-bral or prevertebral ganglia before sendingout postganglionic fibers to target tissues inthe heart and blood vessels.

• Sympathetic activation increases heart rate,inotropy, and dromotropy through the re-lease of norepinephrine, which binds pri-marily to postjunctional cardiac �1-adreno-

ceptors. Norepinephrine released by sym-pathetic nerves constricts blood vessels bybinding to postjunctional �1 and �2-adrenoceptors. The release of norepineph-rine from sympathetic nerve terminals ismodulated by prejunctional �2-adrenocep-tors, �2-adrenoceptors and muscarinic (M2)receptors.

• Parasympathetic activation decreases heartrate, inotropy, and dromotropy, and it pro-duces vasodilation in specific organsthrough the release of acetylcholine, whichbinds to postjunctional muscarinic (M2) re-ceptors.

• Baroreceptors are mechanoreceptors thatrespond to stretch induced by an increasein pressure or volume. Arterial barorecep-tor activity (e.g., carotid sinus and aorticarch receptors) tonically inhibits sympa-thetic outflow to the heart and blood ves-sels, and it tonically stimulates vagal out-flow to the heart. Decreased arterialpressure, therefore, decreases the firing ofarterial baroreceptors, which leads to reflexactivation of sympathetic influences actingon the heart and blood vessels and with-drawal of the vagal activity to the heart.

• Peripheral chemoreceptors (e.g., carotidbodies) and central chemoreceptors (e.g.,medullary chemoreceptors) respond to de-creased pO2 and pH or increased pCO2 ofthe blood. Their primarily function is toregulate respiratory activity, although


TABLE 6-4 EFFECTS OF NEUROHUMORAL ACTIVATION ON BLOOD VOLUME,CARDIAC OUTPUT AND ARTERIAL PRESSURE

INCREASED BLOOD VOLUME CARDIAC OUTPUT ARTERIAL PRESSURE

Sympathetic Activity ↑ ↑ ↑

Vagal Activity — ↓ ↓

Circulating Epinephrine ↑ ↑ ↓↑*

Angiotensin II ↑ ↑ ↑

Aldosterone ↑ ↑ ↑

Atrial Natriuretic Peptide ↓ ↓ ↓

Arginine Vasopressin ↑ ↑ ↑

↑ = increase; ↓ = decrease. *dependent upon plasma epinephrine concentration.

Ch06_117-140_Klabunde 4/21/04 11:26 AM

chemoreceptor activation generally leadsto activation of the sympathetic nervoussystem to the vasculature, which increasesarterial pressure. Heart rate responses de-pend upon changes in respiratory activity.

• Reflexes triggered by changes in blood vol-ume, cerebral and myocardial ischemia,pain, pulmonary activity, muscle and jointmovement, and temperature alter cardiacand vascular function.

• Sympathetic activation of the adrenalmedulla stimulates the release of cate-cholamines, principally epinephrine. Thishormone produces cardiac stimulation (via�1-adrenoceptors), and it either decreases(via vascular �2-adrenoceptors) or in-creases (via vascular �1 and �2-adrenocep-tors) systemic vascular resistance, depend-ing upon the plasma concentration.

• The renin-angiotensin-aldosterone systemplays a major role in regulating renal excre-tion of sodium and water, and therefore itstrongly influences blood pressure throughchanges in blood volume. Renin is releasedby the kidneys in response to sympatheticstimulation, hypotension, and decreasedsodium delivery to distal tubules. Reninacts upon angiotensinogen to form an-giotensin I, which is converted to an-giotensin II (AII) by angiotensin-convert-ing enzyme (ACE). AII has the followingactions: (1) it stimulates aldosterone re-lease from the adrenal cortex, which in-creases renal sodium reabsorption; (2) itacts on renal tubules to increase sodium re-absorption; (3) it stimulates thirst; (4) itproduces systemic vasoconstriction; (5) itenhances sympathetic activity; and (6) itproduces cardiac and vascular hypertrophy.The overall systemic effect of increased AIIis increased blood volume, venous pres-sure, and arterial pressure.

• Atrial natriuretic peptide (ANP), which isreleased by the atria primarily in responseto atrial stretch, functions as a counter-reg-ulatory mechanism for the renin-an-giotensin-aldosterone system. Therefore,increased ANP reduces blood volume, ve-nous pressure, and arterial pressure.

• Arginine vasopressin (AVP; antidiuretichormone), which is released by the poste-rior pituitary when the body needs to re-duce renal loss of water, enhances bloodvolume and increases arterial and venouspressures. At high plasma concentrations,AVP constricts resistance vessels.

Review Questions

Please refer to the appendix for the answersto the review questions.For each question, choose the one best answer:1. The cell bodies for the preganglionic vagal

efferents innervating the heart are foundin which region of the brain?

a. Cortexb. Hypothalamusc. Medullad. Nucleus tractus solitarius

2. Norepinephrine released by sympatheticnerves

a. Binds preferentially to �2-adreno-ceptors on cardiac myocytes.

b. Constricts blood vessels by bindingto �1-adrenoceptors.

c. Inhibits its own release by bindingto prejunctional �2-adrenoceptors.

d. Decreases renin release in the kid-neys.

3. Stimulating efferent fibers of the right va-gus nerve

a. Decreases systemic vascular resis-tance.

b. Increases atrial inotropy.c. Increases heart rate.d. Releases acetylcholine, which binds

to M2 receptors.

4. A sudden increase in carotid artery pressurea. Decreases carotid sinus barorecep-

tor firing rate.b. Increases sympathetic efferent nerve

activity to systemic circulation.c. Increases vagal efferent activity to

the heart.d. Results in reflex tachycardia.

138 CHAPTER 6

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5. Which of the following can cause tachy-cardia?

a. Face submersion in cold waterb. Increased blood pCO2

c. Increased firing of carotid sinusbaroreceptors

d. Vasovagal reflex

6. Infusion of a low-to-moderate dose of epi-nephrine following pharmacologic block-ade of �-adrenoceptors will

a. Decrease mean arterial pressure.b. Have no significant cardiovascular

effects.c. Increase heart rate.d. Increase systemic vascular resis-

tance.

7. In an experimental protocol, intravenousinfusion of acetylcholine was found to de-crease mean arterial pressure and increaseheart rate. These results can best be ex-plained by

a. Direct action of acetylcholine onmuscarinic receptors at the sinoatrialnode.

b. Increased firing of carotid sinusbaroreceptors.

c. Reflex activation of sympatheticnerves.

d. Reflex systemic vasodilation.

8. An increase in circulating angiotensin IIconcentrations

a. Depresses sympathetic activity.b. Increases blood volume.c. Inhibits aldosterone release.d. Inhibits the release of atrial natri-

uretic peptide.

9. Atrial natriuretic peptidea. Enhances renal sodium retention.b. Increases renin release.c. Inhibits the release of aldosterone.d. Increases blood volume and cardiac

output.

SUGGESTED READINGSBerne RM, Levy MN. Cardiovascular Physiology. 8th

Ed. Philadelphia: Mosby, 2001.Melo LG, Pang SC, Ackermann U. Atrial natriuretic

peptide: regulator of chronic arterial blood pressure.News Physiol Sci 2000;15:143–149.

Mendolowitz D. Advances in parasympathetic control ofheart rate and cardiac function. News Physiol Sci1999;14:155–161.


Touyz CB, Dominiczak AF, Webb RC, Johns DB.Angiotensin receptors: signaling, vascular pathophys-iology, and interactions with ceramide. Am J Physiol2001;281:H2337–H2365.


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Ch06_117-140_Klabunde 4/21/04 11:26 AM

CD-ROM CONTENTSLEARNING OBJECTIVESINTRODUCTIONDISTRIBUTION OF CARDIAC OUTPUTLOCAL REGULATION OF BLOOD FLOW

Tissue FactorsEndothelial FactorsSmooth Muscle (Myogenic)

MechanismsExtravascular CompressionAutoregulation of Blood FlowReactive and Active Hyperemia

SPECIAL CIRCULATIONSCoronary CirculationCerebral CirculationSkeletal Muscle CirculationCutaneous CirculationSplanchnic CirculationRenal CirculationPulmonary CirculationSummary of Special Circulations


c h a p t e r

7Organ Blood Flow

AnginaCD CONTENTS

LEARNING OBJECTIVES

Understanding the concepts presented in this chapter will enable the student to:1. Describe the distribution of cardiac output among major organs when a person is at rest.2. Describe how each of the following tissue factors influences blood flow: adenosine, inor-

ganic phosphate, potassium ion, carbon dioxide, hydrogen ion, tissue partial pressure ofoxygen, and paracrine hormones such as histamine, prostaglandins, and bradykinin.

3. Describe how each of the following endothelial factors influences local blood flow: nitricoxide, endothelial-derived hyperpolarizing factor, endothelin-1, and prostacyclin.

4. Explain how extravascular compression alters blood flow in the heart and contractingskeletal muscle.

5. Define autoregulation of blood flow, reactive hyperemia and active (functional) hyperemia.6. Describe and contrast the local regulatory mechanisms that may be involved in autoregula-

tion, reactive hyperemia, and active hyperemia in major vascular beds of the body (coro-nary, cerebral, skeletal muscle, cutaneous, splanchnic, renal, and pulmonary circulations).

7. Compare and contrast autonomic control of blood flow in major vascular beds of the body.8. Describe the specialized vascular anatomy in the following organs: brain, heart, intestines

and liver, skin, kidneys, and lungs.

141

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INTRODUCTION

This chapter describes the blood flow to dif-ferent organs of the body. The first part of thechapter emphasizes local regulatory mecha-nisms by which organs regulate their ownblood flow to meet the metabolic and func-tional requirements of the organ. The secondpart of the chapter examines blood flow inspecific organs of the body.

DISTRIBUTION OF CARDIAC OUTPUT

We have previously seen that arterial pressureis generated as the heart pumps blood into thesystemic circulation. This arterial pressureserves as the driving force for blood flow to allthe organ systems. The relative distribution ofblood flow to the organs is regulated by thevascular resistance of the individual organs,which is influenced by extrinsic (neurohu-moral) and intrinsic (local regulatory) mecha-nisms as summarized in Chapter 5, Figure 5-9.

Table 7-1 summarizes the distribution ofcardiac output when a person is at rest. Mostof the cardiac output (approximately 80%)goes to the gastrointestinal tract, kidneys,skeletal muscle, heart and brain, althoughthese organs make up less than 50% of thebody mass. This relative distribution of car-

diac output, however, changes greatly de-pending on environmental conditions and thestate of physical activity. For example, in a hot,humid environment, the relative blood flow tothe skin increases substantially as the body at-tempts to maintain its core temperature bylosing heat to the environment. When a per-son exercises, the increased cardiac outputprimarily goes to the active skeletal muscles,heart, and skin (see Chapter 9); at the sametime, blood flow decreases to the gastroin-testinal and renal circulations. Another exam-ple of change in cardiac output distributionoccurs following a large meal, when bloodflow to the gastrointestinal circulation in-creases.

Instead of one “normal” blood flow for anorgan, there is a range of blood flows. Basalflow refers to the flow that is measured underbasal conditions (i.e., when a person is in afasted, resting state and at normal environ-mental conditions of temperature and humid-ity). The ratio of basal flow to maximal flow isa measure of the vascular tone, which is thedegree of vascular constriction (see Chapter5). The lower the basal flow relative to themaximal flow, the higher the vascular tone.The difference between basal flow and maxi-mal flow represents the flow capacity or va-sodilator reserve for the organ. Most organs

142 CHAPTER 7

TABLE 7-1 BLOOD FLOW IN MAJOR ORGANS OF THE BODY

PERCENT BODY PERCENT CARDIAC NORMAL FLOW MAXIMAL FLOW

ORGAN WEIGHT OUTPUT AT REST (ML/MIN PER 100 G) (ML/MIN PER 100 G)

Heart 0.4 5 80 400

Brain 2 14 55 150

Skeletal muscle 40 18 3 60

Skin 3 4 10 150

Stomach, intestine, 6 23 30 250liver, spleen, pancreas

Kidneys 0.4 20 400 600

Other 48 16 - -

Normal and maximal flows are approximate values for the whole organ. Many organs (e.g., brain, muscle, kidney,and intestine) have considerable heterogeneity of flow within the organ depending on the type of tissue or regionof organ being perfused. The liver receives blood flow from the gastrointestinal venous drainage as well as from thehepatic artery (only hepatic artery flow is included in this table). “Other” includes reproductive organs, bone, fat,and connective tissue.

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have a relatively large vasodilator reserve,whereas others, such as the kidneys, have arelatively small vasodilator reserve (see Table7-1).

The changes that occur in organ blood flowunder different conditions depend on the in-terplay between neurohumoral and local reg-ulatory mechanisms that govern vascular re-sistance. The neurohumoral mechanismswere discussed in Chapter 6. The followingsections focus on the local regulatory mecha-nisms that affect vascular resistance and organblood flow.

LOCAL REGULATION OF BLOOD FLOW

Tissues and organs have the ability to regulate,to a varying degree, their own blood flow. Thisintrinsic ability to regulate blood flow istermed “local regulation” and can occur in thecomplete absence of any extrinsic neurohu-moral influences. For example, if a muscle isremoved from the body, perfused under con-stant pressure with an oxygenated salt solu-tion, and then electrically stimulated to in-duce muscle contractions, the blood flowincreases. The increase in blood flow occurs inthe absence of neurohumoral influences, andtherefore is a local or intrinsic mechanism.

The mechanisms responsible for local reg-ulation originate from within the blood vessels(e.g., endothelial factors, myogenic mecha-nisms) and from the surrounding tissue (i.e.,tissue factors), many of which are related totissue metabolism or other biochemical path-ways (e.g., arachidonic acid metabolites andbradykinin). Mechanical factors (e.g., com-pressive forces during muscle contraction) canalso influence vascular resistance and therebyalter blood flow.

Tissue Factors

Tissue factors are substances produced by thetissue surrounding blood vessels (Fig. 7-1).These substances act on the blood vessel toproduce either relaxation or contraction of thesmooth muscle, thereby altering resistanceand blood flow. In some cases, these sub-stances indirectly act on the vascular smoothmuscle by affecting endothelial function or byaltering the release of norepinephrine by sym-pathetic nerves. Some of these vasoactive sub-stances are tissue metabolites that are prod-ucts of cellular metabolism or activity (e.g.,adenosine, CO2, H�, K�, lactate). In addition,different cell types surrounding blood vesselscan release vasoactive substances referred toas local, paracrine hormones (e.g., histamine,

ORGAN BLOOD FLOW 143

CellularMetabolism

Arteriole

↓ pO

VasodilatorSubstances

Paracrine-Releasing Cell

ParacrineHormones

HistamineBradykinin

Prostaglandins

AdoPO LactateCOKH

—

++

2

2

4

–

–

±

FIGURE 7-1 Vasoactive substances derived from tissue cells around arterioles. Increased tissue metabolism leads toformation of metabolites that dilate (-) nearby arterioles. Increased oxygen consumption decreases the tissue partialpressure of oxygen (pO2), which dilates arterioles. Some cells release locally acting, paracrine hormones (or their pre-cursors), which can either constrict (�) or dilate (-) arterioles. Ado, adenosine; PO4

-, inorganic phosphate; CO2, car-bon dioxide; K�, potassium ion; H�, hydrogen ion.

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bradykinin, and prostaglandins). A paracrinehormone is a substance released by one cellthat acts on another nearby cell by diffusingthrough the interstitial fluid. This is in con-trast to endocrine hormones that circulatein the blood to reach distant target cells or au-tocrine substances that affect the same cellfrom which they are released.

Increases or decreases in metabolism alterthe release of some of these vasoactive sub-stances; thus, metabolic activity is closely cou-pled to blood flow in most organs of the body.For example, an increase in tissue metabo-lism, as occurs during muscle contraction orduring changes in neuronal activity in thebrain, leads to an increase in blood flow.Extensive evidence shows that the activelymetabolizing cells surrounding arterioles re-lease vasoactive substances that cause vasodi-lation. This is termed the metabolic theoryof blood flow regulation. These vasoactivesubstances, which are linked to tissue metab-olism, ensure that the tissue is adequately sup-plied by oxygen and that products of metabo-lism (e.g., CO2, H�, lactic acid) are removed.Several substances have been implicated inmetabolic regulation of blood flow. Their rela-tive importance depends on the tissue inwhich they are formed as well as differentconditions that might cause their release.

1. Adenosine is a potent vasodilator in mostorgans (although adenosine constricts renalvessels). It is formed by the action of 5’-nu-cleotidase, an enzyme that dephosphory-lates cellular adenosine monophosphate(AMP). The AMP is derived from hydroly-sis of intracellular adenosine triphosphate(ATP) and adenosine diphosphate (ADP).Adenosine formation increases during hyp-oxia and increased oxygen consumption,both of which lead to increased ATP hy-drolysis. Small amounts of ATP hydrolysiscan lead to large increases in adenosine for-mation because intracellular concentra-tions of ATP are about a thousand-foldgreater than adenosine concentrations.Experimental evidence supports the ideathat adenosine formation is a particularlyimportant mechanism for regulating coro-

nary blood flow when myocardial oxygenconsumption increases or during hypoxicconditions.

2. Inorganic phosphate is released by thehydrolysis of adenine nucleotides (ATP,ADP, and AMP). Inorganic phosphate mayhave some vasodilatory activity in contract-ing skeletal muscle, but its importance isfar less than that of adenosine, potassium,and nitric oxide in regulating skeletal mus-cle blood flow.

3. Carbon dioxide formation increases dur-ing states of increased oxidative metabo-lism. CO2 concentrations in the tissue andvasculature can also increase when bloodflow is reduced, which reduces the washoutof CO2. As a gas, CO2 readily diffuses fromparenchymal cells to the vascular smoothmuscle of blood vessels, where it causes va-sodilation. Considerable evidence indicatesthat CO2 plays a significant role in regulat-ing cerebral blood flow through the forma-tion of H�.

4. Hydrogen ion increases when CO2 in-creases or during states of increased anaer-obic metabolism (e.g., during ischemia orhypoxia) when acid metabolites such as lac-tic acid are produced. Increased H� causeslocal vasodilation, particularly in the cere-bral circulation.

5. Potassium ion is released by contractingcardiac and skeletal muscle. Muscle con-traction is initiated by membrane depolar-ization, which results from a cellular influxof Na� and an efflux of K�. Normally, theNa�/K�-ATPase pump is able to restorethe ionic gradients (see Chapter 2); how-ever, the pump does not keep up withrapid depolarizations (i.e., there is a timelag) during muscle contractions, and asmall amount of K� accumulates in the ex-tracellular space. Small increases in extra-cellular K� around blood vessels cause hy-perpolarization of the vascular smoothmuscle cells, possibly by stimulating theelectrogenic Na�/K�-ATPase pump andincreasing K� conductance through potas-sium channels. Hyperpolarization leads tosmooth muscle relaxation. Potassium ionappears to play a significant role in caus-

144 CHAPTER 7

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ing the increase in blood flow in contract-ing skeletal muscle.

6. Oxygen levels within the blood vessel andsurrounding tissue are also important in lo-cal regulation of blood flow. Decreased tis-sue partial pressure of oxygen (pO2) result-ing from reduced oxygen supply orincreased oxygen utilization by tissuescauses vasodilation. Hypoxia-induced va-sodilation may be direct (inadequate O2 tosustain smooth muscle contraction) or indi-rect via the production of vasodilatormetabolites (e.g., adenosine, lactic acid,H�). Although hypoxia causes vasodilationin nearly all vascular beds, there is a no-table exception—it causes vasoconstrictionin the pulmonary circulation.

7. Osmolarity changes in the blood and inthe tissue interstitium have been impli-cated in local blood flow regulation. It iswell known that intra-arterial infusions ofhyperosmolar solutions can produce va-sodilation. The molecules making up thehyperosmolar solution need not be vasoac-tive. Tissue ischemia and increased meta-bolic activity raise the osmolarity of the tis-sue interstitial fluid and venous blood.Therefore, it has been suggested that non-specific changes in osmolarity may play arole in the regulation of blood flow.

Several tissue factors involved in regulat-ing blood flow are not directly coupled to tis-sue metabolism. These include paracrinehormones such as histamine, bradykinin, andproducts of arachidonic acid (eicosanoids).Histamine, released by tissue mast cells in response to injury, inflammation, and al-lergic responses, causes arteriolar vasodila-tion, venous constriction in some vascularbeds, and increased capillary permeability.Both H1 and H2 histamine receptors are in-volved in the vascular effects of histamine.Bradykinin is formed from the action ofkallikrein (a proteolytic enzyme) acting on al-pha2-globulin (kininogen), which is found inblood and tissues. Like histamine, bradykininis a powerful dilator of arterioles. It acts onvascular bradykinin receptors, which stimu-late nitric oxide formation by the vascular

endothelium, thereby producing vasodila-tion. In addition, bradykinin stimulatesprostacyclin formation, which produces va-sodilation. One of the enzymes responsiblefor breaking down bradykinin is angiotensin-converting enzyme (ACE) (see Chapter 6,Fig. 6-10). Therefore, ACE inhibition notonly decreases angiotensin II, it also in-creases bradykinin, which is believed to bepartly responsible for the vasodilation ac-companying ACE inhibition. Arachidonicacid metabolites such as prostacyclin(PGI2) and prostaglandin E2 (PGE2) are va-sodilators, whereas other eicosanoids such asPGF2�, thromboxanes, and leukotrienes aregenerally vasoconstrictors. Drugs that blockthe formation of these eicosanoids (e.g., cy-clo-oxygenase inhibitors such as aspirin oribuprofen) alter vascular control by thesesubstances.

Endothelial Factors

The vascular endothelium serves an impor-tant paracrine role in the regulation ofsmooth muscle tone and organ blood flow. As described in Chapter 3, the vascular en-dothelium produces vasoactive substancesthat have significant effects on vascularsmooth muscle. Circulating (endocrine) andparacrine hormones, shearing forces, hypoxia,and many different drugs can stimulate theformation and release of endothelial sub-stances (Fig. 7-2). Among their many actions,two of these substances, nitric oxide andprostacyclin, are powerful vasodilators, (seeNitric Oxide and Prostaglandins in Chapter 3on CD). In contrast, endothelin-1 is a pow-erful vasoconstrictor [see CD3 – endothelin].Although all three of these endothelial-de-rived substances have important actions onthe vascular smooth muscle, nitric oxide ap-pears to be the most important in terms ofregulating blood flow under normal physio-logic conditions. If nitric oxide synthesis is in-hibited pharmacologically using nitric oxidesynthase (NOS) inhibitors, vasoconstrictionoccurs in most vascular beds. This demon-strates that there normally is a basal release ofnitric oxide that inhibits vascular tone; there-


Ch07_141-170_Klabunde 4/21/04 11:43 AM

fore, blocking nitric oxide formation leads toan increase in tone.

Nitric oxide is involved in what is termedflow dependent vasodilation. Experimentalstudies have shown that an increase in vesselflow (actually an increase in shearing forcesacting on the vascular endothelium) stimulatesendothelial nitric oxide production, whichcauses vasodilation. Flow-dependent vasodila-tion is particularly important as a mechanismfor increasing coronary blood flow when car-diac activity and metabolism are increased.Impaired nitric oxide synthesis or decreasedbioavailability, as occurs during coronary arterydisease, limits the ability of coronary bloodflow to increase when cardiac activity and oxy-gen demand are increased. Other disorderssuch as hypertension, cerebrovascular disease,and diabetes are associated with impaired en-dothelial control of vascular function as well.

Another endothelial factor is endothelial-derived hyperpolarizing factor (EDHF).Some substances (e.g., acetylcholine,

bradykinin) that stimulate nitric oxide produc-tion stimulate EDHF as well. The identity ofthis factor is not known for certain, but its re-lease causes smooth muscle hyperpolarizationand relaxation.

Smooth Muscle (Myogenic)Mechanisms

Myogenic mechanisms originate within thesmooth muscle of blood vessels, particularly insmall arteries and arterioles. When the lumenof a blood vessel is suddenly expanded, as oc-curs when intravascular pressure is suddenlyincreased, the smooth muscle responds bycontracting in order to restore the vessel di-ameter and resistance. Conversely, a reduc-tion in intravascular pressure results insmooth muscle relaxation and vasodilation.Electrophysiologic studies have shown thatvascular smooth muscle cells depolarize whenstretched, leading to contraction.

Myogenic behavior has not been observedin all vascular beds, but it has been noted inthe intestinal and renal circulations, and maybe present to a small degree in skeletal mus-cle. It is difficult to evaluate myogenic mech-anisms in vivo because changes in pressureare usually associated with changes in flowthat trigger metabolic mechanisms, whichusually dominate over myogenic mechanisms.For example, increasing venous pressure to avascular bed should activate myogenic mech-anisms to produce vasoconstriction becauseelevated venous pressures are transmittedback to the precapillary resistance vessels;however, the reduction in blood flow associ-ated with the increase in venous pressure(which reduces perfusion pressure) activatestissue metabolic mechanisms that cause va-sodilation. In most organs, conducting such anexperiment usually results in vasodilation be-cause the metabolic vasodilator responseoverrides the myogenic vasoconstrictor re-sponse, if present.

Extravascular Compression

Mechanical compressive forces can affect vas-cular resistance and blood flow within organs.

146 CHAPTER 7

L-argNOS

NO

ECE

CONTRACTIONVascularSmoothMuscle

Endothelial Cell

Circulating HormonesParacrine Hormones

Shearing ForcesHypoxia

AA

NO ET-1 PGIEDHF

–– – +

2

FIGURE 7-2 Endothelial-derived vasoactive factors.Nitric oxide (NO) formed by nitric oxide synthase (NOS)acting on L-arginine (L-arg), endothelial-derived hyper-polarizing factor (EDHF), and prostacyclin (PGI2) derivedfrom arachidonic acid (AA) inhibit (-) smooth musclecontraction and cause vasodilation. Endothelin-1 (ET-1)formed by endothelin-converting enzyme (ECE) causessmooth muscle contraction (�). The formation and re-lease of these substances are influenced by circulatingand paracrine hormones, shearing forces acting on theendothelium, hypoxia, and many different drugs.

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Sometimes this occurs during normal physio-logic conditions; at other times, compressiveforces can be the result of pathologic mecha-nisms. The pressure that distends the wall of ablood vessel is the transmural pressure (insideminus outside pressure). Therefore, if thepressure outside of the vessel increases, thenthe transmural pressure decreases. At veryhigh extravascular pressures, a vessel cancompletely collapse. Therefore, veins, whichhave a relatively low intravascular pressure,are more likely to collapse when extravascularpressure is elevated; however, arteries can alsobecome significantly compressed when ex-travascular pressure is elevated to very highlevels.

Several examples of mechanical compres-sion affecting organ blood flow exist. Duringcardiac systole or skeletal muscle contraction(particularly tetanic contractions), vascular re-sistance is greatly increased and blood flow isimpeded by mechanical compression. Lunginflation and deflation alter pulmonary vascu-lar transmural pressures (see Fig. 5-12) andthereby have substantial effects on pulmonaryvascular resistance. Excessive distension ofthe gastrointestinal tract can increase vascularresistance to the point at which tissues be-come ischemic. Blood vessels in organs suchas the brain or kidneys, which are surroundedby a rigid cranium or capsule, are particularlysusceptible to increases in extravascular pres-sure that occur with edema, vascular hemor-rhage (e.g., cerebral stroke), or the growth ofa tumor.

Autoregulation of Blood Flow

Autoregulation is the intrinsic ability of anorgan to maintain a constant blood flow de-spite changes in perfusion pressure. For ex-ample, if perfusion pressure is decreased to anorgan by partial occlusion of the artery sup-plying the organ, blood flow will initially fall,then return toward normal levels over thenext few minutes. This autoregulatory re-sponse occurs in isolated, perfused organs,which are not subject to neural or humoral in-fluences. Therefore, it is a local or intrinsic re-sponse of the organ.

When perfusion pressure (arterial – venouspressure; PA – PV) initially decreases, bloodflow (F) falls because of the following rela-tionship between pressure, flow, and resis-tance (R):

F � �(PA �

RPV)

�

The reductions in flow and perfusion pres-sure are thought to activate metabolic or myo-genic mechanisms that cause arteriolar va-sodilation and a fall in resistance (R). Asresistance decreases, blood flow increases de-spite the presence of a reduced perfusionpressure. This autoregulatory response isshown in the left panel of Figure 7-3. For ex-ample, if perfusion pressure is reduced from100 mm Hg to 70 mm Hg, it causes flow todecrease initially by approximately 30%. Overthe next few minutes, however, flow begins toincrease back toward control as the organblood flow is autoregulated (red lines). Bloodflow increases because vascular resistance fallsas the resistance vessels dilate.

If the perfusion pressure to an organ is in-creased and decreased over a wide range ofpressures and the steady-state autoregulatoryflow response is measured, then the relation-ship between steady-state flow and perfusionpressure can be plotted as shown in the rightpanel of Figure 7-3. The red line representsthe autoregulatory range in which flowchanges relatively little despite a large changein perfusion pressure. The “flatness” of the au-toregulation curve varies considerably amongorgans; the flatter the relationship, the betterthe autoregulation. Coronary, cerebral, andrenal circulations show a high degree of au-toregulation, whereas skeletal muscle and gas-trointestinal circulations show only a moder-ate degree of autoregulation. The cutaneouscirculation displays virtually no autoregula-tion.

Autoregulation has limits even in organsthat display a high degree of autoregulation.When the perfusion pressure falls below60–70 mm Hg in the cerebral and coronarycirculations, the resistance vessels becomemaximally dilated and their ability to autoreg-ulate is lost. Furthermore, at very high perfu-sion pressures (approximately 170 mm Hg in


Ch07_141-170_Klabunde 4/21/04 11:43 AM

Fig. 7-3), the upper limit of the autoregulatoryrange is reached and the vessels undergo nofurther constriction with increases in perfu-sion pressure; therefore, flow increases aspressure increases. The autoregulatory re-sponse can be modulated by neurohumoralinfluences and disease states. For example,sympathetic stimulation and chronic hyper-tension can shift the cerebral autoregulatoryrange to the right as described later in thischapter.

Autoregulation may involve both metabolicand myogenic mechanisms. If the perfusionpressure to an organ is reduced, the initial fallin blood flow leads to a fall in tissue pO2 andthe accumulation of vasodilator metabolites.These changes cause the resistance vessels todilate in an attempt to restore normal flow. Areduction in perfusion pressure may also besensed by the smooth muscle in resistancevessels, which responds by relaxing (myogenicresponse), leading to an increase in flow.

Under what conditions does autoregulationoccur, and why is it important? In hypotensioncaused by blood loss, despite baroreceptor re-flexes that lead to constriction of much of thesystemic vasculature, blood flow to the brainand myocardium will not decline appreciably

(unless the arterial pressure falls below theautoregulatory range). This is because of thestrong capacity of these organs to autoregulateand their ability to escape sympathetic vaso-constrictor influences. The autoregulatory re-sponse helps to ensure that these critical or-gans have an adequate blood flow and oxygendelivery even in the presence of systemic hy-potension.

Other situations occur in which systemicarterial pressure does not change, but inwhich autoregulation is very important never-theless. Autoregulation can occur when a dis-tributing artery (e.g., coronary artery) to anorgan becomes partially occluded. This arte-rial stenosis increases resistance and the pres-sure drop along the vessel length. This re-duces pressure in small distal arteries andarterioles, which are the primary vessels forregulating blood flow within an organ. Theseresistance vessels dilate in response to the re-duced pressure and blood flow caused by theupstream stenosis. This autoregulatory re-sponse helps to maintain normal blood flow inthe presence of upstream stenosis, and it isparticularly important in organs such as thebrain and heart in which partial occlusion oflarge arteries can lead to significant reductions

148 CHAPTER 7

0 100 200

Blo

od F

low

A

BB

A

Resistance

Flow(ml/min)

Pressure(mm Hg)

Time (min) Perfusion Pressure (mm Hg)

No Autoregulation

No Autoregulation

Autoregulation

AutoregulatoryRange

FIGURE 7-3 Autoregulation of blood flow. The left panel shows that decreasing perfusion pressure from 100 mm Hgto 70 mm Hg at point A results in a transient decrease in flow. If no autoregulation occurs, resistance remains un-changed and flow remains decreased. With autoregulation (red line), the initial fall in pressure leads to a decrease invascular resistance, which causes flow to increase to a new steady-state level despite the reduced perfusion pressure(point B). The right panel shows steady-state, autoregulatory flows plotted against different perfusion pressures.Points A and B represent the control flow and autoregulatory steady-state flow, respectively, from the left panel. Theautoregulatory range is the range of pressures over which flow shows little change. Below or above the autoregula-tory range, flow changes are approximately proportional to the changes in perfusion pressure. The autoregulatoryrange as well as the flatness of the autoregulatory response curve varies among organs.

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in oxygen delivery, thereby leading to tissuehypoxia and organ dysfunction.

Reactive and Active Hyperemia

Reactive hyperemia is the transient increasein organ blood flow that occurs following abrief period of ischemia, usually produced bytemporary arterial occlusion. Figure 7-4shows the effects of a 2-minute arterial occlu-sion on blood flow. During the occlusion pe-riod, blood flow goes to zero. When the occlu-sion is released, blood flow rapidly increasesabove normal levels (hyperemia) that lasts forseveral minutes. In most tissues, experimentshave suggested that the hyperemia occurs be-cause during the occlusion period, tissue hyp-oxia and a build-up of vasoactive metabolitesdilate arterioles and decrease vascular resis-tance. When the occlusion is released andperfusion pressure is restored, flow becomeselevated because of the reduced vascular re-

sistance. During the hyperemia, oxygen be-comes replenished and vasodilator metabo-lites are washed out of the tissue, causing the resistance vessels to regain their normal


An experiment was conducted using an isolated perfused organ (e.g., intestinal seg-ment) in which arterial and venous pressures were controlled while blood flow wasmeasured. When venous pressure was suddenly raised from 0 mm Hg to 15 mm Hgwhile arterial pressure was maintained at 100 mm Hg, flow decreased by 25%.Calculate the percentage change that occurred in vascular resistance in response to ve-nous pressure elevation. Discuss the involvement of metabolic and myogenic mecha-nisms in this response.

The initial perfusion pressure was 100 mm Hg (mean arterial pressure minus venouspressure). Elevating the venous pressure to 15 mm Hg reduced the perfusion pressureto 85 mm Hg. According to the equation relating blood flow, perfusion pressure andvascular resistance (F � �P/R), flow would decrease by 15% with a 15% decrease inperfusion pressure (assuming that resistance does not change). However, in this case,flow decreased by 25% indicating that resistance increased by 13.3% (R � �P/F). Themetabolic theory for autoregulation states that as perfusion pressure and flow are re-duced, an accumulation of vasodilator metabolites decreases resistance in an attemptto restore flow; however, resistance did not decrease in this experiment. The myogenictheory states that increased transmural pressure causes vascular smooth muscle to con-tract, thereby increasing resistance and decreasing flow. Increasing venous pressure inthis experiment increased the transmural pressure in arterioles, causing them to con-strict and increase their resistance. Therefore, increasing venous pressure produces op-posite and competing responses between these two mechanisms. Because vascular resistance increased in this experiment, we can conclude that the myogenic (vasocon-strictor) mechanism was dominant over the metabolic (vasodilator) mechanism. Theseresults have been observed experimentally in organs such as the intestine.

PROBLEM 7-1

0 2 4 6

Flow NoFlow

Time (min)

Reactive HyperemiaExcess Flow

FIGURE 7-4 Reactive hyperemia. Arterial occlusion(ischemia) followed by reperfusion results in a transientincrease in blood flow (reactive hyperemia). The magni-tude and duration of the reactive hyperemia are directlyrelated to the duration of ischemia.

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vascular tone and thereby return flow to nor-mal levels. The longer the period of occlusion,the greater the metabolic stimulus for vasodi-lation leading to increases in peak flow andduration of hyperemia. Maximal vasodilation,as indicated by a maximal peak hyperemicflow, may occur following less than oneminute of complete arterial occlusion, or itmay require several minutes of occlusion de-pending on the vascular bed and its metabolicactivity. For example, in the beating heart(high metabolic activity), maximal reactive hy-peremic responses are seen with coronary oc-clusions of less than one minute, whereas inresting skeletal muscle (low metabolic activ-ity), several minutes of ischemia are necessaryto elicit a maximal vasodilator response.Myogenic mechanisms may also contribute toreactive hyperemia in some tissues becausearterial occlusion decreases the pressure in arterioles, which can lead to myogenic-mediated vasodilation.

Several examples of reactive hyperemia ex-ist. The application of a tourniquet to a limb,and then its removal, results in reactive hy-peremia. During surgery, arterial vessels areoften clamped for a period of time; release ofthe arterial clamp results in reactive hyper-emia. Transient coronary artery occlusions(e.g., coronary vasospasm) result in subse-quent reactive hyperemia within the myo-cardium supplied by the coronary vessel.

Active hyperemia is the increase in organblood flow that is associated with increasedmetabolic activity of an organ or tissue. Withincreased metabolic activity, vascular resis-tance decreases owing to vasodilation and vas-cular recruitment (particularly in skeletal mus-cle). Active hyperemia occurs during musclecontraction (also termed exercise or func-tional hyperemia), increased cardiac activity,increased mental activity, and increased gas-trointestinal activity during food absorption.

In Figure 7-5, the left panel shows the ef-fects of increasing tissue metabolism for 2minutes on mean blood flow in a rhythmicallycontracting skeletal muscle. Within seconds ofinitiating contraction and the increase inmetabolic activity, blood flow increases. Thevasodilation is thought to be owing to a com-bination of tissue hypoxia and the generationof vasodilator metabolites such as potassiumion, carbon dioxide, nitric oxide, and adeno-sine. This increased blood flow (i.e., hyper-emia) is maintained throughout the period ofincreased metabolic activity and then subsidesas normal metabolism is restored. The ampli-tude of the active hyperemia is closely relatedto the increase in metabolic activity (e.g., oxy-gen consumption) as shown in the right panel.At high levels of metabolic activity, the vascu-lature becomes maximally dilated, resulting ina maximal increase in blood flow. Active hy-peremia is important because it increases oxy-

150 CHAPTER 7

0 2 4 6 Metabolic Activity

Flo

w

Ste

ady-

Sta

te F

low

Time (min)

Active or FunctionalHyperemia

IncreasedMetabolism

FIGURE 7-5 Active hyperemia. The left panel shows that increasing metabolism for 2 minutes transiently increasesblood flow (active or functional hyperemia). The right panel shows that the steady-state increase in blood flow dur-ing active hyperemia is directly related to the increase in metabolic activity until the vessels become maximally dilatedand flow can no longer increase.

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gen delivery to tissues at a time of increasedoxygen demand. Furthermore, the increasedblood flow enhances the removal of metabolicwaste products from the tissue.

The vasodilatory capacity during active hy-peremia differs considerably among organs.In skeletal muscle, blood flow can increasemore than twenty- to fifty-fold during exer-cise. Cerebral blood flow, in contrast, in-creases no more than two-fold at maximalmetabolic activity. The reason for this differ-ence is that resting skeletal muscle has a highdegree of vascular tone in contrast to the cere-bral circulation, which has a relatively low de-gree of vascular tone because of its highermetabolic rate under basal conditions.

SPECIAL CIRCULATIONS

Coronary Circulation

The two major branches of the coronary cir-culation are the left main and right main coro-nary arteries (Fig. 7-6). These vessels arisefrom coronary ostia, which are small openings

in the wall of the ascending aorta just distal tothe aortic valve. The left main coronaryartery is relatively short in length (�1 cm).After coursing behind the pulmonary arterytrunk, it divides into the left anterior de-scending artery, which travels along the in-terventricular groove on the anterior surfaceof the heart, and the circumflex artery,which travels posteriorly along the groove be-tween the left atrium and ventricle. Thesebranches of the left coronary artery supplyblood primarily to the left ventricle andatrium. The right main coronary arterytravels between the right atrium and ventricle(left atrioventricular groove) toward the pos-terior regions of the heart. This vessel and itsbranches serve the right ventricle and atrium,and in most individuals, the inferoposteriorregion of the left ventricle. Significant varia-tion is possible among individuals in theanatomical arrangement and distribution offlow by the coronary vessels.

The major coronary vessels lie on the epicardial surface of the heart and serve aslow-resistance distribution vessels. These


Left Main

Right MainCoronary Artery

Coronary Artery

Circumflex Artery

Left AnteriorDescending Artery

PA

Ao

SVC

IVC

LeftVentricle

RightVentricle

FIGURE 7-6 Anterior view of the heart showing the major coronary arteries. The left main artery arises from the aorta(Ao) just distal to the aortic valve, travels behind the pulmonary artery (PA), and then branches into the circumflexartery (courses along the left atrioventricular groove) and left anterior descending artery (courses along the interven-tricular groove), both of which primarily supply blood to the left ventricle. The right coronary artery arises from theaorta and travels between the right atrium and ventricle toward the posterior regions of the heart to supply the rightventricle and atrium and the inferoposterior wall of the left ventricle. SVC, superior vena cava; IVC, inferior vena cava.

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epicardial arteries give off smaller branchesthat dive into the myocardium and becomethe microvascular resistance vessels that regu-late coronary blood flow. The resistance ves-sels give rise to a dense capillary network sothat each cardiac myocyte is closely associatedwith several capillaries. The high capillary-to-fiber density ensures short diffusion distancesto maximize oxygen transport into the cellsand removal of metabolic waste products(e.g., CO2, H�) (see Chapter 8).

Coronary veins are located adjacent tocoronary arteries. These veins drain into thecoronary sinus located on the posterior as-pect of the heart. Blood flow from the coro-nary sinus empties into the right atrium. Somedrainage also occurs directly into the cardiacchambers through the anterior cardiac veinsand thebesian vessels.

Coronary blood flow is not steady as inmost other organs. When flow is measuredwithin a coronary artery, it is found to de-crease during cardiac systole and increaseduring diastole (Fig. 7-7). Therefore, most ofthe blood flow to the myocardium occurs dur-ing diastole. The reason that coronary flow isinfluenced by the cardiac cycle is that duringsystole, the contraction of the myocardiumcompresses the microvasculature within theventricular wall, thereby increasing resistanceand decreasing flow. During systole, blood

flow is reduced to the greatest extent withinthe innermost regions of the ventricular wall(i.e., in the subendocardium) because this iswhere the compressive forces are greatest.(This results in the subendocardial regions be-ing more susceptible to ischemic injury whencoronary artery disease or reduced aorticpressure is present.) As the ventricle begins torelax in early diastole, the compressive forcesare removed and blood flow is permitted toincrease. Blood flow reaches a peak in earlydiastole and then falls passively as the aorticpressure falls toward its diastolic value.Therefore, it is the aortic pressure during di-astole that is most crucial for perfusing thecoronaries. This explains why increases inheart rate can reduce coronary perfusion. Athigh heart rates, the length of diastole isgreatly shortened, which reduces the time forcoronary perfusion. This is not a problemwhen the coronary arteries are normal, be-cause they dilate with increased heart rate andmetabolism; however, if the coronaries arediseased and their vasodilator reserve is lim-ited, increases in heart rate can limit coronaryflow and lead to myocardial ischemia andanginal pain.

The mechanical forces affecting coronaryflow are greatest within the left ventricle be-cause this chamber develops pressures that areseveral-fold greater than those developed by

152 CHAPTER 7

AorticPressure(mm Hg)

CoronaryFlow

(ml/min/100g)

120

80

0

200

0 0.8Time (sec)

DiastoleSystoleDiastole

FIGURE 7-7 Pulsatile nature of coronary blood flow measured in the left coronary artery. Flow is lower during systolebecause of mechanical compression of intramuscular coronary vessels. Flow is maximal early in diastole, and then itfalls as aortic pressure declines.

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the right ventricle. The right ventricle, and to alesser extent the atria, show some effects ofcontraction and relaxation on blood flow withintheir musculature, but it is much less apparentthan that observed in the left ventricle.

Mean coronary blood flow (averaged overseveral cardiac cycles) can range from 80mL/min per 100 g of tissue at resting heartrates to over 400 mL/min per 100 g during ex-ercise (see Table 7-1). Therefore, the coronaryvasculature normally has a relatively high va-sodilator reserve capacity.

Coronary blood flow is primarily regulatedby tissue metabolism. Adenosine has beenshown to be important in dilating the coronaryvessels when the myocardium becomes hyp-oxic or when cardiac metabolism increases dur-ing increased cardiac work. Experimental stud-ies have shown that inhibiting adenosineformation, enhancing its breakdown to inosine,or blocking vascular adenosine receptors im-pairs coronary vasodilation under these condi-tions. In addition, nitric oxide has been shownto be important in coronary vessels, particularlyin producing flow-dependent vasodilation.

Coronary vessels are innervated by bothsympathetic and parasympathetic nerves.Unlike most other vascular beds, activation ofsympathetic nerves to the heart causes onlytransient vasoconstriction (�1-adrenoceptormediated) followed by vasodilation. The va-sodilation occurs because sympathetic activa-tion of the heart also increases heart rate andinotropy through �1-adrenoceptors, whichleads to the production of vasodilator metabo-lites that inhibit the vasoconstrictor responseand cause vasodilation. This is termed func-tional sympatholysis. If �1-adrenoceptors areblocked experimentally, sympathetic stimula-tion of the heart causes coronary vasoconstric-tion. Parasympathetic stimulation of the heart(i.e., vagal nerve activation) elicits modest coro-nary vasodilation owing to the direct effects ofreleased acetylcholine on the coronaries.However, if parasympathetic activation of theheart results in a significant decrease in myo-cardial oxygen demand, local metabolic mech-anisms increase coronary vascular tone (i.e.,cause vasoconstriction). Therefore, parasympa-thetic activation of the heart generally results in

a decrease in coronary blood flow, although thedirect effect of parasympathetic stimulation ofthe coronary vessels is vasodilation.

Coronary blood flow is crucial for the nor-mal function of the heart. Because of the highoxygen consumption of the beating heart (seeChapter 4) and the fact that the heart relies onoxidative metabolism (see Chapter 3), coro-nary blood flow (oxygen delivery) and themetabolic activity of the heart need to betightly coupled. This is all the more importantbecause, as discussed in Chapter 4, the beat-ing heart extracts more than half of the oxygenfrom the arterial blood; therefore, there is rel-atively little oxygen extraction reserve. Incoronary artery disease, chronic narrowing ofthe vessels or impaired vascular function re-duces maximal coronary blood flow (i.e., thereis reduced vasodilator reserve). When this oc-curs, coronary flow fails to increase adequatelyas myocardial oxygen demands increase (Fig.7-8). This leads to cardiac hypoxia and im-paired contractile function.

The relationship between coronary bloodflow and the metabolic demand of the heart isoften discussed in terms of the myocardialoxygen supply/demand ratio. The oxygensupply is the amount of oxygen delivered tothe myocardium in the arterial blood, which isthe product of the coronary blood flow and


Myocardial Oxygen Consumption

BloodFlow

NormalCoronaries

DiseasedCoronaries

Oxygen Deficit

FIGURE 7-8 Relationship between coronary blood flowand myocardial oxygen consumption. Coronary bloodflow increases as myocardial oxygen consumption in-creases. However, if the coronary vessels are diseasedand have increased resistance owing to stenosis, bloodflow (and therefore oxygen delivery) will be limited athigher oxygen consumptions leading to an oxygendeficit and myocardial hypoxia.

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arterial oxygen content. If blood flow is in theunits of mL blood/min and arterial oxygencontent is expressed in mL O2/mL blood, oxy-gen delivery has the units of mL O2/min. Theoxygen demand of the heart is the myocardialoxygen consumption, which is the product ofcoronary blood flow and the difference be-tween the arterial and venous oxygen con-tents. A decrease in the oxygen supply/de-mand ratio causes tissue hypoxia, which canresult in chest pain (angina pectoris) (seeAngina on CD). This can occur by a decreasein oxygen supply (decreased coronary bloodflow or arterial oxygen content), an increase inmyocardial oxygen consumption, or a combi-nation of the two. One of the therapeutic goalsfor people who have coronary artery diseaseand anginal pain is to increase the oxygen sup-ply/demand ratio either by improving coro-nary flow (e.g., coronary bypass grafts or coro-nary stent placement) or by decreasingmyocardial oxygen consumption by reducingheart rate, inotropy, and afterload (seeChapter 4).

Coronary artery disease is a leading causeof death. Both structural and functionalchanges occur when coronary arteries becomediseased. Atherosclerotic processes decreasethe lumen diameter, causing stenosis. Thiscommonly occurs in the large epicardial arter-

ies, although the disease also afflicts small ves-sels. The large coronary arteries ordinarilyrepresent only a very small fraction of totalcoronary vascular resistance. Therefore,stenosis in these vessels needs to exceed a60% to 70% reduction in lumen diameter (i.e.,exceed the critical stenosis) to have significanteffects on resting blood flow and maximal flowcapacity (see Chapter 5 and Stenosis on CD).

In addition to narrowing the lumen and in-creasing resistance to flow, atherosclerosiscauses endothelial damage and dysfunction.This leads to reduced nitric oxide and prosta-cyclin formation, which can precipitate coro-nary vasospasm and thrombus formation,leading to increased vascular resistance anddecreased flow. Loss of these endothelial fac-tors impairs vasodilation, which decreases thevasodilator reserve capacity. When coronaryflow is compromised by coronary artery dis-ease either at rest or during times of increasedmetabolic demand (e.g., during exercise), themyocardium becomes hypoxic, which can im-pair mechanical function, precipitate arrhyth-mias, and produce angina.

When coronary oxygen delivery is limitedby disease, collateral vessels can play an im-portant adjunct role in supplying oxygen tothe heart. Conditions of chronic stress (e.g.,chronic hypoxia or exercise training) can cause

154 CHAPTER 7

A patient with known coronary artery disease (multiple vessel stenosis) is also hyper-tensive. Explain why blood pressure-lowering drugs that produce reflex tachycardiashould be not be used in such a patient.

It is important to control arterial pressure in patients with coronary artery diseasebecause hypertension increases ventricular afterload and myocardial oxygen demand.However, it is important to lower arterial pressure using drugs that do not cause a re-flex tachycardia for two reasons. First, reflex tachycardia (baroreceptor-mediated) in-creases myocardial oxygen demand and offsets the beneficial effects of reducing after-load (see Chapter 4). Second, tachycardia further impairs coronary perfusion becausethe duration of diastole relative to systole decreases at elevated heart rates. This re-duces the time available for coronary perfusion during diastole, which is the timewhen the greatest amount of coronary perfusion occurs. It is common in clinical prac-tice to give either a �-blocker or calcium-channel blocker to a patient with both coro-nary artery disease and hypertension, because both types of drugs lower pressure andprevent reflex tachycardia.

CASE 7-1

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new blood vessels to form by angiogenesis.Collateralization increases myocardial bloodsupply by increasing the number of parallelvessels, thereby reducing vascular resistancewithin the myocardium. This helps to supplyblood flow to ischemic regions caused by vas-cular stenosis or thrombosis.

Cerebral Circulation

The brain is a highly oxidative organ that con-sumes almost 20% of resting total-body oxy-gen consumption. To deliver adequate oxy-gen, the cerebral blood flow needs to berelatively high, about 50–60 mL/min per 100 gtissue weight (see Table 7-1). Although thebrain represents only about 2% of bodyweight, it receives approximately 14% of thecardiac output.

The brain circulation is supplied by fourprincipal arteries: the left and right carotidarteries and the left and right vertebral ar-teries (Fig. 7-9). The vertebral arteries jointogether on the ventral surface of the pons to

form the basilar artery, which then travelsup the brainstem to join the carotid arteriesthrough interconnecting arteries, forming theCircle of Willis. Arterial vessels originatingfrom the vertebral and basilar arteries as wellas the Circle of Willis distribute blood flow todifferent regions of the brain. This intercon-necting network of arterial vessels at thebrainstem provides a safety mechanism forcerebral perfusion. If, for example, a carotidartery becomes partly occluded and flow is re-duced through that artery, increased flowthrough the other interconnecting arteries canhelp improve perfusion of the affected portionof the brain.

Because the cerebral circulation is locatedwithin a rigid cranium, changes in intracranialpressure can have significant effects on cere-bral perfusion (Fig. 7-10). For example, cere-bral vascular hemorrhage, brain edemacaused by cerebral trauma, or tumor growthcan increase intracranial pressure, which canlead to vascular compression and reducedcerebral blood flow. The venous vessels aremost susceptible to compression because oftheir low intravascular pressure. Because in-tracranial pressure is normally greater thanthe venous pressure outside the cranium andthe venous vessels can easily collapse, the ef-fective perfusion pressure of the brain is notthe mean arterial pressure minus central ve-nous pressure, but rather the mean arterialpressure minus the intracranial pressure.Intracranial pressure normally ranges from0–10 mm Hg; however, if it becomes elevated(e.g., 20 mm Hg or greater), and especially ifthere is systemic hypotension, the effectivecerebral perfusion pressure and blood flowcan be significantly reduced.

Like the coronary circulation, the cerebralblood flow is tightly coupled to oxygen con-sumption. Therefore, cerebral blood flow in-creases (active or functional hyperemia) whenneuronal activity and oxygen consumption areincreased. Changes in neuronal activity in spe-cific brain regions lead to increases in bloodflow to those regions.

The brain shows excellent autoregulationbetween mean arterial pressures of about 60mm Hg and 130 mm Hg (Fig. 7-11). This is


Vertebral

R. InternalCarotid

L. InternalCarotid

Basilar

Circleof

Willis

AnteriorCerebral

R. PosteriorCerebral

L. PosteriorCerebral

FIGURE 7-9 Major cerebral arteries perfusing the brain.This view is of the ventral surface of the brain and brain-stem. The carotid and vertebral arteries are the majorsource of cerebral blood flow and are interconnectedthrough the Circle of Willis and basilar artery. L, left; R,right.

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important because cerebral function relies ona steady supply of oxygen and cannot afford tobe subjected to a reduction in flow caused bya fall in arterial pressure. If mean arterialpressure falls below 60 mm Hg, cerebral per-fusion becomes impaired, which results in de-pressed neuronal function, mental confusion,and loss of consciousness. When arterial pres-sure is above the autoregulatory range (e.g., in

a hypertensive crisis), blood flow and pres-sures within the cerebral microcirculation in-crease. This may cause endothelial and vascu-lar damage, disruption of the blood-brainbarrier, and hemorrhagic stroke. With chronichypertension, the autoregulatory curve shiftsto the right (see Fig. 7-11), which helps toprotect the brain at higher arterial pressures.However, this rightward shift then makes thebrain more susceptible to reduced perfusionwhen arterial pressure falls below the lowerend of the rightward-shifted autoregulatoryrange.

Metabolic mechanisms play a dominantrole in the control of cerebral blood flow.Considerable evidence indicates that changesin carbon dioxide are important for couplingtissue metabolism and blood flow. Increasedoxidative metabolism increases carbon dioxideproduction, which causes vasodilation. It isthought that the carbon dioxide diffuses intothe cerebrospinal fluid, where hydrogen ion isformed by the action of carbonic anhydrase;the hydrogen ion then causes vasodilation. Inaddition, carbon dioxide and hydrogen ion in-crease when perfusion is reduced because ofimpaired washout of carbon dioxide.Adenosine, nitric oxide, potassium ion, andmyogenic mechanisms have also been impli-cated in the local regulation of cerebral bloodflow.

156 CHAPTER 7

ICP increased by:

Increased ICP:

CPP = MAP – ICP

↑ ICP

MAP

CVP

• intracranial bleeding

• cerebral edema

• tumor

• collapses veins

• decreases effective CPP

• reduces blood flow

Rigid Cranium

Artery

Vein

FIGURE 7-10 Effects of intracranial pressure (ICP) on cerebral blood flow. ICP is the pressure within the rigid cranium(gray area of figure). Increased ICP decreases transmural pressure (inside minus outside pressure) of blood vessels(particularly veins), which can cause vascular collapse, increased resistance, and decreased blood flow. Therefore, theeffective cerebral perfusion pressure (CPP) is mean arterial pressure (MAP) minus ICP. CVP, central venous pressure.

0 100 200

Blo

od F

low

Perfusion Pressure (mm Hg)

Normal

Chronic HypertensionAcute Sympathetic Stimulation

FIGURE 7-11 Autoregulation of cerebral blood flow.Cerebral blood flow shows excellent autoregulation be-tween mean arterial pressures of 60 mm Hg and 130mm Hg. The autoregulatory curve shifts to the rightwith chronic hypertension or acute sympathetic activa-tion. This shift helps to protect the brain from the dam-aging effects of elevated pressure.

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Cerebral blood flow is strongly influencedby the partial pressure of carbon dioxide and,to a lesser extent, oxygen in the arterial blood(Fig. 7-12). Cerebral blood flow is highly sen-sitive to small changes in arterial partial pres-sure of CO2 (pCO2) from its normal value ofabout 40 mm Hg, with increased pCO2 (hy-percapnea) causing pronounced vasodilationand decreased pCO2 (hypocapnea) causingvasoconstriction. Hydrogen ion appears to beresponsible for the changes in vascular resis-tance when changes occur in arterial pCO2.The importance of CO2 in regulating cerebralblood flow can be demonstrated when a per-son hyperventilates, which decreases arterialpCO2. When this occurs, a person becomes“light headed” as the reduced pCO2 causescerebral blood flow to decrease. Severe arte-rial hypoxia (hypoxemia) increases cerebralblood flow. Arterial pO2 is normally about95–100 mm Hg. If the pO2 falls below 50 mmHg (severe arterial hypoxia), it elicits a strongvasodilator response in the brain, which helpsto maintain oxygen delivery despite the reduc-tion in arterial oxygen content. As described inChapter 6, decreased arterial pO2 and in-creased pCO2 stimulate chemoreceptors,which activate sympathetic efferents to thesystemic vasculature to cause vasoconstric-tion; however, the direct effects of hypoxia

and hypercapnea override the weak effects ofsympathetic activation in the brain so thatcerebral vasodilation occurs and oxygen deliv-ery is enhanced.

Although sympathetic nerves innervatelarger cerebral vessels, activation of thesenerves has relatively little influence on cere-bral blood flow. Maximal sympathetic activa-tion increases cerebral vascular resistance byno more than 20% to 30%, in contrast to anapproximately 500% increase occurring inskeletal muscle. The reason, in part, for theweak sympathetic response by the cerebralvasculature is that metabolic mechanisms aredominant in regulating flow; therefore, func-tional sympatholysis occurs during sympa-thetic activation. This is crucial to preservenormal brain function; otherwise, every time aperson stands up or exercises, both of whichcause sympathetic activation, cerebral perfu-sion would decrease. Therefore, baroreceptorreflexes have little influence on cerebral bloodflow. Sympathetic activation shifts the au-toregulatory curve to the right, similar to whatoccurs with chronic hypertension.

In recent years, we have learned that neu-ropeptides originating in the brain signifi-cantly influence cerebral vascular tone, andthey may be involved in producing headaches(e.g., migraine and cluster headaches) and


pCO2

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FIGURE 7-12 Effects of arterial partial pressure of oxygen and carbon dioxide on cerebral blood flow. An arterial par-tial pressure of oxygen (pO2) of less than 50 mm Hg (normal value is about 95 mm Hg) causes cerebral vasodilationand increased flow. A reduction in arterial partial pressure of carbon dioxide (pCO2) below its normal value of 40 mmHg decreases flow, whereas pCO2 values greater than 40 mm Hg increase flow. Therefore, cerebral blood flow is moresensitive to changes from normal arterial pCO2 values than from normal arterial pO2 values.

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cerebral vascular vasospasm during strokes.Parasympathetic cholinergic fibers innervat-ing the cerebral vasculature release nitric ox-ide and vasoactive intestinal polypeptide(VIP). These substances, along with acetyl-choline, produce localized vasodilation. Othernerves appear to release the local vasodilatorscalcitonin gene-related peptide (CGRP)and substance-P. Sympathetic adrenergicnerves can release neuropeptide-Y (NPY) inaddition to norepinephrine, which causes lo-calized vasoconstriction.

Skeletal Muscle Circulation

The primary function of skeletal muscle is tocontract and generate mechanical forces toprovide support to the skeleton and producemovement of joints. This mechanical activityconsumes large amounts of energy and there-fore requires delivery of considerableamounts of oxygen and substrates, as well asthe efficient removal of metabolic waste prod-ucts. Both oxygen delivery and metabolicwaste removal functions are performed by thecirculation.

The circulation within skeletal muscle ishighly organized. Arterioles give rise to capil-laries that generally run parallel to the musclefibers, with each fiber surrounded by three tofour capillaries. When the muscle is not con-tracting, relatively little oxygen is required andonly about one-fourth of the capillaries areperfused. In contrast, during muscle contrac-tion and active hyperemia, all the anatomicalcapillaries may be perfused, which increasesthe number of flowing capillaries around eachmuscle fiber (termed capillary recruit-ment). This anatomical arrangement of capil-laries and the ability to recruit capillaries de-creases diffusion distances, leading to anefficient exchange of gasses and molecules be-tween the blood and the myocytes, particu-larly under conditions of high oxygen demand.

In resting humans, almost 20% of cardiacoutput is delivered to skeletal muscle. Thislarge cardiac output to muscle occurs not be-cause blood flow is exceptionally high in rest-ing muscle, but because skeletal musclemakes up about 40% of the body mass. In the

resting, noncontracting state, muscle bloodflow is about 3 mL/min per 100 g. This restingflow is much less than that found in organssuch as the brain and kidneys, in which “rest-ing” flows are about 55 and 400 mL/min per100 g, respectively.

When muscles contract during exercise,blood flow can increase more than twenty-fold. If muscle contraction is occurring duringwhole-body exercise (e.g., running), morethan 80% of cardiac output can be directed tothe contracting muscles. Therefore, skeletalmuscle has a very large flow reserve (or ca-pacity) relative to its blood flow at rest, indi-cating that the vasculature in resting musclehas a high degree of tone (see Table 7-1). Thisresting tone is brought about by the interplaybetween vasoconstrictor (e.g., sympatheticadrenergic and myogenic influences) and va-sodilator influences (e.g., nitric oxide produc-tion, and tissue metabolites). In the restingstate, the vasoconstrictor influences dominate,whereas during muscle contraction, vasodila-tor influences dominate to increase oxygendelivery to the contracting muscle fibers andremove metabolic waste products that accu-mulate.

The blood flow response to skeletal musclecontraction depends on the type of contrac-tion. With rhythmic or phasic contraction ofmuscle (Fig. 7-13, top panel), as occurs duringnormal locomotory activity, mean blood flowincreases during the period of muscle activity.However, if blood flow is measured withoutfiltering or averaging, the flow is found to bephasic—flow decreases during contractionand increases during relaxation phases of themuscle activity because of mechanical com-pression of the vessels. In contrast, a sustainedmuscle contraction (e.g., lifting and holding aheavy weight) decreases mean blood flow dur-ing the period of contraction, followed by apostcontraction hyperemic response when thecontraction ceases (see Fig. 7-13, bottompanel).

The precise mechanisms responsible fordilating skeletal muscle vasculature duringcontraction are not clearly understood.However, considerable evidence indicatesthat increases in interstitial adenosine and K�

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during muscle contraction contribute to thevasodilation. Tissue hypoxia, particularly whenblood flow is mechanically compromised dur-ing forceful sustained muscle contractions,may provide a signal for vasodilation.Evidence also exists that increased endothelialrelease of nitric oxide contributes to the dila-tion of the vasculature. Other suggestedmechanisms include increased levels of lacticacid, CO2, and H� and hyperosmolarity.Another mechanism that facilitates blood flowduring coordinated contractions of groups ofmuscles (as occurs during normal physical ac-tivity such as running) is the skeletal musclepump (see Chapter 5). Regardless of themechanisms involved in producing active hy-

peremia, the outcome is that there is a closecorrelation between the increase in oxygenconsumption and the increase in blood flowduring muscle contraction.

Skeletal muscle vasculature is innervatedprimarily by sympathetic adrenergic fibers.The norepinephrine released by these fibersbinds to �-adrenoceptors and causes vaso-constriction. Under resting conditions, a sig-nificant portion of the vascular tone is gener-ated by sympathetic activity, so that if a restingmuscle is suddenly denervated or the �-adrenoceptors are blocked pharmacologicallyby a drug such as phentolamine, blood flowwill transiently increase two to three-fold un-til local regulatory mechanisms reestablish a


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FIGURE 7-13 Skeletal muscle active hyperemia following phasic and sustained (tetanic) contractions. The top panelshows that phasic contractions cause flow to decrease during contraction and increase during relaxation, althoughthe net effect is an increase in flow during contraction. When contractions cease, a further increase in flow occursbecause mechanical compression of the vasculature is removed. The bottom panel shows that sustained, tetanic con-tractions generate high intramuscular forces that compress the vasculature and reduce flow. When contractionceases, a large hyperemia follows.

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new steady-state flow. Activation of the sym-pathetic adrenergic nervous system (e.g.,baroreceptor reflex in response to hypo-volemia) can dramatically reduce blood flowin resting muscle. When this reduction inblood flow occurs, the muscle extracts moreoxygen (the arterial-venous oxygen differenceincreases) and activates anaerobic pathwaysfor ATP production. However, prolonged hy-poperfusion of muscle caused by intense sym-pathetic activation eventually leads to va-sodilator mechanisms dominating over thesympathetic vasoconstriction, leading to sym-pathetic escape and partial restoration ofblood flow.

Recent evidence suggests that increasedmuscle blood flow seen under some conditionsof generalized sympathetic activation (e.g.,during exercise or mental stress) may involvecirculating catecholamines stimulating �2-adrenoceptors and locally released nitric oxide.

Evidence exists, at least in nonprimatespecies such as cats and dogs, for sympatheticcholinergic innervation of skeletal muscle re-sistance vessels. The neurotransmitter forthese fibers is acetylcholine, which binds tomuscarinic receptors to produce vasodilation.This branch of the autonomic nervous systemhas little or no influence on blood flow underresting conditions; however, activation ofthese fibers in anticipation of exercise andduring exercise can contribute to the increasein blood flow associated with exercise. Thereis no convincing evidence, however, for simi-lar active, neurogenic vasodilator mechanismsexisting in humans.

Cutaneous Circulation

The nutrient and oxygen requirements of theskin are quite low relative to other organs;therefore, cutaneous blood flow does not pri-marily serve a metabolic support role. Instead,the primary role of blood flow to the skin is toallow heat to be exchanged between the bloodand the environment to help regulate bodytemperature. Therefore, the cutaneous circu-lation is under the control of hypothalamicthermoregulatory centers that adjust the sym-pathetic outflow to the cutaneous vasculature.

At normal body and ambient temperatures,the skin circulation is subjected to a high de-gree of sympathetic adrenergic tone. If coretemperature begins to rise (e.g., during physi-cal exertion), the hypothalamus decreasessympathetic outflow to the skin, which causescutaneous vasodilation and increased bloodflow. This enables more warm blood to circu-late in the sub-epidermal layer of the skin sothat more heat energy can be conductedthrough the skin to the environment.Conversely, if core temperature decreases,the hypothalamus attempts to retain heat byincreasing sympathetic outflow to the skin,which decreases cutaneous blood flow andprevents heat loss to the environment. Thesympathetic control of the cutaneous circula-tion is so powerful that cutaneous blood flowcan range from more than 30% of cardiac out-put to less than 1%.

The microvascular network that suppliesskin is unique among organs. Small arteriesarising from the subcutaneous tissues give riseto arterioles that penetrate into the dermisand give rise to capillaries that loop under-neath the epidermis (Fig. 7-14). Blood flowsfrom these capillary loops into venules andthen into an extensive, interconnecting ve-nous plexus. Most of the cutaneous bloodvolume is found in the venous plexus, which isa prominent feature in the nose, lips, ears,toes, and fingers—especially the fingertips.The blood in the venous plexus is also respon-sible for skin coloration in lightly pigmentedindividuals. The venous plexus receives blooddirectly from the small subcutaneous arteriesthrough special interconnecting vessels calledarteriovenous (AV) anastomoses.

The resistance vessels supplying the sub-epidermal capillary loops and the AV anasto-moses are richly innervated by sympatheticadrenergic fibers. Constriction of these vesselsduring hypothalamic-mediated sympatheticactivation decreases blood flow through thecapillary loops and the venous plexus. In addi-tion to sympathetic neural control, the resis-tance vessels and AV anastomoses are verysensitive to �-adrenoceptor-mediated vaso-constriction induced by circulating cate-cholamines.

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Although the AV anastomoses are almostexclusively controlled by sympathetic influ-ences, the resistance vessels respond to bothmetabolic influences and sympathetic influ-ences and therefore demonstrate local regula-tory phenomena such as reactive hyperemiaand autoregulation. These local regulatory re-sponses, however, are relatively weak com-pared to those observed in most other organs.

The cutaneous resistance vessels also re-spond to local paracrine influences, particu-larly during sweating and tissue injury.Activation of cutaneous sweat glands by sym-pathetic cholinergic nerves produces vasodila-tion in addition to the formation of sweat. It isthought that local formation of bradykinin ispartly responsible for this vasodilation.Bradykinin may stimulate the formation of ni-tric oxide to cause vasodilation during sweat-ing. Moreover, evidence suggests that anunidentified vasodilator substance (a co-trans-mitter) is released by sympathetic cholinergicnerves. Tissue injury from mechanical trauma,heat, or chemicals releases paracrine sub-stances such as histamine and bradykinin,which increase blood flow and cause localizededema by increasing microvascular perme-ability. If the skin is firmly stroked with a bluntobject, the skin initially blanches owing to lo-calized vasoconstriction. This is followedwithin a minute by the formation of a red linethat spreads away from the site of injury (redflare); both the red line and red flare arecaused by an increase in blood flow. Localized

swelling (wheal formation) may then follow,caused by increased microvascular permeabil-ity and leakage of fluid into the interstitium.The red line, flare, and wheal are called thetriple response. Both paracrine hormonesand local axon reflexes are believed to be in-volved in the triple response. The vasodilatorneurotransmitter involved in local axon re-flexes has not been identified. This neuro-genic-mediated vasodilation is called “activevasodilation” in contrast to vasodilation thatoccurs during withdrawal of sympatheticadrenergic influences, called “passive vasodi-lation.”

Local changes in skin temperature selec-tively alter blood flow to the affected region.For example, if a heat source is placed on asmall region of the skin on the back of thehand, blood flow will increase only to the re-gion that is heated. This response appears tobe mediated by local axon reflexes and localformation of nitric oxide instead of by changesin sympathetic discharge mediated by the hy-pothalamus. Localized cooling produces vaso-constriction through local axon reflexes. If tis-sue is exposed to extreme cold, a phenomenoncalled cold-induced vasodilation may occurfollowing an initial vasoconstrictor response,especially if the exposed body region is a hand,foot, or face. This phenomenon causes light-colored skin to appear red, and it explains therosy cheeks, ears, and nose a person may ex-hibit when exposed to very cold air tempera-tures. With continued exposure, alternating


Dermis

Epidermis

SubcutaneousTissue

Capillary

Artery

Venous Plexus

Vein

AV anastomosis

FIGURE 7-14 Anatomy of the cutaneous circulation. Arteries within the subcutaneous tissue give rise to either arte-rioles that travel into the dermis and give rise to capillary loops, or to arteriovenous (AV) anastomoses that connectto a plexus of small veins in the subdermis. The venous plexus also receives blood from the capillary loops.Sympathetic stimulation constricts the resistance vessels and AV anastomoses, thereby decreasing dermal blood flow.

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periods of dilation and constriction may occur.The mechanism for cold-induced vasodilationis not clear, but it probably involves changes inlocal axon reflexes and impaired ability of thevessels to constrict because of hypothermia.

Splanchnic Circulation

The splanchnic circulation includes bloodflow to the gastrointestinal tract, spleen, pan-creas, and liver. Blood flow to these combinedorgans represents 20% to 25% of cardiac out-put (see Table 7-1). Three major arteries aris-ing from the abdominal aorta supply blood tothe stomach, intestine, spleen, and liver—theceliac, superior mesenteric, and inferiormesenteric arteries. The following describesblood flow to the intestines and liver.

Several branches arising from the superiormesenteric artery supply blood to the intes-tine. These and subsequent branches travelthrough the mesentery that supports the in-testine. Small arterial branches enter theouter muscular wall of the intestine and divideinto several smaller orders of arteries and ar-terioles, most of which enter into the submu-cosa from which arterioles and capillariesarise to supply blood to the intestinal villi.Water and nutrients transported into the villienter the blood and are carried away by theportal venous circulation.

Intestinal blood flow is closely coupled tothe primary function of the intestine, i.e., theabsorption of water, electrolytes, and nutri-ents from the intestinal lumen. Therefore, in-testinal blood flow increases when food is present within the intestine. Blood flow to the intestine in the fasted state is about 30mL/min per 100 g; following a meal, flow canexceed 250 mL/min per 100 g. This functionalhyperemia is stimulated by gastrointestinalhormones such as gastrin and cholecystokinin,as well as by glucose, amino acids, and fattyacids that are absorbed by the intestine.Evidence exists that submucosal arteriolar va-sodilation during functional hyperemia is me-diated by hyperosmolarity and nitric oxide.

The intestinal circulation is strongly influ-enced by the activity of sympathetic adrener-gic nerves. Increased sympathetic activity dur-

ing exercise or in response to decreasedbaroreceptor firing (e.g., during hemorrhageor standing) constricts both arterial resistancevessels and venous capacitance vessels.Because the intestinal circulation receivessuch a large fraction of cardiac output, sympa-thetic stimulation of the intestine causes asubstantial increase in total systemic vascularresistance. Additionally, the large blood vol-ume contained within the venous vasculatureis mobilized during sympathetic stimulation toincrease central venous pressure.

Parasympathetic activation of the intestineincreases motility and glandular secretions.Increased motility per se does not cause largeincreases in blood flow, but flow neverthelessincreases. This may involve metabolic mecha-nisms or local paracrine influences such as theformation of bradykinin and nitric oxide.

Venous blood leaving the gastrointestinaltract, spleen, and pancreas drains into the he-patic portal vein, which supplies approxi-mately 75% of the hepatic blood flow. The re-mainder of the hepatic blood flow is suppliedby the hepatic artery, which is a branch of theceliac artery. Note that in this arrangement,most of the liver circulation is in series withthe gastrointestinal, splenic, and pancreaticcirculations. Therefore, changes in blood flowin these vascular beds have a significant influ-ence on hepatic flow.

Terminal vessels from the hepatic portalvein and hepatic artery form sinusoids withinthe liver, which function as capillaries. Thepressure within these sinusoids is very low,just a few mm Hg above central venous pres-sure. This is important because the sinusoidsare very permeable (see Chapter 8). Changesin central venous and hepatic venous pressureare almost completely transmitted to the sinu-soids. Therefore, elevations in central venouspressure during right ventricular failure cancause substantial increases in sinusoid pres-sure and fluid filtration, leading to hepaticedema and accumulation of fluid within theabdominal cavity (ascites).

The liver circulation does not show au-toregulation; however, decreases in hepaticportal flow result in reciprocal increases in he-patic artery flow, and vice versa. Sympathetic

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nerve activation constricts vessels derivedfrom both the hepatic portal system and he-patic artery. The most important effect ofsympathetic activation is on venous capaci-tance vessels, which contain a significant frac-tion (approximately 15%) of the venous bloodvolume in the body. The liver, like the gas-trointestinal circulation, functions as an im-portant venous reservoir.

The spleen is an important venous reser-voir containing hemoconcentrated blood insome animals (e.g., dogs). Stressful conditionsin the dog (e.g., blood loss) can cause spleniccontraction, which can substantially increasecirculating blood volume and hematocrit.

Renal Circulation

Approximately 20% of the cardiac output per-fuses the kidneys although the kidneys repre-sent only about 0.4% of total body weight.Renal blood flow, therefore, is about 400mL/min per 100 g of tissue weight, which isthe highest of any major organ within thebody (see Table 7-1). Only the pituitary andcarotid bodies have higher blood flows perunit tissue weight. Whereas blood flow inmany organs is closely coupled to tissue oxida-tive metabolism, this is not the case for thekidneys, in which the blood flow greatly ex-ceeds the need for oxygen delivery. The veryhigh blood flow results in a relatively low ex-traction of oxygen from the blood (about 1 to2 mL O2/mL blood) despite the fact that renaloxygen consumption is high (approximately 5mL O2/min per 100 g). The reason for renalblood flow being so high is that the primaryfunction of the kidneys is to filter blood andform urine. The kidney comprises three majorregions: the cortex (the outer layer that con-tains glomeruli for filtration), the medulla (themiddle region that contains renal tubules andcapillaries involved in concentrating theurine), and the hilum (the inner region wherethe renal artery and vein, nerves, lymphatics,and ureter enter or leave the kidney). Becausemost of the filtering takes place within thecortex, about 90% of the total renal blood flowsupplies the cortex, with the remainder sup-plying the medullary regions.

The vascular organization within the kid-neys is very different from most organs. Theabdominal aorta gives rise to renal arteriesthat distribute blood flow to each kidney. Therenal artery enters the kidney at the hilum andgives off several branches (interlobar arter-ies) that travel in the kidney toward the cor-tex. Subsequent branches (arcuate and in-terlobular arteries) then form afferentarterioles, which supply blood to eachglomerulus (Fig. 7-15). As the afferent arteri-ole enters the glomerulus, it gives rise to acluster of glomerular capillaries, fromwhich fluid is filtered into Bowman’s capsuleand into the renal proximal tubule. Theglomerular capillaries then form an efferentarteriole from which arise peritubular cap-illaries that surround the renal tubules.Efferent arterioles associated with jux-tamedullary nephrons located in the innercortex near the outer medulla give rise to verylong capillaries (vasa recta) that loop downdeep within the medulla. The capillaries areinvolved with countercurrent exchange andthe maintenance of medullary osmotic gradi-ents. Capillaries eventually form venules andthen veins, which join together to exit the kid-ney as the renal vein. Therefore, within thekidney, a capillary bed (glomerular capillaries)is located between the two principal sites ofresistance (afferent and efferent arterioles).Furthermore, a second capillary bed (per-itubular capillaries) is in series with theglomerular capillaries and is separated by theefferent arteriole.

The vascular arrangement within the kid-ney is very important for filtration and reab-sorption functions of the kidney. Changes inafferent and efferent arteriole resistance af-fect not only blood flow, but also the hydro-static pressures within the glomerular andperitubular capillaries. Glomerular capillarypressure, which is about 50 mm Hg, is muchhigher than that in capillaries found in otherorgans. This high pressure drives fluid filtra-tion (see Chapter 8). The peritubular capillarypressure, however, is low (about 10–20 mmHg). This is important because it permits fluidreabsorption to limit water loss and urine ex-cretion. About 20% of the plasma entering the


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kidney is filtered. If significant reabsorptiondid not occur, a high rate of urine formationwould rapidly lead to hypovolemia and hy-potension and an excessive loss of electrolytes.Figure 7-16 shows the effects of afferent andefferent arteriole constriction on blood flowand glomerular capillary pressure. If the affer-ent arteriole constricts, distal pressures,glomerular filtration, and blood flow are re-duced (see Fig. 7-16, Panel B). In contrast, al-though efferent arteriole constriction reducesflow and peritubular capillary pressure, it in-creases glomerular capillary pressure andglomerular filtration (see Fig. 7-16, Panel D).

The renal circulation exhibits strong au-toregulation between arterial pressures ofabout 80–180 mm Hg. Autoregulation ofblood flow is accompanied by autoregulationof glomerular filtration so that filtration re-mains essentially unchanged over a widerange of arterial pressures. For this to occur,glomerular capillary pressure must remain un-changed when arterial pressure changes. Thistakes place because the principal site for au-

toregulation is the afferent arteriole. If arterialpressure falls, the afferent arteriole dilates,which helps to maintain the glomerular capil-lary pressure and flow despite the fall in arte-rial pressure.

Two mechanisms have been proposed toexplain renal autoregulation: myogenic mech-anisms and tubuloglomerular feedback.Myogenic mechanisms were described earlierin this chapter. Briefly, a reduction in afferentarteriole pressure is sensed by the vascularsmooth muscle, which responds by relaxing;an increase in pressure induces smooth mus-cle contraction. The tubuloglomerularfeedback mechanism is poorly understood,and the actual mediators have not been iden-tified. It is believed, however, that changes inperfusion pressure alter glomerular filtrationand therefore tubular flow and sodium deliv-ery to the macula densa of the juxtaglomeru-lar apparatus, which then signals the afferentarteriole to constrict or dilate. The maculadensa of the juxtaglomerular apparatus is agroup of specialized cells of the distal tubule

164 CHAPTER 7

Arcuate Artery

InterlobularArtery

AfferentArteriole

EfferentArteriole

GlomerularCapillaries

PeritubularCapillaries

ProximalTubule

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FIGURE 7-15 Renal vascular anatomy. Small vessels derived from branches of the renal artery form arcuate arteriesand interlobular arteries, which then become afferent arterioles that supply blood to the glomerulus. As the afferentarteriole enters the glomerulus, it gives rise to a cluster of glomerular capillaries, from which fluid is filtered intoBowman’s capsule and into the renal proximal tubule. The glomerular capillaries then form an efferent arteriole fromwhich arise peritubular capillaries that surround the renal tubules.

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that lie adjacent to the afferent arteriole as thedistal tubule loops up back toward theglomerulus. These cells sense solute osmolar-ity, particularly sodium chloride. Some inves-tigators have proposed that adenosine (whichis a vasoconstrictor in the kidney), locally pro-duced angiotensin II (a vasoconstrictor), orvasodilators such as nitric oxide, prostaglandinE2, and prostacyclin are involved in tubu-loglomerular feedback and autoregulation.Locally produced angiotensin II strongly in-fluences efferent arteriole tone. Thus, inhi-bition of angiotensin II formation by an angiotensin-converting enzyme (ACE) in-hibitor dilates the efferent arteriole, which de-creases glomerular capillary pressure and re-duces glomerular filtration under someconditions (e.g., renal artery stenosis). Drugsthat inhibit prostaglandin and prostacyclinbiosynthesis (cyclo-oxygenase inhibitors) alterrenal hemodynamics and function, particu-larly with long-term use.

The renal circulation responds strongly tosympathetic adrenergic stimulation. Undernormal conditions, relatively little sympathetictone on the renal vasculature occurs; however,with strenuous exercise or in response to se-vere hemorrhage, increased renal sympatheticnerve activity can virtually shut down renalblood flow. Because renal blood flow receivesa relatively large fraction of cardiac outputand therefore contributes significantly to sys-temic vascular resistance, renal vasoconstric-tion can serve an important role in maintain-ing arterial pressure under these conditions;however, intense renal vasoconstriction seri-ously impairs renal perfusion and function,and it can lead to renal failure.

Pulmonary Circulation

Two separate circulations perfusing respira-tory structures exist: the pulmonary circula-tion, which is derived from the pulmonary


↓R*↑P ↑P

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AA GC EA PC

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↓F

A

B

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FIGURE 7-16 Effects of renal afferent and efferent arteriole resistances on blood flow and renal capillary pressures.Panel A: Decreased afferent arteriole (AA) resistance increases glomerular capillary (GC ) and peritubular capillary (PC )pressures and increases flow (F ). Panel B: Increased AA resistance decreases GC and PC pressures and decreases F.Panel C: Decreased efferent arteriole (EA) resistance decreases GC pressure, increases PC pressure, and increases F.Panel D: Increased EA resistance increases GC pressure, decreases PC pressure, and decreases F. *,arteriole undergo-ing resistance change; R, resistance; P, pressure.

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artery and supplies blood flow to the alveolifor gas exchange, and the bronchial circula-tion, which is derived from the thoracic aortaand supplies nutrient flow to the trachea andbronchial structures. The pulmonary circula-tion receives all of the cardiac output of theright ventricle, whereas the bronchial circula-tion receives about 1% of the left ventricularoutput.

The pulmonary circulation is a low-resis-tance, low-pressure, high-compliance vascularbed. Although the pulmonary circulation re-ceives virtually the same cardiac output as thesystemic circulation, the pulmonary pressuresare much lower. The pulmonary artery systolicand diastolic pressures are about 25 mm Hgand 10 mm Hg, respectively. The mean pul-monary artery pressure is therefore about 15mm Hg. If we assume that the left atrial pres-sure averages 8 mm Hg, the perfusion pres-sure for the pulmonary circulation (mean pul-monary artery pressure minus left atrialpressure) is only about 7 mm Hg. This is con-siderably lower than the perfusion pressurefor the systemic circulation (about 90 mmHg). Because the flow is essentially the same,but the perfusion pressure is much lower inthe pulmonary circulation, the pulmonary vas-cular resistance must be very low. In fact, pul-monary vascular resistance is generally ten- tofifteen-fold lower than systemic vascular resis-tance. The reason for the much lower pul-monary vascular resistance is that the vesselsare larger in diameter, shorter in length, andhave many more parallel elements than thesystemic circulation.

Pulmonary vessels are also much morecompliant than systemic vessels. Because ofthis, an increase in right ventricular outputdoes not cause a proportionate increase inpulmonary artery pressure. The reason forthis is that the pulmonary vessels passively dis-tend as the pulmonary artery pressure in-creases, which lowers their resistance.Increased pressure also recruits additionalpulmonary capillaries, which further reducesresistance. This high vascular compliance andability to recruit capillaries are importantmechanisms for preventing pulmonary vascu-

lar pressures from rising too high when car-diac output increases (e.g., during exercise).

Increased pulmonary vascular pressure canhave two adverse consequences. First, in-creased pulmonary artery pressure increasesthe afterload on the right ventricle, which canimpair ejection, and with chronic pressure el-evation, cause right ventricular failure.Second, an increase in pulmonary capillarypressure increases fluid filtration (see Chapter8), which can lead to pulmonary edema.Pulmonary capillary pressures are ordinarilyabout 10 mm Hg, which is less than half thevalue found in most other organs.

Because of their low pressures and highcompliance, pulmonary vascular diametersare strongly influenced by gravity and bychanges in intrapleural pressure during respi-ration. When a person stands up, gravity in-creases hydrostatic pressures within vessels lo-cated in the lower regions of the lungs, whichdistends these vessels, decreases resistance,and increases blood flow to the lower regions.In contrast, vessels located in the upper re-gions of the lungs have reduced intravascularpressures; this increases resistance and re-duces blood flow when a person is standing.Changes in intrapleural pressure during respi-ration (see Chapter 5) alter the transmuralpressure that distends the vessels. For exam-ple, during normal inspiration, the fall in in-trapleural pressure increases vascular trans-mural pressure, which distends nonalveolarvessels, decreases resistance, and increases re-gional flow. The opposite occurs during aforced expiration, particularly against a highresistance (e.g., Valsalva maneuver). The cap-illaries associated with the alveoli are com-pressed as the alveoli fill with air during inspi-ration. With very deep inspirations, thiscapillary compression can cause an increase inoverall pulmonary resistance.

The primary purpose of the pulmonary cir-culation is to perfuse alveoli for the exchangeof blood gasses. Gas exchange depends, inpart, on diffusion distances and the surfacearea available for exchange. The capillary-alveolar arrangement is such that diffusion dis-tances are minimized and surface area is max-

166 CHAPTER 7

Ch07_141-170_Klabunde 4/21/04 11:43 AM

imized. Pulmonary capillaries differ from theirsystemic counterparts in that they form thininterconnecting sheets around and betweenadjacent alveoli, which greatly increase theirsurface area and reduce diffusion distances.

Unlike other organs, alveolar or arterialhypoxia causes pulmonary vasoconstriction.The mechanism is not known; however, evi-dence suggests that endothelin, reactive oxy-gen species, leukotrienes, and thromboxanesmay be involved. This hypoxic vasoconstric-tion, especially in response to regional varia-tions in ventilation, helps to maintain normalventilation-perfusion ratios in the lung.Maintenance of normal ventilation-perfusionratios is important because high blood flow tohypoxic regions, for example, would decreasethe overall oxygen content of the blood leav-ing the lungs.

Sympathetic adrenergic innervation of thepulmonary vasculature occurs, and sympatheticactivation increases pulmonary vascular resis-tance and pulmonary artery pressure. Sym-pathetic activation also decreases pulmonaryvascular compliance and mobilizes pulmonaryblood volume to the systemic circulation.

Summary of Special Circulations

Perfusion pressure and vascular resistance de-termine blood flow in organs. Under normalcircumstances, the perfusion pressure re-

mains fairly constant owing to baroreceptormechanisms. Therefore, the primary meansby which blood flow changes within an organis by changes in vascular resistance, which isinfluenced by extrinsic factors (e.g., sympa-thetic nerves and hormones) and intrinsic fac-tors (e.g., tissue metabolites and endothelial-derived substances). Basal vascular tone isdetermined by the net effect of the extrinsicand intrinsic factors acting on the vasculature.Resistance can either increase or decreasefrom the basal state by alterations in the rela-tive contribution of extrinsic and intrinsic fac-tors. Table 7-2 summarizes the relative impor-tance of sympathetic and metabolic controlmechanisms and the intrinsic autoregulatorycapacity of several major organ vascular beds.


• The relative distribution of blood flow toorgans is regulated by the vascular resis-tance of the individual organs, which is de-termined by extrinsic (neurohumoral) andintrinsic (local regulatory) mechanisms.

• Important local mechanisms regulating or-gan blood flow include the following: (1)tissue factors such as adenosine, K�, O2,CO2, and H�; (2) paracrine hormones suchas bradykinin, histamine, and prosta-glandins; (3) endothelial factors such as


TABLE 7-2 COMPARISON OF VASCULAR CONTROL MECHANISMS IN DIFFERENT VASCULAR BEDS

CIRCULATORY BED SYMPATHETIC CONTROL METABOLIC CONTROL AUTOREGULATION

Coronary �1 ��

Cerebral � ��

Skeletal muscle ��

Cutaneous ��

Intestinal ��

Renal ��

Pulmonary � �2 �

��, strong; ��, moderate, �, weak. 1 Sympathetic vasoconstriction in the coronaries is overridden by metabolicvasodilation during sympathetic activation of the heart. 2 Hypoxia causes vasoconstriction, the opposite of all otherorgans.

Ch07_141-170_Klabunde 4/21/04 11:43 AM

nitric oxide, endothelin-1, and prostacyclin;and (4) myogenic mechanisms intrinsic tothe vascular smooth muscle.

• The following local factors produce vasodi-lation in most tissues: adenosine, K�, H�,CO2, hypoxia, bradykinin, histamine,prostaglandin E2, prostacyclin, and nitricoxide. The following local factors producevasoconstriction: endothelin-1 and themyogenic response to vascular stretch.

• Mechanical compression of blood vesselsstrongly influences blood flow in the coro-nary circulation and in contracting skeletalmuscle.

• Autoregulation, which is the intrinsic abil-ity of an organ to maintain a constant bloodflow despite changes in perfusion pressure,is important in organs such as the heart,brain, and kidneys; the gastrointestinal andskeletal muscles circulations show moder-ate autoregulation.

• In organs such as the heart, brain, skeletalmuscle, and gastrointestinal tract, bloodflow is tightly coupled to oxidative metabo-lism; therefore, an increase in tissue oxygenconsumption leads to an increase in bloodflow. This is called active or functional hy-peremia.

• Blood flow in the following organs is mod-erately to strongly influenced by sympa-thetic vasoconstrictor mechanisms: restingskeletal muscle, kidneys, gastrointestinalcirculation, and skin (related to thermoreg-ulation).

• Vascular control mechanisms linked to ox-idative metabolism (metabolic mecha-nisms) are particularly strong in the heart,brain, and skeletal muscle.

Review Questions

Please refer to the appendix for the answersto the review questions.For each question, choose the one best answer:1. Which of the following causes vasodilation

in most vascular beds?a. Decreased tissue pCO2

b. Increased tissue pO2

c. Increased interstitial K�

d. Increased release of endothelin-1

2. Two minutes after perfusion pressure tothe kidney is suddenly reduced from 100mm Hg to 70 mm Hg, which of the fol-lowing will occur?

a. Afferent arterioles will be dilated.b. Renal blood flow will be reduced by

30%.c. Renal vascular resistance will be in-

creased.d. The kidney will become hypoxic.

3. If a coronary artery is occluded for oneminute and then the occlusion is released,

a. A period of active hyperemia fol-lows.

b. Coronary flow will increase becauseof vasoconstriction occurring duringthe ischemia.

c. Endothelial release of nitric oxidewill contribute to the reactive hyper-emia.

d. Interstitial adenosine concentrationswill increase and constrict coronaryarterioles.

4. Which one of the following organ circula-tions is most strongly constrictedduring sympathetic activation resultingfrom a baroreceptor reflex when a personsuddenly stands up?

a. Brainb. Heartc. Intestined. Skin

Match the organs listed in questions 5–10with answers “a” through “i” below. Eachquestion may have more than one correct an-swer.

Answers:a. Blood flow is primarily regulated by

CO2 and H�.b. Capillary beds found between two

in-series arteriolesc. Hypoxic vasoconstrictiond. Highest capillary pressuree. Highest arterial-venous oxygen dif-

ference

168 CHAPTER 7

Ch07_141-170_Klabunde 4/21/04 11:43 AM

f. Abundant arterial-venous anasto-moses

g. Largest organ massh. Receives most of its blood supply di-

rectly from other organsi. Controlled primarily by hypothala-

mic thermoregulatory centers

5. Skin circulation _____

6. Renal circulation _____

7. Coronary arteries _____

8. Pulmonary circulation _____

9. Cerebral circulation _____

10. Skeletal muscle circulation _____

SUGGESTED READINGSFolkow B, Neil E. Circulation. New York: Oxford

University Press, 1971.Johnson PC. Autoregulation of blood flow. Circ Res

1986;59:483–495.Joyner MJ, Halliwill JR. Sympathetic vasodilation in hu-

man limbs. J Physiol 2000;526:471–480.Lassen NA: Brain. In Johnson PC, ed. Peripheral

Circulation. New York: John Wiley & Sons, 1978.Boron WF, Boulpaep EL. Medical Physiology – A

Cellular and Molecular Approach. Philadelphia: W.B. Saunders, 2003.


Berne RM, Levy MN. Cardiovascular Physiology. 8thEd. Philadelphia: Mosby, 2001.


Ch07_141-170_Klabunde 4/21/04 11:43 AM

Ch07_141-170_Klabunde 4/21/04 11:43 AM

CD-ROM CONTENTSLEARNING OBJECTIVESINTRODUCTIONMECHANISMS OF EXCHANGEEXCHANGE OF OXYGEN AND CARBON

DIOXIDETRANSCAPILLARY FLUID EXCHANGE

Physical Mechanisms GoverningFluid Exchange

Capillary Exchange Model

EDEMA FORMATIONSUMMARY OF IMPORTANT CONCEPTSREVIEW QUESTIONSSUGGESTED READINGS

c h a p t e r

8Exchange Function of the Microcirculation

Capillary PressureInterstitial ComplianceOsmosis and Osmotic Pressure

CD CONTENTS

LEARNING OBJECTIVES

Understanding the concepts presented in this chapter will enable the student to:1. Describe the principal mechanisms by which each of the following moves across the capil-

lary endothelium: lipid-insoluble substances, lipid-soluble substances, fluid, and elec-trolytes.

2. Write out and explain Fick’s First Law for diffusion.3. Name three different types of capillaries; know the organs in which they are found, and

describe their differences in permeability to macromolecules and fluid.4. Describe the factors that determine oxygen’s rate of exchange between the microcircula-

tion and tissue.5. Describe how changes in tissue (interstitial) and plasma hydrostatic and oncotic pressures

affect transcapillary fluid movement.6. Explain how changes in each of the following affect capillary pressure: arterial and ve-

nous pressures, precapillary and postcapillary resistances.7. Explain what determines the rate of fluid movement across capillaries for a given net dri-

ving force of hydrostatic and oncotic pressures.8. Explain why changes in venous pressure have a greater affect on capillary pressure than

do changes in arterial pressure.9. Explain why oncotic pressure (colloid osmotic pressure) rather than total osmotic pressure

governs fluid exchange across the capillary.10. Describe the significance of the reflection coefficient for proteins in terms of how it af-

fects the oncotic pressure generated by proteins.11. Describe the function of lymphatics in the maintenance of interstitial fluid volume.12. Describe how changes in capillary hydrostatic pressure, plasma oncotic pressure, capillary

permeability, and lymphatic function can lead to tissue edema.

171

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INTRODUCTION

The microcirculation consists of small arter-ies, arterioles, capillaries, venules, small veins,and small lymphatic vessels found within or-gans and tissues (see Chapter 5, Fig. 5-1).These vessels have several important func-tions. First, the small arteries and arteriolesare the principal sites of resistance within thesystemic circulation and therefore play a ma-jor role in the regulation of arterial bloodpressure and blood flow within organs (seeChapter 5). Second, venules and small veinshave an important capacitance function andtherefore determine the distribution of bloodvolume within the body. Third, the microcir-culation allows passage of leukocytes from theblood into the extravascular space. Fourth, themicrocirculation is the exchange site of gases,nutrients, metabolic wastes, and thermal energy between the blood and tissues.Capillaries are quantitatively the most impor-tant site for exchange because of their physi-cal structure (small volume-to-surface area ra-tio and thin walls), large number, andenormous surface area available for exchange.

This chapter focuses on the exchange functionof capillaries.

MECHANISMS OF EXCHANGE

Fluid, electrolytes, gases, and small and largemolecular weight substances transverse thecapillary endothelium by several differentmechanisms: diffusion, bulk flow, vesiculartransport, and active transport (Fig. 8-1).Diffusion is the movement of a molecule froma high concentration to a low concentration.This mechanism of exchange is particularlyimportant for gases (O2 and CO2) and otherlipid-soluble substances (e.g., steroid hor-mones, anesthetics). Fluid and electrolytesalso are exchanged across the endothelium, inpart, by diffusion.

The movement of a substance by diffusionis described by Fick’s First Law of diffusion(Equation 8-1), in which the movement of amolecule per unit time (flux JS; moles/sec)equals the diffusion constant (D) of the bar-rier (e.g., capillary wall) multiplied by the sur-face area (A) available for diffusion and theconcentration gradient (�C/�X), which is the

172 CHAPTER 8

TissueInterstitium

Blood

Diffusion Bulk Flow VesiclesActive

Transport

EndothelialCell

O2, CO2,lipid-solublesubstances

H2O,electrolytes,

small moleculesMacro-

moleculesIons, smallmolecules

FIGURE 8-1 Mechanisms of exchange across the capillary endothelium. Lipid-soluble substances like oxygen and car-bon dioxide readily exchange across capillary endothelial cells by diffusion. Water and electrolytes move across theendothelium primarily by bulk flow through intercellular clefts (“pores”). Vesicular transport mechanisms move largemolecules across the endothelium. Active transport mechanisms move ions and other small molecules across the en-dothelium.

Ch08_171-184_Klabunde 4/21/04 11:45 AM

concentration difference across the barrier (�C) divided by the diffusion distance (�X).

JS � DA��

�

XC�

The diffusion constant is a value that repre-sents the ease with which a specific substancecan cross the capillary wall (or other barrier)by diffusion. The diffusion constant of a capil-lary wall is different for different substances.For example, the diffusion constant for oxy-gen is very high compared to glucose.

Therefore, Equation 8-1 tells us that therate of diffusion is directly related to the con-centration difference, the diffusion constant,and the area available for diffusion, and it isinversely related to the diffusion distance. Thediffusion distance (�X) in Equation 8-1 issometimes combined with the diffusion con-stant (D) and called the permeability coeffi-cient (P). This simplifies Equation 8-1 to JS �PS(�C) in which S is the surface area availablefor exchange. The combined value of the per-meability coefficient times the surface areahas been calculated for different substances inmany organs and tissues; it is called the PSproduct.

A second mechanism for exchange is bulkflow. This mechanism is important for themovement of water and lipid-insoluble sub-stances across capillaries. Bulk flow of fluidand electrolytes and of small molecules occursthrough intercellular clefts between endothe-lial cells (see Fig. 8-1). These extracellularpathways are sometimes referred to as“pores.”

The physical structure of capillaries variesconsiderably among organs; these differencesgreatly affect exchange by bulk flow. Somecapillaries (e.g., skeletal muscle, skin, lung,and brain) have a very “tight” endotheliumand continuous basement membrane (termedcontinuous capillaries), which reduces bulkflow across the capillary wall. In contrast,some vascular beds have fenestrated capil-laries (e.g., in exocrine glands, renalglomeruli, and intestinal mucosa), which haveperforations (fenestrae) in the endothelium,resulting in relatively high permeability andbulk flow. Discontinuous capillaries (found

in the liver, spleen, and bone marrow) havelarge intercellular gaps, as well as gaps in thebasement membrane, and therefore have thehighest permeability.

Bulk flow follows Poiseuille’s equation forhydrodynamic flow (see Chapter 5, Equation5-6). Changes in pressure gradients (eitherhydrostatic or colloid osmotic) across a capil-lary alter fluid movement across the capillary.In addition, changes in the size and number of“pores” or intercellular clefts alter exchange.Pore size and path length are analogous tovessel radius and length in Poiseuille’s equa-tion; they are major factors in the resistance tobulk flow across capillaries. In some organs,precapillary sphincters (circular bands ofsmooth muscle at the entrance to capillaries)can regulate the number of perfused capillar-ies. An increase in perfused capillaries in-creases the surface area available for fluid ex-change and the net movement of fluid acrosscapillaries by bulk flow.

Vesicular transport is a third mechanismby which exchange occurs between blood andtissue. This mechanism is particularly impor-tant for the translocation of macromolecules(e.g. proteins) across capillary endothelium.Compared to diffusion and bulk flow, vesicu-lar transport plays a relatively minor role intranscapillary exchange (except for macromol-ecules). Evidence exists, however, that vesi-cles can sometimes fuse together, creating achannel through a capillary endothelial cell,thereby permitting bulk flow to occur.

Active transport is a fourth mechanism ofexchange. Some molecules (e.g., ions, glucose,amino acids) are actively transported acrosscapillary endothelial cells; however, this is notnormally thought of as a mechanism for ex-change between plasma and interstitium, butrather as a mechanism for exchange betweenan individual cell and its surrounding milieu.

EXCHANGE OF OXYGEN AND CARBON DIOXIDE

Oxygen diffuses from the blood to the tissuesto support mitochondrial respiration. Thelipid solubility of oxygen enables it to readilydiffuse through tissues; however, the distance

EXCHANGE FUNCTION OF THE MICROCIRCULATION 173

Eq. 8-1

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that oxygen is able to diffuse within a tissue islimited by cellular utilization of oxygen. Forexample, as oxygen diffuses out of a capillaryin skeletal muscle, the muscle cells adjacent tothe capillary take up the oxygen for use by themitochondria. Consequently, little oxygen dif-fuses all the way through one cell to reach an-other. Therefore, in tissues having a high de-mand for oxygen, it is essential that thecapillary density is great enough to provideshort diffusion distances.

Large amounts of oxygen diffuse across thecapillaries not only because of their thin wallsand high diffusion constant for oxygen, butmore importantly, because of their large sur-face area available for diffusion. It has beenobserved that significant amounts of oxygenalso diffuse out of arterioles. Some of this oxy-gen diffuses through arteriolar walls into thesurrounding cells, and in some cases, it dif-fuses from arterioles into the venules that of-ten are found adjacent to arterioles. Normally,systemic arterial blood is fully saturated withoxygen and has a pO2 of about 95 mm Hg.Direct measurements of pO2 in small arteri-oles (20–80 � diameter) of some tissues revealthat the pO2 is only 25–35 mm Hg, which cor-responds to a 30% to 60% loss of oxygen con-tent of the blood. Therefore, substantialamounts of oxygen diffuse out of the blood be-fore the blood reaches the capillaries; how-ever, capillaries are the most important site fortissue oxygenation because the relatively highcapillary density ensures that diffusion dis-tances between the blood and tissue cells areshort.

Because oxygen diffusion follows Fick’sFirst Law (Equation 8-1), the rate of oxygendiffusion can be enhanced by increasing arte-rial pO2, decreasing tissue pO2, or increasingthe area available for diffusion (i.e., increasingthe number of flowing vessels, particularlycapillaries). For a single capillary having afixed diffusion constant, diffusion length, andsurface area, the rate of oxygen diffusion (JO2)primarily depends on the concentration dif-ference of oxygen (expressed as pO2 differ-ence) between the capillary blood and the tis-sue surrounding the capillary (the pO2

difference is 20 mm Hg in Figure 8-2).

Therefore, increasing capillary blood pO2 (asoccurs when a person breathes pure oxygen)or decreasing tissue pO2 (as occurs with in-creased tissue oxygen consumption) increasesthe rate of oxygen diffusion into the tissue.Capillary pO2 is also increased by dilation ofresistance vessels. This increases microvascu-lar blood flow, thereby delivering more oxygento the capillaries per unit time, which resultsin higher pO2 values in the capillary blood. Ifvasodilation is accompanied by an increase inthe number of flowing capillaries (as occursduring skeletal muscle contraction), this in-creases the surface area available for oxygendiffusion and further enhances oxygen trans-port into the tissue.

Carbon dioxide is a by-product of oxidativemetabolism and must be removed from thetissue and transported to the lungs by theblood. Like oxygen, carbon dioxide is verylipid-soluble and readily diffuses from cellsinto the blood. In fact, its diffusion constant isabout 20 times greater than oxygen in aqueoussolutions. The removal of carbon dioxide fromtissues is not diffusion-limited; its removal de-pends primarily on the blood flow. Therefore,reduced tissue perfusion leads to an increasein tissue and venous pCO2.

174 CHAPTER 8

Capillary

pO =25 mmHg

pO =5 mm Hg

J = DA ( C/ X)J C

O O

∆ ∆∝ ∆

∆X ∆C = 25 – 5 mm Hg= 20 mm Hg

JO

2

2

22

2

Interstitium

FIGURE 8-2 Diffusion of oxygen (JO2) from capillariesinto the tissue follows Fick’s First Law of diffusion.Because the diffusion constant (D), the area for ex-change (A), and the diffusion distance (�X) remain rel-atively constant in a single capillary, the diffusion of oxy-gen is governed primarily by the difference in partialpressure of oxygen (pO2) between the blood and tissue(�C ), which is 20 mm Hg in this example. Increasing thepO2 difference increases the rate of diffusion.

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TRANSCAPILLARY FLUID EXCHANGE

The body is comprised of two basic fluid com-partments: intravascular and extravascular.The intravascular compartment contains fluid(i.e., blood) within the cardiac chambers andblood vessels of the body. The extravascularsystem is everything outside of the intravascu-lar compartment. The extravascular compart-ment is made up of many subcompartmentssuch as the cellular, interstitial, and lymphaticsubcompartments and a specialized systemcontaining cerebrospinal fluid within the cen-tral nervous system.

Fluid readily exchanges between the in-travascular and extravascular compartments.Fluid leaves blood vessels (primarily capillar-ies) and enters the tissue interstitium of theextravascular compartment. This is calledfluid filtration (Fig. 8-3). It is estimated thatabout 1% of the plasma is filtered into the in-terstitium in a typical organ. The interstitialfluid is exchanged with the fluid found withinthe subcompartments of the extracellularcompartment. It is crucial that a steady state isachieved in which the same volume of fluidthat leaves the vasculature is returned to thevasculature; otherwise the extravascular com-partment would swell with fluid (i.e., becomeedematous).

There are two routes by which fluid is re-turned to the blood. First, fluid reabsorp-tion returns most of the filtered fluid to theblood at the venular end of capillaries or atpostcapillary venules (see Fig. 8-3). The rateof reabsorption is less than filtration; thereforea second mechanism is required to maintainfluid balance. This second mechanism in-volves lymphatic vessels. These specializedvessels, similar in size to venules, comprise anendothelium with intercellular gaps sur-rounded by a highly permeable basementmembrane. Terminal lymphatics end as blindsacs within the tissue. The terminal lymphat-ics take up the excess fluid (including elec-trolytes and macromolecules) and transport itinto larger lymphatics that leave the tissue. Itis estimated that 5% to 10% of capillary filtra-tion is transported out of tissues by the lym-phatics. The larger lymphatics have smoothmuscle cells that undergo spontaneous vaso-motion that serves to “pump” the lymph.Vasomotion is spontaneous rhythmic contrac-tion and relaxation of the lymphatic vessels.Evidence exists that as a lymphatic vessel fillswith fluid, the increased pressure stretchesthe vessel and induces a myogenic contrac-tion. Sympathetic nerves can modulate thisvasomotion. Lymphatic vessels contain one-


Lymphatic

Capillary

Filtration

Reabsorption

Lymph Flow

Filtration = Reabsorption + Lymph Flow

FIGURE 8-3 Capillary filtration, reabsorption, and lymph flow. Fluid filters out of the arteriolar end of the capillaryand into the interstitium. Most of this fluid is reabsorbed at the venular end of the capillary, with the rest of the fluidentering terminal lymphatics to be carried away from the tissue and eventually returned to the blood. Fluid exchangeis in balance (i.e., at a steady state) when filtration equals reabsorption plus lymph flow.

Ch08_171-184_Klabunde 4/21/04 11:45 AM

way valves that direct lymph away from thetissue and eventually back into the systemiccirculation via the thoracic duct and subcla-vian veins. Approximately 2–4 L/day of lymphare returned to the circulation by this manner.

In the steady state, the rate of fluid enter-ing the tissue interstitium by filtration is thesame as that of the fluid leaving the tissue bycapillary reabsorption and lymph flow. That is,filtration equals reabsorption plus lymph flow.When this balance is altered, the volume andpressure of fluid within the interstitiumchanges. For example, if net filtration tran-siently increases and lymph flow does not in-crease to the same extent, interstitial volumeand pressure will increase, causing edema.Factors that cause edema are discussed in thelast section of this chapter.

Physical Mechanisms GoverningFluid Exchange

The movement of fluid across a capillary is determined by several physical factors: the hy-drostatic pressure, oncotic pressure, and phys-ical nature of the barrier (i.e., the permeabil-ity of the capillary wall) separating the fluid inthe blood from the fluid within the intersti-tium. As described earlier, the movement offluid can be related to Poiseuille’s equation for

hydrodynamic flow (see Equation 5-6), or inmore simplified terms, to the general hydro-dynamic equation (Equation 5-3) that relatesflow (F), driving pressure (�P), and resistance(R) (i.e., F � �P/R). A more common way toexpress this hydrodynamic equation for tran-scapillary fluid exchange is to substitute vascu-lar conductance (C) for resistance, which arereciprocally related (i.e., F � C · �P). Fluidflux is the number of molecules of water (orvolume) per unit time that moves across theexchange barrier; therefore, fluid flux can beexpressed in similar units as flow. If net fluidflux (J) is substituted for flow, net driving force(NDF) is substituted for driving pressure(�P), and filtration constant (KF) and surfacearea (A) are substituted for vascular conduc-tance, the following relationship is obtained(Equation 8-2):

J � KF � A (NDF)

Equation 8-2 and Figure 8-4 show that netfluid movement (fluid flux, J) is directly re-lated to the filtration constant (KF), the sur-face area available for fluid exchange (A), andthe net driving force (NDF). At a given NDF(assuming that the NDF is not equal to zero),the amount of fluid filtered or reabsorbed perunit time is determined by the filtration con-stant and surface area available for exchange.

176 CHAPTER 8

H2O

H2O

H2OH2O

H2O

H2O

H2OH2O

NDF

KF⋅A

J

J = KF⋅A (NDF)FIGURE 8-4 Factors determining fluid movement. The rate of fluid movement (flux, J) across the capillary endothe-lium, designated as water molecules in this figure, is determined by the net driving force (NDF), the capillary filtra-tion constant (KF), and the capillary surface area (A) available for exchange.

Eq. 8-2

Ch08_171-184_Klabunde 4/21/04 11:45 AM

The filtration constant is determined by thephysical properties of the barrier (i.e., size andnumber of “pores” and the thickness of thecapillary barrier), and therefore it representsthe permeability of the capillaries. For exam-ple, fenestrated capillaries have a higher KF

(i.e., permeability) than continuous capillar-ies. Furthermore, paracrine substances suchas histamine, bradykinin, and leukotrienes in-crease KF. The surface area (A) is primarily re-lated to the length, diameter, and number ofvessels (capillaries and postcapillary venules)available for exchange. The surface area is dy-namic in vascular beds such as skeletal mus-cle. In that tissue, the number of perfusedcapillaries can increase several-fold during ex-ercise. In experimental studies using wholeorgans, KF and A are combined and called thecapillary filtration coefficient (CFC).

The direction of fluid movement (filtrationor reabsorption) in Equation 8-2 depends onwhether the NDF is positive (filtration) ornegative (reabsorption). If the NDF is zero,no net fluid movement occurs even if KF andA are very large.

The NDF is determined by hydrostatic andoncotic forces. Two hydrostatic and two on-cotic pressures affect transcapillary fluid ex-change: capillary hydrostatic pressure, tissue(interstitial) hydrostatic pressure, capillary(plasma) oncotic pressure, and tissue (intersti-tial) oncotic pressure (Fig. 8-5). These physi-cal forces are sometimes referred to asStarling forces in honor of Ernest Starling,who pioneered much of the early research oncapillary fluid exchange. The net hydrostaticpressure driving fluid out of the capillary (fil-tration) is the intracapillary pressure minusthe interstitial hydrostatic pressure (Pc – Pi).The net oncotic pressure drawing fluid intothe capillary (reabsorption) is the capillaryplasma oncotic pressure minus the interstitialoncotic pressure (�c - �i).

Capillary hydrostatic pressure (PC) drives fluid out of the capillary, and it is high-est at the arteriolar end of the capillary andlowest at the venular end. Depending on theorgan, the pressure may drop along the lengthof the capillary (axial or longitudinal pressuregradient) by 15–30 mm Hg owing to capillary

resistance. Because of this pressure gradientalong the capillary length, filtration is favoredat the arteriolar end of the capillary wherecapillary hydrostatic pressure is greatest.

The average capillary hydrostatic pressureis determined by arterial and venous pres-sures (PA and PV), and by the ratio of post-to-precapillary resistances (RV/RA). An increasein either arterial or venous pressure in-creases capillary pressure; however, the ef-fects of elevations in venous pressure aremuch greater than those of an equivalent el-evation in arterial pressure. The reason forthis is that postcapillary resistance is muchlower than precapillary resistance. In mostorgans, the precapillary resistance is five toten times greater than postcapillary resis-tance; therefore, RV/RA ranges from 0.1 to0.2. If we assume that RV/RA � 0.2, the fol-lowing relationship (Equation 8-3) can bederived (for details, see Capillary Pressureon CD):


InterstitiumCapillary

c

c

i

i

c c ii

FIGURE 8-5 Net driving force for fluid movement acrosscapillaries. Hydrostatic and oncotic pressures within thecapillary (Pc , �c) and the tissue interstitium (Pi , �i) de-termine the net driving force (NDF) for fluid movementout of the capillary (filtration) or into the capillary (reab-sorption). The hydrostatic pressure difference favors fil-tration (red arrow) because Pc is greater than Pi. The on-cotic pressure difference favors reabsorption (blackarrow) because �c is greater than �i. The oncotic pres-sure difference is multiplied by the reflection coefficient(�), a factor that represents the permeability of the cap-illary to the proteins responsible for generating the on-cotic pressure.

Ch08_171-184_Klabunde 4/21/04 11:45 AM

PC � ⇒PC � �0.2P

1A

.2 PV�

Equation 8-3 shows that increasing ve-nous pressure by 20 mm Hg increases meancapillary pressure by 16.7 mm Hg. In con-trast, increasing arterial pressure by 20 mmHg increases mean capillary pressure by only3.3 mm Hg. The reason for this difference isthat the high precapillary resistance bluntsthe effects of increased arterial pressure onthe downstream capillaries. Therefore, mean

��RR

A

V�� PA PV

��1 ��

RR

A

V��

capillary hydrostatic pressure is morestrongly influenced by changes in venouspressure than by changes in arterial pressure.This has significant clinical implication.Conditions that increase venous pressure(e.g., right ventricular failure, cirrhosis of theliver, venous thrombosis) can lead to edemain peripheral organs and tissues by increasingcapillary hydrostatic pressure and capillaryfluid filtration.

Tissue (interstitial) hydrostatic pres-sure (Pi) is the pressure within the tissue in-terstitium that is exerted against the outsidewall of the capillary, and therefore opposes

178 CHAPTER 8

In an experimental study, the control mean arterial and venous pressures perfusing anorgan are 90 mm Hg and 10 mm Hg, respectively, and the post-to-precapillary resis-tance ratio is 0.20. After inducing heart failure, the mean arterial pressure falls to 80mm Hg, and the venous pressure increases to 20 mm Hg. Furthermore, the post-to-pre-capillary resistance ratio decreases to 0.15. Calculate the increase in mean capillarypressure caused by the heart failure.

Use Equation 8-3 to calculate the mean capillary pressure for both the control condi-tion and the condition during heart failure. The difference represents the increase incapillary pressure caused by the heart failure.

Control: PC � � �0.2(9

10.)2 10� � 23.3 mm Hg

Heart Failure: PC � �0.15(

18.01)5 20

� � 27.8 mm Hg

Therefore, capillary pressure increased by 4.5 mm Hg.Note: This problem illustrates the relationship between capillary pressure, arterial and

venous pressures, and precapillary and postcapillary resistances. In an actual ex-perimental study, unlike this problem, the capillary pressure would be measuredand the precapillary and postcapillary resistances would be calculated becausethese resistances can only be known if capillary, arterial, and venous pressuresare first known. The ratio of post-to-precapillary resistances can be calculatedfrom:

�RR

A

V� � �

((PP

A

C

PP

V

C

))

�

This calculation assumes that the precapillary flow equals the postcapillary flow, whichgenerally is an acceptable assumption (see Capillary Pressure on CD).

��RR

A

V�� PA PV

��1 ��

RR

A

V��

PROBLEM 8-1

Eq. 8-3

Ch08_171-184_Klabunde 4/21/04 11:45 AM

the capillary hydrostatic pressure. This pres-sure is determined by the interstitial fluid vol-ume and the compliance of the tissue (seeInterstitial Compliance on CD). In many tis-sues under normal states of hydration, tissuehydrostatic pressure is subatmospheric by afew millimeters of mercury (mm Hg),whereas in others it is slightly positive by afew mm Hg. Increased tissue fluid volume, asoccurs during states of enhanced capillaryfluid filtration or lymphatic blockage, in-creases tissue hydrostatic pressure. In con-trast, dehydration reduces tissue hydrostaticpressure.

Capillary plasma oncotic pressure (�c)is the osmotic pressure within the capillarythat is determined by the presence of pro-teins. Because this is an osmotic force withinthe plasma, it opposes filtration and pro-motes reabsorption. Because the capillarybarrier is readily permeable to ions, the ionshave no significant effect on osmotic pres-sure within the capillary (see Osmosis andOsmotic Pressure on CD). Instead, the os-motic pressure is principally determined byplasma proteins that are relatively imperme-able. Rather than being called “osmotic”pressure, this pressure is referred to as the“oncotic” pressure or “colloid osmotic” pres-sure because it is generated by macromolec-ular colloids. Albumin, the most abundantplasma protein, generates about 70% of theoncotic pressure; globulins and fibrinogengenerate the remainder of the oncotic pres-sure. The plasma oncotic pressure typically is25–30 mm Hg. The oncotic pressure in-creases along the length of the capillary, par-ticularly in capillaries having high net filtra-tion (e.g., renal glomerular capillaries). Thisoccurs because the filtered fluid leaves be-hind proteins, increasing the plasma proteinconcentration.

When oncotic pressure is determined, it ismeasured across a semipermeable mem-brane—i.e., a membrane that is permeable tofluid and electrolytes but not permeable tolarge protein molecules. In most capillaries,however, the endothelial barrier has a finitepermeability to proteins. The actual perme-ability to proteins depends on the type of cap-

illary and on the nature of the proteins (size,shape, and charge). Because of this finite per-meability, the effective oncotic pressure gen-erated across the capillary membrane is lessthan that calculated from the protein concen-tration. The reflection coefficient (�) acrossa capillary is the effective oncotic pressure di-vided by the oncotic pressure, calculated fromthe concentration difference of the proteinsacross the capillary wall. If the capillary is im-permeable to protein, � � 1. If the capillary isfreely permeable to protein, � � 0. Continuouscapillaries have a high � (greater than 0.9),whereas discontinuous capillaries, which arevery “leaky” to proteins, have a relatively low�. In the latter case, plasma and tissue oncoticpressures may have a negligible influence onthe NDF. Therefore, the effective oncoticpressure is the oncotic pressure calculatedfrom the protein concentrations multiplied bythe reflection coefficient for capillaries in aparticular tissue.

The tissue (or interstitial) oncotic pres-sure (�i), a force that promotes filtration, isdetermined by the interstitial protein concen-tration and the reflection coefficient of thecapillary wall for those proteins. The proteinconcentration is influenced, in part, by theamount of fluid filtration into the interstitium.For example, increased capillary filtration intothe interstitium decreases interstitial proteinconcentration and reduces the oncotic pres-sure. This effect of filtration on protein con-centration serves as a mechanism to limit ex-cessive capillary filtration. The interstitialoncotic pressure, which is typically about 5mm Hg, acts on the capillary fluid to enhancefiltration and oppose reabsorption.

Together, the hydrostatic and oncoticforces are related to the NDF as shown inEquation 8-4. The net hydrostatic pressure,which normally promotes filtration, is repre-sented by (Pc – Pi). The net oncotic pressure,which promotes reabsorption, is representedby �c – �i), multiplied by the reflection coeffi-cient (�). This equation shows that the NDFis increased by increases in Pc and �i and de-creased by increases in Pi and �c.

NDF � (Pc Pi) �(�c �i)


Eq. 8-4

Ch08_171-184_Klabunde 4/21/04 11:45 AM

If the above expression for NDF is incor-porated into Equation 8-2, the followingequation is derived:

J � KF � A[(Pc Pi) � (�c �i)]

The expression in brackets represents theNDF. If the NDF is positive, filtration occurs,and if it is negative, reabsorption occurs. For agiven NDF, the rate of fluid movement (J) isdetermined by the product of KF and A.

Capillary Exchange Model

Capillary fluid exchange can be modeled asshown in Figure 8-6. This model assumes thatthe following values remain constant alongcapillary length: Pi � 1 mm Hg, �c � 25 mmHg, �i � 6 mm Hg, and �� 1. According toEquation 8-4, if Pc is 30 mm Hg at the en-trance to the capillary and falls linearly to 15mm Hg at the end of the capillary, the NDFchanges from 10 at the entrance of the cap-illary to –5 at the end of the capillary.Filtration occurs along most of the length ofthe capillary wherever NDF is greater thanzero. Reabsorption occurs where NDF is lessthan zero, which is near the venular end of thecapillary. Net fluid movement is zero at thepoint along the capillary where NDF � 0. Therate of filtration or reabsorption (J) dependson the product of KF and A, and the NDF.

180 CHAPTER 8

Given that Pc � 22 mm Hg, Pi � –3 mm Hg, �c � 26 mm Hg, �i � 6 mm Hg, and � � 0.9,answer the following questions:

a) What is the net driving force for transcapillary fluid exchange?b) Is filtration or reabsorption occurring?c) If the product of KF and A is doubled, what will happen to the net rate of fluid

movement across the capillary, assuming that the net driving force does notchange?

Answer:a) The net driving force, NDF � [(Pc – Pi) – �(�c – �i)]. Substituting the given values,

the NDF � 7 mm Hg.NDF � [22 – (–3)] – 0.9 [(26 – 6)] � 7 mm Hg

b) Because the NDF is greater than zero, filtration is occurring.c) The net rate of fluid movement, J � KF � A (NDF). Therefore, if the product of KF and

A is doubled, then J (the filtration in this problem) is doubled because the NDF ≠ 0.

PROBLEM 8-2

30

20

10

0

P

P

Capillary

Arteriole Venule

Capillary Length

NDF

Filtr

Filtration

Reabsorption

Reab

10

5

0

-5

c

c

FIGURE 8-6 Model of capillary fluid exchange.Assuming that Pi � 1, �c � 25, �i � 6 mm Hg, and � �

1, and assuming that capillary hydrostatic pressure (Pc)at the beginning and end of the capillary are 30 mm Hgand 15 mm Hg, respectively, the net driving force [NDF � (Pc – Pi) – (�C – �i)] is positive along most of thelength of the capillary, which causes filtration (Filtr) tooccur. Near the venular end of the capillary, the NDF isless than zero and reabsorption (Reab) occurs.

Eq. 8-5

Ch08_171-184_Klabunde 4/21/04 11:45 AM

This model is highly simplified because itassumes that Pi, �c, and �i remain constant,which does not occur in vivo. As fluid leavesthe arteriolar end of the capillary, �c increases,Pi increases, and �i decreases. These changesoppose the filtration. For most capillaries, thefraction of fluid filtered from the capillary (fil-tration fraction) is less than 1%, so Pi, �c, and�i do not change appreciably. Renal capillar-ies, however, are different because the filtra-tion fraction in these capillaries is very high(approximately 20%), which leads to signifi-cant increases in plasma oncotic pressure. Innon-renal capillaries, if capillary permeabilityis increased, or if capillary hydrostatic pres-sure is increased to high levels by venous oc-clusion or heart failure, the increase in filtra-tion can lead to significant changes in Pi, �c,and �i in a manner that opposes and thereforelimits the net filtration of fluid.

Lymphatics (not shown in Fig. 8-6) pick upexcess filtered fluid and transport it out of thetissue. When net filtration increases, lym-phatic flow also increases. The lymphatics,therefore, along with the dynamic changes inPc, Pi, �c, and �i help to maintain a properstate of interstitial hydration and thereby pre-vent edema from occurring.

EDEMA FORMATION

When the fluid volume within the interstitialcompartment increases because filtration ex-ceeds the rate of capillary reabsorption pluslymphatic flow, the interstitial compartmentincreases in volume, leading to tissue swelling(i.e., edema). The change in interstitial pres-sure that results from an increase in intersti-tial volume depends on the compliance of the interstitial compartment. For example,edema in the brain causes large increases ininterstitial pressure because of the rigid cra-nium (i.e., low compliance). Soft, highly com-pliant tissues such as the skin and subcuta-neous tissues can undergo considerableswelling before substantial increases in tissuepressure occur.

Edema can damage organs and, in somecases, cause death. For example, cerebraledema following brain trauma can lead to cel-

lular death because the increased interstitialpressure damages neurons and causes tissueischemia by compressing blood vessels. Evenin tissues that are relatively compliant, such asskin and skeletal muscle, severe edema canlead to tissue necrosis. Pulmonary edema canbe life threatening because gas exchange isimpaired.

Table 8-1 lists some of the many causes ofedema. Every cause of edema can be relatedto one or more of the following:

• Increased capillary hydrostatic pressure• Increased capillary permeability• Decreased plasma oncotic pressure• Lymphatic obstruction

The most common cause of edema is ele-vated capillary pressure, such as occurs duringheart failure or venous obstruction. Both con-ditions increase venous pressure, which istransmitted back to the capillaries, causing anincrease in fluid filtration. Localized edema intissues is commonly caused by injury or in-flammation (e.g., sprained ankle, bee sting),which causes the release of local paracrinesubstances (e.g., histamine, bradykinin, andleukotrienes) that increase capillary and venu-lar permeability. Some of these substances(e.g., histamine) also increase capillary pres-sure by dilating arterioles and constrictingvenules.

The treatment for edema involves modify-ing one or more of the physical factors thatregulates fluid movement. For example, inpulmonary or systemic edema secondary toheart failure, diuretics are given to the patientto reduce blood volume and venous pressure,therefore reducing capillary hydrostatic pres-sure. A patient suffering from ankle edemafollowing an injury will be instructed to keepthat foot elevated whenever possible to dimin-ish the effects of gravity on capillary pressureand to use a tight fitting elastic stocking orbandage around the ankle to increase tissuehydrostatic pressure (which opposes filtra-tion). Drugs (e.g., antihistamines) are some-times used to block the release or action ofparacrine substances that increase capillarypermeability following tissue injury or inflam-mation.


Ch08_171-184_Klabunde 4/21/04 11:45 AM


• Diffusion is the primary mechanism for theexchange of gasses and lipid-soluble sub-stances across the capillary barrier. Withdiffusion, the rate of molecular movement(flux, J) is directly related to the diffusionconstant of the substance (D), the surfacearea available for diffusion (A), and theconcentration difference across the capil-lary wall (�C). It is inversely related to thediffusion distance (thickness of diffusionbarrier, �X) as shown by Fick’s First Law ofdiffusion: JS � DA(�C�X).

• The exchange of water and electrolytesacross capillaries (and postcapillaryvenules) occurs primarily through bulkflow through intercellular clefts (“pores”)between endothelial cells. Bulk flow is gov-erned by the same factors that determinethe blood flow through vessels; these fac-tors are described by Poiseuille’s equation(see Chapter 5).

• The net driving force (NDF) that deter-mines fluid movement is the net hydrostaticpressure across the capillary wall (capillaryminus interstitial hydrostatic pressures, Pc –Pi) minus the opposing effective oncoticpressure gradient across the capillary wall(capillary minus interstitial oncotic pres-

sures, �c – �i, multiplied by the reflectioncoefficient [�]). Therefore, the NDF � (Pc – Pi) – �(�c – �i).

• Changes in capillary hydrostatic pressuresignificantly alter fluid exchange. Capillarypressure is determined by arterial and ve-nous pressures and by the ratio of precapil-lary and postcapillary resistances. Changesin venous pressure have a much greaterquantitative influence on capillary pressurethan do similar changes in arterial pres-sure.

• Filtration occurs when the NDF is greaterthan zero, which generally occurs at the ar-teriolar end of the capillary. Reabsorptionoccurs when the NDF is less than zero,which generally occurs at the venular endof the capillary where capillary hydrostaticpressure is lower.

• The net fluid flux (J) is directly related tothe NDF, the capillary filtration constant(KF), and the surface area (A) available forfluid exchange; therefore, J � KF · A(NDF). At a given NDF, the greater the fil-tration constant or the greater the capillarysurface area, the greater the net amount offluid movement across the capillary.

• Fluid balance within a tissue is achievedwhen capillary filtration equals the sum ofcapillary reabsorption and lymphatic flow.

182 CHAPTER 8

TABLE 8-1 CAUSES OF EDEMA

Increased Capillary Pressure

Increased venous pressure

- Heart failure

- Increased blood volume

- Venous obstruction (thrombosis orcompression)

- Incompetent venous valves

- Gravity

Increased arterial pressure

- Hypertension

Decreased arterial resistance

- Vasodilation (physiologic or pharmacologic)

Increased Capillary Permeability

Vascular damage (e.g., burns, trauma)

Inflammation

Decreased Plasma Oncotic Pressure

Reduced plasma proteins (e.g., malnutri-tion, burns, liver dysfunction)

Lymphatic Blockage (Lymphedema)

Tissue injury

Inflammation of lymphatics

Lymphatic invasion by parasites (e.g., filariasis)

Ch08_171-184_Klabunde 4/21/04 11:45 AM

An increase in tissue fluid volume (edema)occurs when the rate of fluid filtration ex-ceeds the sum of the rate of fluid reabsorp-tion and lymphatic flow.

• Edema can occur when increased capillaryhydrostatic pressure, increased capillarypermeability, decreased plasma oncoticpressure, or lymphatic blockage occurs.

Review Questions

Please refer to the appendix for the answersto the review questions.For each question, choose the one best answer:1. Which of the following mechanisms is

most important quantitatively for the ex-change of electrolytes across capillaries?

a. Bulk flowb. Diffusionc. Osmosisd. Vesicular transport

2. Oxygen exchange between blood and tis-sues is enhanced by

a. Decreased arteriolar flow.b. Decreased arteriolar pO2.c. Decreased tissue pO2.d. Decreased number of flowing capil-

laries.

3. Net capillary fluid filtration is enhanced bya. Decreased capillary plasma oncotic

pressure.b. Decreased venous pressure.c. Increased precapillary resistance.d. Increased tissue hydrostatic pres-

sure.

4. If capillary hydrostatic pressure � 15 mmHg, capillary oncotic pressure � 28 mmHg, tissue interstitial pressure � 5 mmHg, and tissue oncotic pressure � 6 mmHg (assume that � � 1), these Starlingforces will result in

a. Net filtration.b. Net reabsorption.c. No net fluid movement.

5. If capillary filtration is enhanced by hista-mine during tissue inflammation,

a. Lymphatic flow will increase.b. Capillary filtration fraction will de-

crease.c. The capillary filtration constant will

be lower than normal.d. Tissue interstitial pressure will de-

crease.

6. Edema can result froma. Increased arteriolar resistance.b. Increased plasma protein concentra-

tion.c. Reduced venous pressure.d. Obstructed lymphatic.

SUGGESTED READINGSDuling BR, Berne RM. Longitudinal gradients in periar-

teriolar oxygen tension. A possible mechanism forthe participation of oxygen in local regulation ofblood flow. Circ Res 1970;27:669–678.

Intaglietta M, Johnson PC. Principles of capillary ex-change. In, Johnson PC, ed. Peripheral Circulation.New York: John Wiley & Sons, 1978.

Michel CC, Curry RE. Microvascular permeability.Physiol Rev 1999;79:703–761.


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Ch08_171-184_Klabunde 4/21/04 11:45 AM

CD-ROM CONTENTSLEARNING OBJECTIVESINTRODUCTIONCARDIOVASCULAR RESPONSES TO

EXERCISEMechanisms Involved in

Cardiovascular Response toExercise

Steady-State Changes inCardiovascular Function duringExercise

Factors Influencing CardiovascularResponse to Exercise

MATERNAL CHANGES INCARDIOVASCULAR FUNCTION DURINGPREGNANCY

HYPOTENSIONCauses of HypotensionCompensatory Mechanisms during

Hypotension

Decompensatory MechanismsFollowing Severe and ProlongedHypotension

Physiologic Basis for TherapeuticIntervention

HYPERTENSIONEssential (Primary) HypertensionSecondary HypertensionPhysiologic Basis for Therapeutic

InterventionHEART FAILURE

Causes of Heart FailureSystolic versus Diastolic DysfunctionSystemic Compensatory Mechanisms in

Heart FailureExercise Limitations Imposed by Heart

FailurePhysiologic Basis for Therapeutic

InterventionSUMMARY OF IMPORTANT CONCEPTSREVIEW QUESTIONSSUGGESTED READINGS

c h a p t e r

9Cardiovascular Integration and Adaptation

Pulmonary Capillary Wedge PressurePressure Natriuresis

CD CONTENTS

LEARNING OBJECTIVES

Understanding the concepts presented in this chapter will enable the student to:1. Describe the mechanical, metabolic, and neurohumoral mechanisms that lead to changes

in cardiac output, central venous pressure, systemic vascular resistance, mean arterialpressure, and arterial pulse pressure during exercise.

2. Describe how exercise affects blood flow to the following organs: brain, heart, activeskeletal muscle, nonactive muscle, skin, gastrointestinal tract, and kidneys.

3. Explain the mechanisms that enable ventricular stroke volume to increase during exerciseat high heart rates.

4. Describe how each of the following influences the cardiovascular responses to exercise:type of exercise (dynamic versus static), body posture, physical conditioning, altitude,temperature and humidity, age, and gender.

5. Describe the effects of pregnancy on blood volume, central venous pressure, ventricularstroke volume, heart rate, systemic vascular resistance, and arterial pressure.

6. Describe the mechanisms by which each of the following conditions can lead to hypoten-sion: hemorrhage, dehydration, heart failure, cardiac arrhythmias, changing from supineto standing position, and autonomic dysfunction. 185

Ch09_185-214_Klabunde 4/21/04 11:46 AM

INTRODUCTION

Previous chapters emphasized physiologicconcepts concerning cardiac and vascularfunction at the cellular and organ level. In ad-dition, they examined mechanisms, such asbaroreceptors and circulating hormones, thatregulate overall cardiovascular function. Thischapter integrates all the components of thecardiovascular system and shows how theywork together to maintain normal perfusion oforgans under conditions of increased organdemand for blood flow (e.g., during exerciseand pregnancy) or during abnormal stressfulconditions such as hemorrhage. This chapteralso examines some of the changes that occurin cardiovascular function during pathologicconditions such as hypertension and heart failure.

CARDIOVASCULAR RESPONSES TO EXERCISE

The cardiovascular system must be able to re-spond to a wide range of demands placed on itby the body. Previous chapters focused on car-diovascular function in normal resting states;however, physical activity, is (or should be!) anormal, regular event in the daily activity ofhumans. Physical movement is associated withincreases in the metabolic activity of contract-ing muscles. This increased metabolic activityis largely oxidative; therefore, the cardiovascu-lar system needs to increase blood flow andoxygen delivery to the contracting muscles.

The cardiovascular responses to physicalactivity are summarized in Table 9-1.Contracting muscles undergo metabolic va-sodilation (see Chapter 7). If large muscle

186 CHAPTER 9

7. Describe the autonomic and hormonal compensatory mechanisms that are activated torestore arterial pressure following hemorrhage.

8. Explain why the baroreceptor reflex is a short-term compensatory mechanism, whereasrenal mechanisms are considered long-term for restoring arterial pressure following hemorrhage.

9. Describe how each of the following positive feedback mechanisms can lead to irre-versible shock and death following severe hemorrhage: cardiac depression, vascularsympathetic escape, metabolic acidosis, cerebral ischemia, rheological factors, and sys-temic inflammatory responses.

10. Describe how altered renal function and changes in systemic vascular resistance can leadto hypertension.

11. Describe the mechanisms by which each of the following conditions can lead to sec-ondary hypertension: renal artery stenosis, renal disease, primary hyperaldosteronism,pheochromocytoma, aortic coarctation, pregnancy, hyperthyroidism, and Cushing’s syndrome.

12. Describe the physiologic rationale for using the following drug classes in the treatmentof essential hypertension: diuretics, �-adrenoceptor blockers, �-adrenoceptor blockers,calcium-channel blockers, and angiotensin-converting enzyme inhibitors.

13. Define systolic and diastolic ventricular failure and show how these two types of failureaffect ventricular pressure-volume loops.

14. Describe how the following serve as compensatory mechanisms in heart failure: ventric-ular dilation and hypertrophy, increased sympathetic activity, activation of the renin-angiotensin-aldosterone system, enhanced vasopressin secretion, and increased bloodvolume.

15. Compare cardiovascular function at rest and cardiovascular responses at maximal exer-cise in a normal subject and in a heart failure patient.

16. Describe the physiologic rationale for using the following drug classes in the treatmentof heart failure: diuretics, vasodilators, angiotensin-converting enzyme inhibitors andangiotensin receptor blockers, �-adrenoceptor blockers, and positive inotropic drugs.

Ch09_185-214_Klabunde 4/21/04 11:46 AM

groups are involved in the physical activity(e.g., running, bicycling), the metabolic va-sodilation in these muscles causes a large fallin systemic vascular resistance. Ordinarily, thiswould cause arterial pressure to fall; however,during physical activity, arterial pressure in-creases because cardiac output increases atthe same time that systemic vascular resis-tance begins to fall. Furthermore, increasedsympathetic activity (see Chapter 6) leads tovasoconstriction in the gastrointestinal tract,nonactive muscles, and kidneys, which helpsto limit the fall in systemic vascular resistanceas well as shift blood flow to the active mus-cles. Venous return to the heart is augmentedby venous constriction and by the skeletalmuscle and abdominothoracic pumps (seeChapter 5). Enhanced venous return enablesthe cardiac output to increase by preventing afall in cardiac preload that would otherwiseoccur as heart rate and inotropy increase (seeChapter 4). Therefore, all the cardiovascularchanges occurring during physical activity en-sure that active muscles are supplied with in-creased blood flow and oxygen while main-

taining normal, or even elevated, arterial pres-sures.

Mechanisms Involved inCardiovascular Response to Exercise

Four fundamental mechanisms are responsi-ble for cardiovascular changes during physicalactivity: mechanical, metabolic, autonomic,and hormonal. When a person suddenly be-gins to run, cardiac output increases beforemetabolic and neurohumoral mechanisms areactivated. This initial increase in cardiac out-put results primarily from the skeletal musclepump system, which enhances venous returnand increases cardiac output by the Frank-Starling mechanism. Within a few seconds ofthe initiation of muscle contraction, metabolicmechanisms in the contracting muscle dilateresistance vessels and increase blood flow. Afew seconds following the onset of running,changes occur in the autonomic nervous sys-tem (Fig. 9-1). Hypothalamic centers coordi-nate a pattern of increased sympathetic anddecreased parasympathetic (vagal) outflow

CARDIOVASCULAR INTEGRATION AND ADAPTATION 187

TABLE 9-1 SUMMARY OF CARDIOVASCULAR CHANGES DURING EXERCISE

↑ Cardiac output

• ↑ heart rate (↑ sympathetic adrenergic and ↓ parasympathetic activity)

• ↑ stroke volume (↑ CVP; ↑ inotropy; ↑ lusitropy)

↑ Mean arterial pressure and pulse pressure

• CO increases more than SVR decreases

• ↑ stroke volume increases pulse pressure

↑ Central venous pressure

• venous constriction (↑ sympathetic adrenergic activity)

• muscle pump activity

• abdominothoracic pump

↓ Systemic vascular resistance

• metabolic vasodilation in active muscle and heart

• cutaneous vasodilation (↓ sympathetic adrenergic activity)

• vasoconstriction in splanchnic, nonactive muscle, and renal circulation (↑ sympatheticadrenergic activity)

CVP, central venous pressure; CO, cardiac output; SVR, systemic vascular resistance.

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from the medullary cardiovascular centers(see Chapter 6). This leads to an increase inheart rate, inotropy, and lusitropy, which in-creases cardiac output. Increased sympatheticefferent activity constricts resistance and ca-pacitance vessels in the splanchnic circulationand nonactive muscles to help maintain arte-rial pressure and central venous pressure. Inaddition, during strenuous activity, sympa-thetic nerves constrict the renal vasculature.

Exercise activates several different hor-monal systems that affect cardiovascular func-tion. Many of the hormonal systems are acti-vated by sympathetic stimulation. Thecardiovascular effects of hormone activationare generally slower than the direct effects ofautonomic activation on the heart and circula-tion.

Sympathetic nerves innervating theadrenal medulla cause the secretion of epi-nephrine and lesser amounts of norepineph-rine into the blood (see Chapter 6). Plasmanorepinephrine concentrations increase morethan ten-fold during exercise. A large fractionof this norepinephrine comes from sympa-thetic nerves. Normally, most of the norepi-nephrine released by sympathetic nerves istaken back up by the nerves (neuronal re-uptake); however, some of the norepinephrinecan diffuse into the capillary blood (i.e.,

spillover) and enter the systemic circulation.This spillover is greatly enhanced when thelevel of sympathetic activity is high in thebody. The blood transports the epinephrineand norepinephrine to the heart and other or-gans, where they act upon alpha- and beta-adrenoceptors to enhance cardiac functionand either constrict or dilate blood vessels. InChapter 6, we learned that epinephrine (atlow concentrations) binds to �2-adrenoceptorsin skeletal muscle, which causes vasodilation.At high concentrations, epinephrine alsobinds to postjunctional �1 and �2-adrenocep-tors on blood vessels to cause vasoconstric-tion. Circulating norepinephrine constrictsblood vessels by binding preferentially to �1-adrenoceptors in most organs. During exer-cise, circulating levels of norepinephrine andepinephrine can become very high so that thenet effect on the vasculature is �-adrenocep-tor-mediated vasoconstriction, except in thoseorgans (e.g., heart and active skeletal muscle)in which metabolic mechanisms produce va-sodilation. It is important to note that vaso-constriction produced by sympathetic nervesand circulating catecholamines does not occurin the active skeletal muscle, coronary circula-tion, or brain. Blood flow in these organs isprimarily controlled by local metabolic va-sodilator mechanisms.

188 CHAPTER 9

Hypothalamus

Medulla

Heart Adrenals Blood Vessels

Arterial and venous constriction

↑↑

Heart rateInotropy

↑ Lusitropy

Catecholaminerelease

CentralCommand

Muscle and JointAfferents

++

+ +

+–

SympatheticActivation

ParasympatheticInhibition

FIGURE 9-1 Summary of adrenergic and cholinergic control mechanisms during exercise. The hypothalamus func-tions as an integrative center that receives information from the brain and muscle and joint receptors, then modu-lates sympathetic and parasympathetic (vagal) outflow from the medulla. Sympathetic nerves are activated (�) andparasympathetic nerves are inactivated (-) during exercise, leading to adrenal release of catecholamines, cardiac stim-ulation, and vasoconstriction.

Ch09_185-214_Klabunde 4/21/04 11:46 AM

Increased sympathetic activity stimulatesrenal release of renin, which leads to the for-mation of angiotensin II. Increased an-giotensin II increases renal sodium and waterreabsorption by directly affecting renal func-tion and by stimulating aldosterone secretion;in addition, angiotensin II augments sympa-thetic activity (see Chapter 6). Circulatingarginine vasopressin (antidiuretic hormone)also increases during exercise, most likely re-sulting from increased plasma osmolarity.Although these hormonal changes promoterenal retention of sodium and water, espe-cially after prolonged periods of exercise,blood volume often decreases during exercise(particularly in hot environments) because ofwater loss through sweating and increasedrespiratory exchange.

Two mechanisms operate to activate theautonomic nervous system during exercise.One mechanism is referred to as “centralcommand.” When physical activity is antici-pated or already underway, higher brain cen-ters (e.g., the cortex) relay this information tohypothalamic centers to coordinate auto-nomic outflow to the cardiovascular system.By this central command mechanism, antici-pation of exercise can lead to autonomicchanges that increase cardiac output and arte-rial pressure before exercise begins. Thisserves to prime the cardiovascular system forexercise. A second mechanism involves mus-cle mechanoreceptors and chemoreceptors.Once physical activity is underway, these mus-cle receptors respond to changes in musclemechanical activity and tissue chemical envi-ronment (e.g., increased lactic acid), and thenrelay that information to the central nervoussystem via afferent fibers. This information isprocessed by the hypothalamus and medullarycardiovascular centers to enhance the sympa-thetic outflow to the heart and systemic vascu-lature.

Arterial baroreceptor function is alteredduring physical activity. Exercise normally isassociated with a rise in both arterial pressureand heart rate. If arterial baroreceptor func-tion were not modified, the increase in arter-ial pressure would result in a reflex bradycar-dia. Instead, the baroreceptor reflex is

modified (reset to a higher control point) bythe central nervous system (see Chapter 6).

Steady-State Changes in Cardiovascular Function during Exercise

Changes in cardiovascular function duringphysical activity depend upon the level ofphysical exertion. If the level of physical exer-tion is expressed as workload, heart rate, car-diac output, and arterial pressure increase innearly direct proportion to the increase inworkload (Fig. 9-2, Panel A). In contrast, sys-temic vascular resistance falls as workload in-creases. Ventricular stroke volume increasesat low to moderate workloads, then plateaus.Although not shown in Figure 9-2, the in-crease in stroke volume is responsible for anincrease in arterial pulse pressure.

Stroke volume may decline at very highworkloads because ventricular filling time isreduced as heart rate increases. Decreasedfilling time decreases ventricular filling (de-creases preload), which decreases stroke vol-ume by the Frank-Starling mechanism. Thiswould prevent the heart from increasing car-diac output during physical activity if not forseveral mechanisms that work together toensure that stroke volume is maintained andeven increased as heart rate increases (Table9-2). For example, during a physical activitysuch as running, enhanced venous return bythe muscle pump and abdominothoracicpump systems helps to maintain preload de-spite the increase in heart rate (see Chapter5). Furthermore, increased atrial and ven-tricular inotropy enhances ventricular strokevolume and ejection fraction, and increasedlusitropy helps to augment ventricular filling.When the heart rate approaches its maximalrate, the effects of reduced filling time canpredominate over these compensatory mech-anisms, thereby causing ventricular fillingand stroke volume to fall. The point at whichincreased heart rate begins to decreasestroke volume varies considerably among in-dividuals because of age, health, and physicalconditioning. Furthermore, this point canvary within an individual depending on the


Ch09_185-214_Klabunde 4/21/04 11:46 AM

type of exercise and the environmental con-ditions.

Blood flow to major organs depends uponthe level of physical activity (Fig. 9-2, PanelB). During whole-body exercise (e.g., run-ning), the blood flow to the active workingmuscles may increase more than twenty-fold(see Chapter 7). At rest, muscle blood flow isabout 20% of cardiac output; this value mayincrease to 90% during strenuous exercise.Coronary blood flow can increase several-foldas the metabolic demands of the myocardiumincrease and local regulatory mechanismscause coronary vasodilation. The need for in-creased blood flow to active muscles and thecoronary circulation would exceed the reservecapacity of the heart to increase its output if

not for blood flow being reduced to other or-gans. During exercise, blood flow decreases tothe splanchnic circulation (gastrointestinal,splenic, and hepatic circulations) and nonac-tive skeletal muscle as workload increases.This is brought about primarily by increasedsympathetic nerve activity to these organs.With very strenuous exercise, renal blood flowis also decreased by sympathetic-mediatedvasoconstriction.

Skin blood flow increases with increasingworkloads, but it can then decrease at veryhigh workloads, especially in hot environ-ments. Increases in cutaneous blood flow arecontrolled by hypothalamic thermoregulatorycenters (see Chapter 7). During physical ac-tivity, increased blood temperature is sensed

190 CHAPTER 9

Rest RestModerate ModerateHeavy Heavy

0 0

100 500

200 1000

400

300 1500

2000CO Muscle

HR

Skin

SV

BrainMAPRenal

SVR GI

Pe

rce

nt C

ha

ng

e

Pe

rce

nt C

ha

ng

e

Pe

rce

nt C

ha

ng

e(M

usc

le)

A B

FIGURE 9-2 Systemic hemodynamic and organ blood flow responses at different levels of exercise intensity. Panel Ashows systemic hemodynamic changes. Systemic vascular resistance (SVR) decreases because of vasodilation in ac-tive muscles; mean arterial pressure (MAP) increases because cardiac output (CO) increases more than SVR decreases.CO and heart rate (HR) increase almost proportionately to the increase in workload. Stroke volume (SV) plateaus athigh heart rates. Panel B shows organ blood flow changes. Muscle blood flow increases to very high levels becauseof active hyperemia; skin blood flow increases because of the need to remove excess heat from the body.Sympathetic-mediated vasoconstriction decreases gastrointestinal (GI) blood flow and renal blood flow. Brain bloodflow changes very little.

TABLE 9-2 MECHANISMS MAINTAINING STROKE VOLUME AT HIGH HEARTRATES DURING EXERCISE

• Increased venous return promoted by the abdominothoracic and skeletal muscle pumpsmaintains central venous pressure and therefore ventricular preload.

• Venous constriction (decreased venous compliance) maintains central venous pressure.

• Increased atrial inotropy augments atrial filling of the ventricles.

• Increased ventricular inotropy decreases end-systolic volume, which increases stroke vol-ume and ejection fraction.

• Enhanced rate of ventricular relaxation (lusitropy) aids in filling.

Ch09_185-214_Klabunde 4/21/04 11:46 AM

by thermoreceptors in the hypothalamus. Toenhance heat loss through the skin, the hypo-thalamus decreases sympathetic nerve activityto cutaneous blood vessels, which increasesskin blood flow. At the same time, activation ofsympathetic cholinergic nerves to the skincauses sweating, which is mediated in part bybradykinin that acts as a vasodilator.

While cutaneous vasodilation is essentialfor thermoregulation during physical activity,this requirement must be balanced by theneed to maintain arterial pressure. Cutaneousvasodilation contributes to the fall in systemicvascular resistance that is also brought aboutby the active muscles. If increased cardiacoutput is unable to maintain arterial pressureat very high workloads, baroreceptor mecha-nisms restore sympathetic tone to the skin anddecrease its blood flow. Although this mayhelp to preserve arterial pressure temporarily,reduced heat exchange through the skin canlead to dangerous elevations in core tempera-ture, resulting in organ damage and loss of au-tonomic control. Heat stroke is a potentiallylethal condition that occurs when core tem-peratures rise above 105°F.

Factors Influencing CardiovascularResponse to Exercise

The cardiovascular changes associated withphysical activity are modified by many differ-ent factors. The level of activity, which is com-monly expressed as work performed or wholebody oxygen consumption, affects the cardiacand vascular responses. Several other impor-tant factors influence cardiovascular re-sponses to physical activity.

The type of exercise significantly affectscardiovascular responses. The previous sectiondescribed the cardiovascular responses to dy-namic exercise such as running, walking, bicy-cling, or swimming. This type of activity resultsin joint movement as muscles contract rhyth-mically. In contrast, muscle contraction with-out joint movement (isometric or static con-traction) elicits a different cardiovascularresponse. An example of this activity would betrying to lift a very heavy weight at maximal ef-fort (e.g., bench or leg press). This type of ac-tivity does not incorporate rhythmic contrac-tion of synergistic and antagonistic musclegroups; therefore, the muscle pump system


A 45-year-old male with type 2 diabetes is diagnosed with autonomic neuropathy,which impairs autonomic function. He complains of becoming weak and “lightheaded” when he performs physical work such as mowing the lawn. Explain how thispatient’s autonomic dysfunction may account for his inability to be engaged in normalphysical activities.

Autonomic neuropathy affects the function of most organ systems of the body be-cause autonomic nerves play a vital role in regulating normal function. In the cardio-vascular system, autonomic nerves, particularly sympathetic adrenergic nerves, regulatearterial pressure through their actions on the heart and vasculature. Patients with type2 diabetes who have impaired autonomic control of the cardiovascular system mayhave abnormal responses to exercise because heart rate and inotropy may not increasenormally and sympathetic stimulation of the arterial and venous system may be im-paired. This loss of sympathetic control may result in a fall in arterial pressure duringexercise owing to a greater-than-normal reduction in systemic vascular resistance, a de-crease in central venous pressure owing to loss of venous tone, and a reduction in car-diac output caused by smaller-than-normal increases in heart rate and stroke volume.Hypotension during exercise impairs muscle perfusion, causing fatigue. Decreased cere-bral perfusion caused by hypotension can lead to dizziness, visual disturbances, andsyncope.

CASE 9-1

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cannot operate to promote venous return andso cardiac output increases relatively little.Furthermore, the abdominothoracic pumpdoes not contribute to enhancing venous re-turn, particularly if the subject holds his or herbreath during the forceful contraction, effec-tively performing a Valsalva maneuver (seeValsalva in Chapter 5 on CD). Unlike dynamicexercise, static exercise leads to a large in-crease in systemic vascular resistance, particu-larly if a large muscle mass is being contractedat maximal effort. The increased systemic vas-cular resistance results from enhanced sympa-thetic adrenergic activity to the peripheral vas-culature and from mechanical compression ofthe vasculature in the contracting muscles. Asa result, systolic arterial pressure may increaseto over 250 mm Hg during forceful isometriccontractions, particularly those involving largemuscle groups. This acute hypertensive statecan produce vascular damage (e.g., hemor-rhagic stroke) in susceptible individuals. Incontrast, dynamic exercise leads to only mod-est increases in arterial pressure.

Body posture also influences how the car-diovascular system responds to exercise be-cause of the effects of gravity on venous re-turn and central venous pressure (see Chapter5). When a person exercises in the supine po-sition (e.g., swimming), central venous pres-sure is higher than when the person is exercis-ing in the upright position (e.g., running). Inthe resting state before the physical activitybegins, ventricular stroke volume is higher inthe supine position than in the upright posi-tion owing to increased right ventricular pre-load. Furthermore, the resting heart rate islower in the supine position. When exercisecommences in the supine position, the strokevolume cannot be increased appreciably bythe Frank-Starling mechanism because thehigh resting preload reduces the reserve ca-pacity of the ventricle to increase its end-diastolic volume. Stroke volume still increasesduring exercise although not as much as whenexercising while standing; however, the in-creased stroke volume is resulting primarilyfrom increases in inotropy and ejection frac-tion with minimal contribution from theFrank-Starling mechanism. Because heart

rate is initially lower in the supine position,the percent increase in heart rate is greater inthe supine position, which compensates forthe reduced ability to increase stroke volume.Overall, the change in cardiac output duringexercise, which depends upon the fractionalincreases in both stroke volume and heartrate, is not appreciably different in the supineversus standing position.

The level of physical conditioning signif-icantly influences maximal cardiac output andtherefore maximal exercise capacity. A condi-tioned individual is able to achieve a highercardiac output, whole-body oxygen consump-tion, and workload than a person who has asedentary lifestyle. The increased cardiac out-put capacity is a consequence, in part, of in-creased ventricular and atrial responsivenessto inotropic stimulation by sympatheticnerves. Conditioned individuals also have hy-pertrophied hearts, much like what happensto skeletal muscle in response to weight train-ing. Coupled with enhanced capacity for pro-moting venous return by the muscle pumpsystem, these cardiac changes permit highlyconditioned individuals to achieve ventricularejection fractions that exceed 90% during ex-ercise. In comparison, a sedentary individualmay not be able to increase ejection fractionabove 75%. Although the maximal heart rateof a conditioned individual is not necessarilyany greater than that of a sedentary individual,the lower resting heart rates of a conditionedperson allow for a greater percent increase inheart rate. Heart rate is lower in conditionedindividuals because resting stroke volume isincreased owing to the larger heart size andincreased inotropy. Because resting cardiacoutput is not necessarily increased in a condi-tioned person, the heart rate is reduced by in-creased vagal tone to offset the increase inresting stroke volume, thereby maintaining anormal cardiac output at rest. The enhancedreserve capacity for increasing heart rate andstroke volume enables conditioned individualsto achieve maximal cardiac outputs (and work-loads) that can be 50% higher than thosefound in sedentary people. Another importantdistinction between a sedentary and condi-tioned person is that for a given workload, the

192 CHAPTER 9

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conditioned person has a lower heart rate.Furthermore, a conditioned person is able tosustain higher workloads for a longer durationand recover from the exercise much morerapidly.

Environmental factors affect cardiovas-cular responses to exercise. High altitudes, forexample, decrease maximal stroke volume andcardiac output. The reason for this is that thepO2 in arterial blood is reduced at higher ele-vations because of decreased atmosphericpressure. This decreases oxygen delivery totissues, particularly to contracting muscle(both skeletal and cardiac), thereby resultingin insufficient oxygenation at lower workloads.Myocardial hypoxia decreases inotropy, whichresults in reduced stroke volume. Reducedoxygen delivery to exercising muscle reducesexercise capacity in the muscle and results inincreased production of lactic acid as the mus-cle switches over to more anaerobic metabo-lism in the absence of adequate oxygen; i.e.,the anaerobic threshold is reached at a lowerworkload.

Increased temperature and humidity affectcardiovascular responses during exercise bydiverting a greater fraction of cardiac outputto the skin to enhance heat removal from thebody. This decreases the availability of bloodflow for the contracting muscles. With ele-vated temperature and humidity, maximal car-diac output and oxygen consumption arereached at lower workloads, thereby reducingexercise capacity as well as endurance.Furthermore, dehydration can accompanyhigh temperatures. Dehydration reducesblood volume and central venous pressure,and it attenuates the normal increase in car-diac output associated with exercise. This canlead to a fall in arterial pressure and heat ex-haustion. Signs of heat exhaustion includegeneral fatigue, muscle weakness, nausea, andmental confusion; it usually results from dehy-dration and loss of sodium chloride associatedwith physical activity in a hot environment—core temperature is not necessarily elevated.

Increased age reduces maximal exercisecapacity. Maximal oxygen consumption de-creases about 40% between 20 and 70 years ofage. Many reasons exist for this decline. With

increasing age, maximal heart rate decreases.Maximal heart rate is approximately 220beats/minute minus the age of a person.Therefore, the maximal heart rate of a 70-year-old person is about 25% lower than themaximal heart rate of a 20-year-old person.Increasing age also reduces maximal strokevolume because of impaired ventricular filling(decreased ventricular compliance) and re-duced inotropic responsiveness to sympa-thetic stimulation. Together, these changes re-duce maximal cardiac output substantially.Older individuals have reduced skeletal mus-cle mass as well as decreased maximal muscleblood flow per unit weight of muscle. Recentresearch indicates a reduction in vasodilatorycapacity of resistance vessels in skeletal mus-cle in older persons may be related to reducedendothelial production or bioavailability of ni-tric oxide and altered vascular smooth muscleresponsiveness to metabolic vasodilators.Although increasing age inevitably limits exer-cise capacity, exercise habits and generalhealth can significantly influence the declinein maximal cardiac output with age.

Finally, gender influences cardiovascularresponses to exercise. Generally, males canreach and sustain significantly higher work-loads and maximal oxygen consumptions thancan females. Maximal cardiac outputs areabout 25% less in females, although the maxi-mal heart rates are similar. This difference ispartly owing to increased skeletal muscle massand to increased cardiac mass in males.

MATERNAL CHANGES INCARDIOVASCULAR FUNCTIONDURING PREGNANCY

Pregnancy causes significant changes in thecardiovascular system (Fig. 9-3). Increaseduterine mass and the developing fetus requirelarge amounts of blood flow. To supply thisflow, cardiac output increases by 30% to 50%during the first and second trimesters andthen plateaus during the third trimester. Inthe first half of the pregnancy, the cardiacoutput is primarily increased through in-creases in stroke volume. By the thirdtrimester, however, stroke volume may be


Ch09_185-214_Klabunde 4/21/04 11:46 AM

only slightly elevated. At this stage of preg-nancy, the increased cardiac output is sus-tained by an elevated heart rate, which mayincrease by 10–20 beats/minute.

Cardiac output increases because bloodvolume increases dramatically during preg-nancy. By week 6, blood volume may be in-creased by 10%. By the end of the thirdtrimester, blood volume may be increased by50%. The increase in blood volume is broughtabout by estrogen-mediated activation of therenin-angiotensin-aldosterone system, whichincreases sodium and water retention by thekidneys.

Although cardiac output is elevated, meanarterial pressure generally falls owing to a dis-proportionate decrease in systemic vascularresistance. The fall in systemic vascular resis-tance may be caused in part by hormonalchanges that dilate resistance vessels; how-ever, the major factor contributing to the re-duced resistance is the development of low-resistance uterine circulation, particularly inthe later stages of pregnancy. Diastolic pres-sure falls more than systolic pressure becauseof reduced systemic vascular resistance, sothere is an increase in pulse pressure.Increased pulse pressure results from the in-crease in stroke volume during the first andsecond trimesters.

Pregnancy significantly alters the cardio-vascular responses to exercise. Because car-diac output at rest is substantially elevated,there is less capacity for it to increase duringexercise. In addition, compression of the infe-rior vena cava caused by an elevated intra-abdominal pressure, particularly during thethird trimester, limits venous return andthereby prevents stroke volume from increas-ing as it normally would during exercise.Compression of the inferior vena cava, espe-cially in the supine position, can also diminishvenous return at rest, thereby reducing car-diac output and arterial pressure (supine hy-potensive syndrome).

HYPOTENSION

Causes of Hypotension

Hypotension is often defined clinically as asystolic arterial pressure less than 90 mm Hg,or a diastolic pressure less than 60 mm Hg.There are many causes of hypotension as sum-marized in Figure 9-4. Because arterial pres-sure is the product of cardiac output and sys-temic vascular resistance, a decrease in eitherwill reduce arterial pressure (see Chapter 5).

A reduction in systemic vascular tone orimpaired vasoconstrictor responsiveness tobaroreceptor reflexes can lead to hypotension.For example, septic shock (or SystemicInflammatory Response Syndrome, SIRS),which usually results from a bacterial infec-tion in the blood, causes a loss of vascular toneand hypotension. Septic shock is caused bythe release of bacterial endotoxins (e.g.,lipopolysaccharide) that activate the inflam-matory cascade. This leads to the productionof cytokines (e.g., tumor necrosis factor, in-terleukins) and excessive amounts of nitric oxide, causing systemic vasodilation. Systemicvascular resistance can also be decreased ifautonomic dysfunction occurs. For example,in diabetic individuals having autonomic neu-ropathy, baroreceptor-mediated reflex vaso-constriction may be depressed, which can re-sult in a fall in arterial pressure when theperson stands up (orthostatic hypotension)and when the person exercises. Injury to the

194 CHAPTER 9

FirstTrimester

ThirdTrimester

SecondTrimester

0

-25

-50

+25

+50

Per

cent

Cha

nge SV

HR

CO

MAP

SVR

FIGURE 9-3 Changes in maternal hemodynamics dur-ing pregnancy. Early in the course of pregnancy, cardiacoutput (CO) increases because stroke volume (SV) in-creases owing to an increase in blood volume; systemicvascular resistance (SVR) and mean arterial pressure(MAP) decrease. Heart rate (HR) gradually increasesthroughout pregnancy; SV declines as HR increases.

Ch09_185-214_Klabunde 4/21/04 11:46 AM

spinal cord can remove sympathetic tone inmajor organs, leading to hypotension.

Hypotension, however, more commonlyoccurs because cardiac output is reduced by adecrease in either heart rate or stroke volume.Ventricular rate can be reduced by sinusbradycardia, which may be caused by exces-sive vagal activation of the SA node. Second-and third-degree AV nodal blockade (seeChapter 2) reduce ventricular rate. A vasova-gal reflex can lower heart rate and arterialpressure sufficiently to cause syncope (seeChapter 6).

Stroke volume can be reduced by de-creases in either inotropy or ventricular filling(preload) (see Chapter 4). Reduced inotropyoccurs during heart failure (systolic failure)and when autonomic dysfunction decreasessympathetic outflow or cardiac responsivenessto sympathetic stimulation. Decreased pre-load can be caused by several conditions: (1)hypovolemia, which results from blood loss(hemorrhage) or dehydration; (2) a redistribu-tion of blood volume, as occurs when a personstands up (see Chapter 5); (3) reduced venousreturn, which can result from compression of

the vena cava (e.g., during pregnancy); and (4)some types of cardiac arrhythmias (e.g., atrialfibrillation, ventricular tachycardia).

Compensatory Mechanisms duringHypotension

When hypotension occurs, the body attempts torestore arterial pressure by activating neurohu-moral compensatory mechanisms (see Chapter6). Initial, short-term mechanisms involve thebaroreceptor reflex, which constricts systemicvascular beds and stimulates the heart. This in-creases arterial pressure and helps to maintainnormal cerebral and coronary perfusion at theexpense of reduced blood flow to less essentialorgans. The baroreceptor compensatory mech-anism for hypotension that results from bloodloss (hemorrhagic hypotension) is summa-rized in Figure 9-5. More slowly activated, long-term compensatory mechanisms include therenin-angiotensin-aldosterone system and vaso-pressin. These hormone systems, summarizedin Figure 9-6, serve to increase blood volumeand reinforce the vasoconstriction caused by in-creased sympathetic activity.


CardiacOutput

SystemicVascular Resistance

StrokeVolume

HeartRate

Inotropy

Circulatory Shock- sepsis

Autonomic Dysfunction

Heart FailureCardiogenic ShockAutonomic Dysfunction

Hypovolemia- hemorrhage- dehydration

Volume Redistribution- postural changes- impaired venous return

Arrhythmias- atrial fibrillation- tachycardia

Arrhythmias- sinus bradycardia- AV nodal block- ventricular fibrillation

↓ ↓

↓

↓

↓

↓ Preload

Hypotension

•

•

•••

•

•

•

•

FIGURE 9-4 Mechanisms and causes of hypotension. Ultimately, hypotension occurs because there is a reduction incardiac output, systemic vascular resistance, or both.

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Most of the compensatory responses occurregardless of the cause of hypotension; how-ever, the ability of the heart and vasculature torespond to a specific compensatory mecha-nism may differ depending upon the cause ofthe hypotension. For example, if hypotensionis caused by cardiogenic shock (a form ofacute heart failure) secondary to a myocardialinfarction, the heart will not be able to re-spond to sympathetic stimulation in the samemanner as would a normal heart. As anotherexample, vascular responsiveness to sympa-thetic-mediated vasoconstriction is signifi-cantly impaired in a person in septic shock.The following discussion specifically ad-dresses compensatory mechanisms in hy-potension caused by hemorrhage-induced hy-povolemia.

The baroreceptor reflex is the first com-pensatory mechanism to become activated inresponse to hypotension caused by blood loss(see Fig. 9-5). This reflex occurs within sec-onds of a fall in arterial pressure. As describedin Chapter 6, a reduction in mean arterialpressure or arterial pulse pressure decreasesthe firing of arterial baroreceptors. This acti-vates the sympathetic nervous system and in-hibits vagal influences to the heart. Thesechanges in autonomic activity increase heartrate and inotropy. It is important to note thatcardiac stimulation alone does not lead to asignificant increase in cardiac output. For car-diac output to increase, some mechanismmust increase central venous pressure andtherefore filling pressure for the ventricles.This is accomplished, at least initially follow-

196 CHAPTER 9

↓ CardiacOutput

↓ BaroreceptorFiring

↑ Sympathetic ↓ Parasympathetic

↑

↑

Heart Rate

Contractilityand

↑ VenousTone

↓ StrokeVolume

↑ Systemic VascularResistance

↓ Central VenousPressure

Blood Loss

↓ ArterialPressure

+

+

+

+

FIGURE 9-5 Activation of baroreceptor mechanisms following acute blood loss (hemorrhage). Blood loss reduces car-diac preload, which decreases cardiac output and arterial pressure. Reduced firing of arterial baroreceptors activatesthe sympathetic nervous system, which stimulates cardiac function, and constricts resistance and capacitance vessels.These actions increase systemic vascular resistance, central venous pressure, and cardiac output, thereby partiallyrestoring arterial pressure.

Ch09_185-214_Klabunde 4/21/04 11:46 AM

ing hemorrhage, by an increase in venous toneproduced by sympathetic stimulation of thevenous capacitance vessels. The partially re-stored central venous pressure increasesstroke volume through the Frank-Starlingmechanism. The increased preload, coupledwith cardiac stimulation, causes cardiac out-put and arterial pressure to increase towardtheir normal values.

Although the baroreceptor reflex can re-spond quickly to a fall in arterial pressure andprovide initial compensation, the long-termrecovery of cardiovascular homeostasis re-quires activation of hormonal compensatorymechanisms to restore blood volume throughrenal mechanisms (see Fig. 9-6). Some ofthese humoral systems also reinforce thebaroreceptor reflex by causing cardiac stimu-lation and vasoconstriction.

The renin-angiotensin-aldosterone systemis activated by increased renal sympatheticnerve activity and renal artery hypotension via

decreased sodium delivery to the maculadensa. Increased circulating angiotensin IIconstricts the systemic vasculature directly bybinding to AT1 receptors and indirectly by en-hancing sympathetic effects. Angiotensin IIstimulates aldosterone secretion. Vasopressinsecretion is stimulated by reduced atrialstretch, sympathetic stimulation, and an-giotensin II. Working together, angiotensin II,aldosterone, and vasopressin cause the kid-neys to retain sodium and water, thereby in-creasing blood volume, cardiac preload, andcardiac output. Increased vasopressin alsostimulates thirst so that more fluid is ingested.The renal and vascular responses to these hor-mones are further enhanced by decreased se-cretion of atrial natriuretic peptide by theatria, owing to decreased atrial stretch associ-ated with the hypovolemic state.

The vascular responses to angiotensin IIand vasopressin occur rapidly in response toincreased plasma concentrations of these


+

↑ Catecholamines(Epi, NE)

↑ Renin↑ Angiotensin II

↑ Aldosterone

↑ Vasopressin

↑ BloodVolume

↑ Renal Na &H O Retention2

+ Symp

+ Symp

+ CVP+ CO+ SVR

+ CVP+ CO

+ SVR

+ SVR

+ Thirst

Blood Loss


+ +

Pituitary

AdrenalCortex

AdrenalMedulla

Kidney

FIGURE 9-6 Activation of humoral mechanisms following acute blood loss (hemorrhage). Decreased arterial pressureactivates the sympathetic nervous system (�Symp) (baroreceptor reflex). Renin release is stimulated by the enhancedsympathetic activity, increased circulating catecholamines, and hypotension, which leads to the formation of an-giotensin II and aldosterone. Vasopressin release from the posterior pituitary is stimulated by angiotensin II, reducedatrial pressure (not shown), and increased sympathetic activity (not shown). These hormones act together to increaseblood volume through their renal actions (sodium and water retention), which increases central venous pressure(�CVP) and cardiac output (�CO). Angiotensin II and vasopressin also increase systemic vascular resistance (�SVR).Increased circulating catecholamines (Epi, epinephrine; NE, norepinephrine) reinforce the effects of sympathetic acti-vation on the heart and vasculature. These changes in systemic vascular resistance, central venous pressure, and car-diac output partially restore the arterial pressure.

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vasoconstrictors. The renal effects of an-giotensin II, aldosterone, and vasopressin, incontrast, occur more slowly as decreasedsodium and water excretion gradually in-creases blood volume over several hours anddays.

Enhanced sympathetic activity stimulatesthe adrenal medulla to release catecholamines(epinephrine and norepinephrine). Thiscauses cardiac stimulation (�1-adrenoceptormediated) and peripheral vasoconstriction (�-adrenoceptor mediated), and contributes tothe release of renin by the kidneys through re-nal �-adrenoceptors.

Other mechanisms besides the barorecep-tor reflex and hormones have a compensatoryrole in hemorrhagic hypotension. Severe hy-potension can lead to activation of chemore-ceptors (see Chapter 6). Low perfusion pres-sures and reduced organ blood flow causesincreased production of lactic acid as organsare required to switch over to anaerobic gly-colysis for the production of ATP. Acidosisstimulates peripheral and central chemore-ceptors, leading to increased sympathetic ac-tivity to the systemic vasculature. Stagnant hy-poxia in the carotid body chemoreceptors,

which results from reduced carotid bodyblood flow, stimulates chemoreceptor firing. Ifcerebral perfusion becomes impaired and thebrain becomes ischemic, intense sympathetic-mediated vasoconstriction of the systemic vas-culature will result.

Reduced arterial and venous pressures,coupled with a decrease in the post-to-precapillary resistance ratio, decreases capil-lary hydrostatic pressures (see Chapter 8).This leads to enhanced capillary fluid reab-sorption. This mechanism can result in up to 1 liter/hour of fluid being reabsorbed back into the intravascular compartment,which can lead to a significant increase inblood volume and arterial pressure after a few hours. Although capillary fluid reabsorp-tion increases intravascular volume and servesto increase arterial pressure, it also leads to areduction in hematocrit and dilution ofplasma proteins until new blood cells andplasma proteins are synthesized. The reducedhematocrit decreases the oxygen-carrying capacity of the blood. Dilution of plasma proteins decreases plasma oncotic pres-sure, which limits the amount of fluid reab-sorption.

198 CHAPTER 9

A patient who is being aggressively treated for severe hypertension with a diuretic, anangiotensin-converting enzyme inhibitor, and a calcium-channel blocker is in a seriousautomobile accident that causes significant intra-abdominal bleeding. How mightthese drugs affect the compensatory mechanisms that are activated following hemor-rhage? How might this alter the course of this patient’s recovery?

Recovery from hemorrhage partly involves arterial and venous constriction, cardiacstimulation, and renal retention of sodium and water. The diuretic would counter thenormal renal compensatory mechanisms of sodium and water retention. The an-giotensin-converting enzyme inhibitor would reduce the formation of circulating an-giotensin II that normally plays an important compensatory role through constrictingblood vessels and increasing blood volume by enhancing renal reabsorption of sodiumand water. The calcium-channel blocker, depending upon its class, would depress car-diac function and cause systemic vasodilation, both of which would counteract normalcompensatory responses to hemorrhage. These drugs, therefore, would impair and pro-long the recovery process following hemorrhage. Fortunately, many of these drugshave relatively short half-lives so that their effects diminish within several hours.

CASE 9-2

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Decompensatory MechanismsFollowing Severe and ProlongedHypotension

Severe, prolonged hypotension can lead to ir-reversible shock and death. This occurs whennormal compensatory mechanisms (and addi-tional medical resuscitation) are unable to re-store arterial pressure to adequate levels in atimely manner. For example, if 40% of a per-son’s blood volume is lost by hemorrhage, ar-terial pressure may begin to recover as com-pensatory mechanisms are activated; however,the recovery may last only an hour or two be-fore arterial pressure once again falls, causingdeath despite heroic interventions.

This secondary fall in arterial pressure re-sults from the activation of decompensatorymechanisms. These decompensatory mecha-nisms are positive feedback cycles, in con-trast to the negative feedback control offeredby compensatory mechanisms. A negativefeedback mechanism attempts to restore acontrolled variable (in this case arterial pres-sure) to its normal value, whereas a positivefeedback mechanism causes the controlledvariable to move even farther away from itscontrol point.

In the case of severe hemorrhagic shockand some other forms of hypotensive shock(e.g., cardiogenic and septic shock), severalpotential positive feedback mechanisms canlead to irreversible shock and death. Thesemechanisms include cardiac depression, sym-pathetic escape, metabolic acidosis, cerebralischemia, rheological factors, and systemic in-flammatory responses.

Figure 9-7 illustrates how cardiac depres-sion and sympathetic escape can lead to de-compensation. A large decrease in blood vol-ume decreases cardiac output and arterialpressure. If mean arterial pressure falls below60 mm Hg, coronary perfusion becomes re-duced, because this pressure is below thecoronary autoregulatory range (see Chapter7). Reduced coronary blood flow causes myo-cardial hypoxia, which impairs cardiac con-tractions (reduces inotropy). When this oc-curs, stroke volume and cardiac outputdecrease, causing additional decreases in arte-rial pressure and coronary perfusion—a posi-tive feedback cycle. Also shown in Figure 9-7is the effect of hypotension on organ bloodflow. Hypotension decreases organ blood flowby decreasing perfusion pressure and throughbaroreceptor-mediated sympathetic activation


↓ CardiacOutput

SevereHemorrhage


TissueHypoxia↓ Inotropy

↓ CoronaryPerfusion

Vasodilation(Sympathetic Escape)

↓ OrganBlood Flow

FIGURE 9-7 Positive feedback decompensatory mechanisms triggered by severe hypotension. Impairment of coro-nary perfusion leads to a loss in cardiac inotropy and an additional decrease in cardiac output and pressure. Prolongedtissue ischemia caused by hypotension (and sympathetic activation) leads to vasodilation (sympathetic escape), whichreduces systemic vascular resistance and arterial pressure.

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that constricts resistance vessels. This reducedflow causes tissue hypoxia. The more hypoxica tissue becomes and the longer it remains hy-poxic (especially under low flow conditions),the greater the buildup of vasodilator metabo-lites. These metabolites eventually overridethe sympathetic-mediated vasoconstriction(sympathetic escape), and blood flow beginsto increase within the organ. When this sym-pathetic escape occurs within major organs ofthe body (e.g., skeletal muscle and gastroin-testinal tract), systemic vascular resistancefalls. This reduces arterial pressure and fur-ther reduces organ perfusion, which leads tofurther vasodilation and hypotension—a posi-tive feedback cycle.

Several other positive feedback cycles cancontribute to irreversible shock:

• Prolonged hypotension with accompanyingtissue hypoxia results in metabolic acidosisas organs begin to generate ATP by anaer-obic pathways. Acidosis impairs cardiaccontraction and vascular smooth musclecontraction, which decreases cardiac out-put and systemic vascular resistance,thereby lowering arterial pressure evenmore.

• Cerebral ischemia and hypoxia during se-vere hypotension, although initially causingstrong sympathetic activation, eventuallyresults in depression of all autonomic out-flow as the cardiovascular regulatory cen-ters cease to function because of the lack ofoxygen. This withdrawal of sympathetictone causes arterial pressure to fall, whichfurther reduces cerebral perfusion.

• Reduced organ perfusion during hypoten-sion and intense sympathetic vasoconstric-tion causes increased blood viscosity withinthe microcirculation, microvascular plug-ging by leukocytes and platelets, and dis-seminated intravascular coagulation. Low-flow states within the microcirculationcause red blood cells to adhere to eachother, which increases the viscosity of theblood. Furthermore, low-flow states en-hance leukocyte-endothelial adhesion andplatelet-platelet adhesion. This reduces or-gan perfusion even more and can lead to is-chemic damage and stimulation of inflam-

matory processes, which can further en-hance metabolic acidosis and impair car-diac and vascular function.

In summary, the body responds to hy-potension by activating neurohumoral mecha-nisms that serve as negative feedback—com-pensatory mechanisms to restore arterialpressure. With severe hypotension, positivefeedback control mechanisms may becomeoperative. These mechanisms counteract thecompensatory mechanisms and eventuallylead to an additional reduction in arterial pres-sure.


Treatment for hypotension depends upon theunderlying cause of the hypotension. If hy-potension is caused by hypovolemia owing tohemorrhage or excessive fluid loss (e.g., dehy-dration), increasing blood volume by adminis-tration of blood or fluids becomes a treatmentpriority. Restoring blood volume increasespreload on the heart and thereby increasescardiac output, which is reduced in hypo-volemic states. Administration of fluids is oc-casionally accompanied by the administrationof pressor agents. These drugs increase arte-rial pressure by increasing systemic vascularresistance (e.g., �-adrenoceptor agonists suchas norepinephrine and phenylephrine) or bystimulating cardiac function (e.g., �-adreno-ceptor agonists such as dobutamine).Treatment of hypotension caused by cardio-genic shock often includes drugs that stimu-late the heart (e.g., �-adrenoceptor agonistssuch as dobutamine or dopamine, or cAMP-dependent phosphodiesterase inhibitors suchas milrinone that inhibit the degradation ofcAMP); however, depending upon the magni-tude of the hypotension, either pressor or de-pressor agents may be used. Because the pri-mary cause of hypotension in cardiogenicshock is impaired cardiac function, drugs suchas phosphodiesterase inhibitors that stimulatethe heart and dilate arterial vessels can im-prove cardiac function by enhancing inotropyand decreasing afterload on the heart.Systemic vasodilators, however, cannot be

200 CHAPTER 9

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used alone if the hypotension is severe, be-cause arterial pressure may fall further.Hypotension associated with septic shock re-sults from systemic vasodilation and, in itslater stages, cardiac depression. Therefore,pressor agents are commonly used with thisform of shock in addition to administration offluid and antibiotics.

HYPERTENSION

High blood pressure (hypertension) is a con-dition that afflicts more than 50 millionAmericans and is a leading cause of morbidityand mortality. Hypertension is much morethan a “cardiovascular disease” because it candamage other organs such as kidney, brain,and eye. One-third of hypertensive people arenot aware of being hypertensive because it isusually asymptomatic until the damaging ef-fects of hypertension (such as stroke, myocar-dial infarction, renal dysfunction, visual dis-turbances, etc.) are observed.

The term “hypertension” can apply to ele-vations in mean arterial pressure, diastolicpressure, or systolic pressure above normalvalues. Normal arterial pressure is defined asa systolic pressure less than 120 mm Hg (butgreater than 90 mm Hg) and diastolic pres-sure less than 80 mm Hg (but greater than 60mm Hg). Diastolic pressures of 80–89 mm Hgand systolic pressures of 120–139 mm Hg areconsidered prehypertension. Hypertension isdefined as diastolic or systolic pressures equalto or greater than 90 mm Hg or 140 mm Hg,respectively. Both diastolic and systolic hyper-tension have been shown to be significant riskfactors for causing other cardiovascular disor-ders such as stroke and myocardial infarction.Mean arterial pressure is usually not discussedin the context of hypertension because it is notnormally measured in a patient.

Hypertension is caused by either an in-crease in systemic vascular resistance or an in-crease in cardiac output, and both are usuallyincreased in chronic hypertension. For exam-ple, administration of a vasoconstrictor drug(e.g., an �1-adrenoceptor agonist such asphenylephrine) increases arterial pressureacutely by increasing systemic vascular resis-

tance. Cardiac stimulation with a �-adreno-ceptor agonist (e.g., isoproterenol) causes asmall increase in cardiac output and arterialpressure by increasing heart rate and inotropy.

To sustain a hypertensive state (i.e., chronichypertension), it is necessary to increase bloodvolume through renal retention of sodium andwater. Evidence for this comes from studiesshowing that acute elevations in arterial pres-sure (e.g., by infusing a vasoconstrictor) causepressure natriuresis in the kidneys (seePressure Natriuresis on CD. Briefly, an eleva-tion in renal artery pressure increasesglomerular filtration and excretion of sodiumand water. The loss of sodium and water de-creases blood volume and restores pressure.Therefore, with normal renal function, anacute elevation in arterial pressure caused byincreasing systemic vascular resistance orstimulating the heart is compensated by a re-duction in blood volume, which restores thearterial pressure to normal. Considerable evi-dence shows that in chronic hypertension, thepressure natriuresis curve is shifted to theright so that a higher arterial pressure is re-quired to maintain sodium balance. The ele-vated pressure is sustained by an increase inblood volume. These changes in renal han-dling of sodium and water can be broughtabout by changes in sympathetic activity andhormones that affect renal function (e.g., an-giotensin II, aldosterone, vasopressin). In ad-dition, changes in renal function associatedwith renal disease alter kidney filtration andsodium balance, which can shift the pressurenatriuresis curve to the right, leading to sus-tained hypertension.

Essential (Primary) Hypertension

Essential (or primary) hypertension accountsfor approximately 90% to 95% of patients diagnosed with hypertension (Table 9-3).Despite many years of active research, no uni-fying hypothesis accounts for the pathogenesisof essential hypertension. However, a naturalprogression of this disease suggests that earlyelevations in blood volume and cardiac outputmight precede and then initiate subsequentincreases in systemic vascular resistance. This


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has led some investigators to suggest that thebasic underlying defect in hypertensive pa-tients is an inability of the kidneys to ade-quately handle sodium. Increased sodium re-tention could account for the increase inblood volume. Indeed, many excellent experi-mental studies as well as clinical observationshave shown that impaired renal natriuresis(sodium excretion) can lead to chronic hyper-tension.

Besides the renal involvement in hyperten-sion, it is well known that vascular changes cancontribute to hypertensive states, especially inthe presence of impaired renal function. Forexample, essential hypertension is usually as-sociated with increased systemic vascular re-sistance caused by a thickening of the walls ofresistance vessels and by a reduction in lumendiameters. In some forms of hypertension,this is mediated by enhanced sympathetic ac-tivity or by increased circulating levels of an-giotensin II, causing smooth muscle contrac-

tion and vascular hypertrophy. In recent years,experimental studies have suggested thatchanges in vascular endothelial function maycause these vascular changes. For example, inhypertensive patients, the vascular endothe-lium produces less nitric oxide. Nitric oxide,besides being a powerful vasodilator, inhibitsvascular hypertrophy. Increased endothelin-1production may enhance vascular tone and in-duce hypertrophy. Evidence suggests that hy-perinsulinemia and hyperglycemia in type 2diabetes (non–insulin-dependent diabetes)cause endothelial dysfunction through in-creased formation of reactive oxygen speciesand decreased nitric oxide bioavailability, bothof which may contribute to the abnormal vas-cular function and hypertension often associ-ated with diabetes.

Essential hypertension is related to hered-ity, age, race, and socioeconomic status. Thestrong hereditary correlation may be relatedto genetic abnormalities in renal function and

202 CHAPTER 9

TABLE 9-3 CAUSES OF HYPERTENSION

Essential hypertension (90% to 95%)

• Unknown causes

• Involves:

- increased blood volume

- increased systemic vascular resistance (vascular disease)

• Associated with:

- heredity

- abnormal response to stress

- diabetes and obesity

- age, race, and socioeconomic status

Secondary hypertension (5% to10%)

• Renal artery stenosis

• Renal disease

• Hyperaldosteronism (primary)

• Pheochromocytoma (catecholamine-secreting tumor)

• Aortic coarctation

• Pregnancy (preeclampsia)

• Hyperthyroidism

• Cushing’s syndrome (excessive glucocorticoid secretion)

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neurohumoral control mechanisms. The inci-dence of essential hypertension increases withage, and people of African descent are morelikely to develop hypertension than areCaucasians. Hypertension is more prevalentamong lower socioeconomic groups.

Some patients with essential hypertensionare more strongly influenced by stressful con-ditions than are normotensive individuals.Stress not only leads to acute elevations in ar-terial pressure, but it can also lead to chronicelevations in pressure. Stress activates thesympathetic nervous system, which increasescardiac output and systemic vascular resis-tance. Furthermore, stress causes the adrenalmedulla to secrete more catecholamines (epi-nephrine and norepinephrine) than normal.Sympathetic activation increases circulatingangiotensin II, aldosterone, and vasopressin,which together can increase systemic vascularresistance and, through their renal effects, in-crease sodium and water retention. In addi-tion, prolonged elevation of angiotensin II andcatecholamines leads to vascular and cardiachypertrophy.

Secondary Hypertension

Secondary hypertension accounts for 5% to10% of hypertensive cases. This form of hy-pertension has identifiable causes that oftencan be remedied. Regardless of the underly-ing cause, arterial pressure becomes elevatedowing to an increase in cardiac output, an in-crease in systemic vascular resistance, or both.When cardiac output is elevated, it is often re-lated to increased blood volume and neurohu-moral activation of the heart. Several causes ofsecondary hypertension are summarized inTable 9-3 and discussed below.

Renal artery stenosis occurs when therenal artery becomes narrowed (stenotic) ow-ing to atherosclerotic or fibromuscular lesions.This reduces the pressure at the afferent arte-riole, which stimulates the release of renin bythe kidney (see Chapter 6). Increased plasmarenin activity increases circulating angiotensinII and aldosterone. Angiotensin II causesvasoconstriction by binding to vascular AT1 re-ceptors and by augmenting sympathetic influ-

ences. Furthermore, angiotensin II along withaldosterone increases renal sodium and waterreabsorption. The net effect of the renal ac-tions is an increase in blood volume that aug-ments cardiac output by the Frank-Starlingmechanism. In addition, chronic elevation ofangiotensin II promotes cardiac and vascularhypertrophy. Therefore, hypertension causedby renal artery stenosis is associated with in-creases in cardiac output and systemic vascu-lar resistance.

Renal disease (e.g., diabetic nephropathy,glomerulonephritis) damages nephrons in thekidney. When this occurs, the kidney cannotexcrete normal amounts of sodium, whichleads to sodium and water retention, in-creased blood volume, and increased cardiacoutput. Renal disease may increase the re-lease of renin, leading to a renin-dependentform of hypertension. The elevation in arterialpressure secondary to renal disease can beviewed as an attempt by the kidney to increaserenal perfusion, thereby restoring normalglomerular filtration and sodium excretion.

Primary hyperaldosteronism is in-creased secretion of aldosterone by an adrenaladenoma or adrenal hyperplasia. This condi-tion causes renal retention of sodium and wa-ter, thereby increasing blood volume and arte-rial pressure. Aldosterone acts upon the distalconvoluted tubule and cortical collecting ductof the kidney to increase sodium reabsorptionin exchange for potassium and hydrogen ion,which are excreted in the urine. Plasma reninlevels generally are decreased as the body at-tempts to suppress the renin-angiotensin sys-tem. In addition, hypokalemia is associatedwith the high levels of aldosterone.

A pheochromocytoma (a catecholamine-secreting tumor, usually in the adrenalmedulla) can cause high levels of circulatingcatecholamines (both epinephrine and norep-inephrine). A pheochromocytoma is diag-nosed by measuring plasma or urine cate-cholamine levels and their metabolites(vanillylmandelic acid and metanephrine).This condition leads to �-adrenoceptor-medi-ated systemic vasoconstriction and �1-adreno-ceptor-mediated cardiac stimulation that cancause substantial elevations in arterial pres-


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sure. Although arterial pressure rises to veryhigh levels, tachycardia still occurs because ofthe direct effects of the catecholamines on theheart and vasculature. Excessive �1-adreno-ceptor stimulation in the heart often leads toarrhythmias in addition to the hypertension.

Aortic coarctation is a narrowing of theaortic arch usually just distal to the left sub-clavian artery. It is a congenital defect that ob-structs aortic outflow, leading to elevatedpressures proximal to the coarctation (i.e., el-evated arterial pressures in the head andarms). Distal pressures, however, are not nec-essarily reduced as would be expected fromthe hemodynamics associated with a stenosis.The reason for this is that reduced systemicblood flow, and in particular reduced renalblood flow, leads to an increase in the releaseof renin and an activation of the renin-angiotensin-aldosterone system. This in turnelevates blood volume and arterial pressure.Although the aortic arch and carotid sinusbaroreceptors are exposed to higher-than-nor-mal pressures, the baroreceptor reflex isblunted owing to structural changes in thewalls of vessels where the baroreceptors arelocated. Furthermore, baroreceptors becomedesensitized to chronic elevation in pressureand become “reset” to the higher pressure.

Preeclampsia is a type of hypertensionthat occurs in about 5% of pregnancies duringthe third trimester. Preeclampsia differs fromless severe forms of pregnancy-induced hy-pertension in that preeclampsia causes a lossof albumin in the urine because of renal dam-age, and it is accompanied by significant sys-temic edema. Preeclampsia results from in-creased blood volume and tachycardia, as wellas increased vascular responsiveness to vaso-constrictors, which can lead to vasospasm. It isunclear why some women develop this condi-tion during pregnancy; however, it usually dis-appears after parturition unless an underlyinghypertensive condition exists.

Hyperthyroidism induces systemic vaso-constriction, an increase in blood volume, andincreased cardiac activity, all of which can leadto hypertension. It is less clear why some pa-tients with hypothyroidism also develop hy-pertension, but it may be related to decreased

tissue metabolism reducing the release of va-sodilator metabolites, thereby producing vaso-constriction and increased systemic vascularresistance.

Cushing’s syndrome, which results fromexcessive glucocorticoid secretion, can lead tohypertension. Glucocorticoids such as corti-sol, which are secreted by the adrenal cortex,share some of the same physiologic propertiesas aldosterone, a mineralocorticoid also se-creted by the adrenal cortex. Therefore, ex-cessive glucocorticoids can lead to volume ex-pansion and hypertension.


If a person has secondary hypertension, it issometimes possible to correct the underlyingcause. For example, renal artery stenosis canbe corrected by placing a wire stent within therenal artery to maintain vessel patency; aorticcoarctation can be surgically corrected; apheochromocytoma can be removed.However, for the majority of people who haveessential hypertension, the cause is unknownso it cannot be targeted for correction.Therefore, the therapeutic approach for thesepatients involves modifying the factors thatdetermine arterial pressure by using drugs.

Because hypertension results from an in-crease in cardiac output and increased sys-temic vascular resistance, these are the twophysiologic mechanisms that are targeted indrug therapy. In most hypertensive patients,altered renal function causes sodium and wa-ter retention. This increases blood volume,cardiac output, and arterial pressure.Therefore, the most common treatment forhypertension is the use of a diuretic to stimu-late renal excretion of sodium and water. Thisreduces blood volume and arterial pressurevery effectively in most patients. In addition toa diuretic, most hypertensive patients aregiven at least one other drug. This is becausedecreasing blood volume with a diuretic leadsto activation of the renin-angiotensin-aldo-sterone system, which counteracts the effectsof the diuretic. Therefore, many patients aregiven an angiotensin-converting enzyme

204 CHAPTER 9

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(ACE) inhibitor or angiotensin receptorblocker (ARB) as well.

In addition to using diuretics, cardiac out-put can be reduced using �-blockers and themore cardiac-selective calcium-channelblockers (e.g., verapamil). Beta-blockers areparticularly useful in patients who may haveexcessive sympathetic stimulation owing toemotional stress, and these drugs also inhibitsympathetic-mediated release of renin.

In combination with a diuretic, some hy-pertensive patients can be effectively treatedwith an �-adrenoceptor antagonist, which di-lates resistance vessels and reduces systemicvascular resistance. Other drugs that reducesystemic vascular resistance include ACE inhibitors, angiotensin receptor blockers, calcium-channel blockers (especially dihy-dropyridines), and direct-acting arterial dila-tors such as hydralazine.

Although pharmacologic intervention is animportant therapeutic modality in treating hy-pertension, improved diet and exercise havebeen shown to be effective in reducing arte-rial pressure in many patients. A proper, bal-anced diet that includes sodium restrictioncan prevent the progressive of, and in somecases reverse, cardiovascular changes associ-ated with hypertension. Regular exercise, es-pecially aerobic exercise, reduces arterialpressure and has beneficial effects on vascularfunction.

HEART FAILURE

Heart failure occurs when the heart is unableto supply adequate blood flow and thereforeoxygen delivery to peripheral tissues and or-gans, or to do so only at elevated filling pres-sures. Heart failure most commonly involvesthe left ventricle. Right ventricular failure, al-though sometimes found alone or in associa-tion with pulmonary disease, more often oc-curs secondary to left ventricular failure. Mildheart failure is manifested as reduced exercisecapacity and the development of shortness ofbreath during physical activity (exertionaldyspnea). In more severe forms of heart fail-ure, a patient may have virtually no capacityfor physical exertion and will experience dys-

pnea even while at rest. Furthermore, the pa-tient will likely have significant pulmonary orsystemic edema.

More than 400,000 new cases of heart fail-ure are diagnosed each year in the UnitedStates. It is estimated that 15 million newcases of heart failure occur each year world-wide. The numbers are rapidly increasing ow-ing to the aging population. Despite manynew advances in drug therapy, the prognosisfor chronic heart failure remains poor. One-year mortality figures are 50% to 60% for pa-tients diagnosed with severe failure, 15% to30% for patients in mild to moderate failure,and about 10% for patients in mild or asymp-tomatic failure.

Causes of Heart Failure

Heart failure can be caused by factors origi-nating from the heart (i.e., intrinsic disease orpathology) or from external factors that placeexcessive demands upon the heart. The number-one cause of heart failure is coronaryartery disease, which reduces coronary bloodflow and oxygen delivery to the myocardium,thereby causing myocardial hypoxia and im-paired function. Another common cause ofheart failure is myocardial infarction.Infarcted tissue does not contribute to thegeneration of mechanical activity, and nonin-farcted regions must compensate for the lossof function. Over time, the additional de-mands placed upon the noninfarcted tissuecan cause functional changes leading to fail-ure. Valvular disease and congenital defectsplace increased demands upon the heart thatcan precipitate failure. Cardiomyopathies (in-trinsic diseases of the myocardium that resultin a loss of inotropy) of known origin (e.g.,bacterial or viral; alcohol-induced) or idio-pathic can lead to failure. Infective or nonin-fective myocarditis (inflammation of the myo-cardium) can have a similar effect. Chronicarrhythmias also can precipitate ventricularfailure.

External factors precipitating heart failureinclude increased afterload (pressure load;e.g., uncontrolled hypertension), increasedstroke volume (volume load; e.g., arterial-


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venous shunts), and increased body demands(high output failure; e.g., thyrotoxicosis, preg-nancy).

Systolic versus Diastolic Dysfunction

Heart failure can result from impaired abilityof the heart muscle to contract (systolic fail-ure) or impaired filling of the heart (dias-tolic failure). Systolic failure is caused bychanges in cellular signal transduction mech-anisms and excitation-contraction couplingthat lead to a loss in inotropy (see Chapter 3).Functionally, this causes a downward shift inthe Frank-Starling curve (Fig. 9-8). This de-creases stroke volume and causes a compen-satory rise in preload (clinically measured asincreased ventricular end-diastolic pressureor volume, or increased pulmonary capillarywedge pressure [see Pulmonary WedgePressure on CD). The rise in preload is an important compensatory mechanism becauseit activates the Frank-Starling mechanism tohelp maintain stroke volume despite the lossof inotropy. If preload did not undergo a compensatory increase, the decline in strokevolume would be even greater for a given loss of inotropy. As systolic failure pro-gresses, the ability of the heart to compen-sate by the Frank-Starling mechanism be-comes exhausted.

The effects of a loss of inotropy on strokevolume, end-diastolic volume, and end-sys-tolic volume can be depicted using ventricu-lar pressure-volume loops (Fig. 9-9, panel A)(the concept of pressure-volume loops wasdeveloped in Chapter 4). Systolic failure de-creases the slope of the end-systolic pressure-volume relationship, which occurs because ofreduced inotropy. Because of this change, atany given ventricular volume, less pressurecan be generated during systole and thereforeless volume can be ejected. This leads to anincrease in end-systolic volume. The pres-sure-volume loop also shows that the end-diastolic increases (compensatory increase inpreload). Ventricular preload increases be-cause as the heart loses its ability to ejectblood, more blood remains in the ventricle atthe end of ejection. This results in the ventri-cle filling to a larger end-diastolic volume asvenous return enters the ventricle. The in-crease in end-diastolic volume, however, isnot as great as the increase in end-systolicvolume. Therefore, the net effect is a de-crease in stroke volume (decreased width ofthe pressure-volume loop). Because strokevolume decreases and end-diastolic volumeincreases, a substantial reduction in ejectionfraction occurs. Ejection fraction is normallygreater than 55%, but it can fall below 20% insevere systolic failure.

The second type of heart failure is diastolicfailure, which is caused by impaired ventricu-lar filling. Diastolic failure can be caused byeither decreased ventricular compliance (e.g.,as occurs with ventricular hypertrophy; seeChapter 4) or impaired relaxation (decreasedlusitropy; see Chapter 3). Reduced ventricularcompliance, whether of anatomic or physio-logic origin, shifts the ventricular end-diastolicpressure-volume relationship (i.e., passive fill-ing curve) up and to the left (Fig. 9-9, panelB). This results in less ventricular filling (de-creased end-diastolic volume) and a greaterend-diastolic pressure. Stroke volume, there-fore, decreases. Depending upon the relativechange in stroke volume and end-diastolic vol-ume, ejection fraction may or may not change.For this reason, reduced ejection fraction isuseful only as an indicator of systolic failure.

206 CHAPTER 9

100

50

0

StrokeVolume

(mL)

LVEDP (mm Hg)

0 10 20 30

A

B

FIGURE 9-8 Effects of systolic failure on left ventricularFrank-Starling curves. Systolic failure decreases strokevolume and leads to an increase in ventricular preload(left ventricular end-diastolic pressure, LVEDP). Point A,control point; point B, systolic failure.

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Decreased

LV Volume (mL)0 200100

Loss ofInotropy


Compliance


Systolic Failure

Diastolic Failure

Systolic & Diastolic Failure

A

B

C

FIGURE 9-9 Effects of systolic, diastolic, and combined failures on left ventricular pressure-volume loops. Panel Ashows that systolic failure decreases the slope of the end-systolic pressure-volume relationship and increases end-systolic volume. This causes a secondary increase in end-diastolic volume. The net effect is that stroke volume andejection fraction decrease. Panel B shows that diastolic failure increases the slope of the end-diastolic pressure-volume relationship (passive filling curve) because of reduced ventricular compliance caused either by hypertrophy ordecreased lusitropy. This reduces the end-diastolic volume and increases end-diastolic pressure. End-systolic volumemay decrease slightly as a result of reduced afterload. The net effect is reduced stroke volume; ejection fraction mayor may not change. Panel C shows that combined systolic and diastolic failure reduces end-diastolic volume and in-creases end-systolic volume so that stroke volume is greatly reduced; end-diastolic pressure may become very high.

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Increased ventricular end-diastolic pres-sure (which can exceed 30 mm Hg in left ven-tricular failure—normally less than 10 mmHg) can have serious clinical consequencesbecause left atrial and pulmonary capillarypressures rise. This can lead to pulmonaryedema when the pulmonary capillary wedgepressure exceeds 20 mm Hg. If the right ven-tricle is in diastolic failure, the increase inend-diastolic pressure is reflected back intothe right atrium and systemic venous vascula-ture. This can lead to peripheral edema andabdominal ascites.

It is not uncommon in chronic heart failureto have a combination of both systolic and di-astolic dysfunction to varying degrees (Fig. 9-9, panel C). With both systolic and diastolicdysfunction, the slope of the end-systolic pres-sure-volume relationship is decreased and theslope of the passive filling curve is increased.This causes a dramatic reduction in stroke vol-ume because end-systolic volume is increasedand end-diastolic volume is decreased. This

combination of systolic and diastolic dysfunc-tion can lead to high end-diastolic pressuresthat can cause pulmonary congestion andedema.

Systemic CompensatoryMechanisms in Heart Failure

Heart failure, whether systolic or diastolic innature, leads to a reduction in cardiac output.In the absence of compensatory mechanisms,a fall in cardiac output has two effects: de-creased arterial pressure and increased cen-tral venous pressure (see Fig. 5-14). Thesechanges activate neurohumoral mechanismsthat attempt to restore cardiac output and ar-terial pressure (Fig. 9-10).

In response to an acute reduction in car-diac output and arterial pressure, decreasedfiring of arterial baroreceptors activates thesympathetic adrenergic nerves to the heartand vasculature. The baroreceptor reflex re-sponds only to acute changes in arterial pres-

208 CHAPTER 9

CardiacOutput

ArterialPressure

↑↑↑↑

Sympathetic

Aldosterone Vasopressin

SystemicVascular

Resistance VenousTone

BloodVolume Venous

PressurePulmonary EdemaSystemic Edema↑

↑

↑↑

↓

↓ +

+

–

–––

VentricularFailure

↑ AtrialNatriuretic

Peptide

Angiotensin II

FIGURE 9-10 Summary of neurohumoral changes associated with heart failure. Activation of the sympathetic ner-vous system, the renin-angiotensin-aldosterone system, and vasopressin cause an increase in systemic vascular resis-tance, blood volume, and central venous pressure. Although increased central venous pressure helps to enhance car-diac output by the Frank-Starling mechanism, it can also lead to pulmonary and systemic edema. The increasedsystemic vascular resistance, although helping to maintain arterial pressure, can impair cardiac output because of in-creased afterload. Increased atrial natriuretic peptide counter-regulates the other hormonal systems.

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sure and therefore cannot be responsible forthe increased sympathetic drive when hy-potension accompanies chronic heart failure.In addition, not all patients in chronic heartfailure are hypotensive; therefore, it is notclear what drives the characteristic increase insympathetic activity in heart failure.

Important humoral changes occur duringheart failure to help compensate for the re-duction in cardiac output. Arterial hypoten-sion, along with sympathetic activation, stimu-lates renin release, leading to the formation ofangiotensin II and aldosterone. Vasopressin(antidiuretic hormone) release from the pos-terior pituitary is also stimulated. Increasedvasopressin release seems paradoxical becauseright atrial pressure is often elevated in heartfailure, which should inhibit the release of va-sopressin (see Chapter 6). It may be that va-sopressin release is stimulated in heart failureby sympathetic activation and increased an-giotensin II.

These changes in neurohumoral status con-strict resistance vessels, which causes an in-crease in systemic vascular resistance to helpmaintain arterial pressure. Venous capaci-tance vessels constrict as well. This increasedvenous tone further increases venous pres-sure. Angiotensin II and aldosterone, alongwith vasopressin, increase blood volume by in-creasing renal reabsorption of sodium and wa-ter. This contributes to a further increase invenous pressure, which increases cardiac pre-

load and helps to maintain stroke volumethrough the Frank-Starling mechanism.Increased right atrial pressure stimulates thesynthesis and release of atrial natriuretic peptide to counter-regulate the renin-angiotensin-aldosterone system. These neuro-humoral responses function as compensatorymechanisms, but they can aggravate heart fail-ure by increasing ventricular afterload (whichdepresses stroke volume) and increasing pre-load to the point at which pulmonary or sys-temic congestion and edema occur.

Exercise Limitations Imposed by Heart Failure

Heart failure can severely limit exercise ca-pacity. In early or mild stages of heart failure,cardiac output and arterial pressure may benormal at rest because of compensatorymechanisms. When the person in heart failurebegins to perform physical work, however, themaximal workload is reduced and he or sheexperiences fatigue and dyspnea at less thannormal maximal workloads.

A comparison of exercise responses in anormal person and in a heart failure patient isshown in Table 9-4. In this example, the de-gree of heart failure is moderate to severe. Atrest, the person with congestive heart failure(CHF) has reduced cardiac output (decreased29%) caused by a 38% decrease in stroke volume. Mean arterial pressure is slightly


TABLE 9-4 COMPARISON OF CARDIOVASCULAR FUNCTION IN A NORMALPERSON AND A PATIENT WITH MODERATE-TO-SEVERECONGESTIVE HEART FAILURE (CHF) AT REST AND AT MAXIMAL(MAX) EXERCISE

CO HR SV MAP VO2 A–VO2

(LITERS/MIN) (BEATS/MIN) (ML) (MM HG) (ML O2/MIN) (ML O2/100 ML)

Normal (Rest) 5.6 70 80 95 220 4.0

Normal (Max) 18.0 170 106 120 2500 13.9

CHF (Rest) 4.0 80 50 90 220 5.5

CHF (Max) 6.0 120 50 85 780 13.0

CO, cardiac output; HR, heart rate; SV, stroke volume; MAP, mean arterial pressure; VO2, whole-body oxygen con-sumption; A–VO2, arterial–venous oxygen difference. VO2 is calculated from the product of CO and A–VO2, after theunits for CO are converted to mL/min and the units for A–VO2 are converted to mL O2/mL blood.

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decreased, and resting heart rate is elevated.Whole-body oxygen consumption is normal atrest, but the reduced cardiac output results inan increase in the arterial-venous oxygen dif-ference as more oxygen is extracted from theblood because organ blood flow is reduced. Ata maximally tolerated exercise workload, theCHF patient can increase cardiac output byonly 50%, compared to a 221% increase in thenormal person. The reduced cardiac output isa consequence of the inability of the left ven-tricle to augment stroke volume as well as alower maximal heart rate. The CHF patienthas a significant reduction in arterial pressureduring exercise in contrast to the normal per-son’s increase in arterial pressure. Arterialpressure falls because the increase in cardiacoutput is not sufficient to maintain arterialpressure as the systemic vascular resistancefalls during exercise. The maximal whole-bodyoxygen consumption is greatly reduced in theCHF patient because reduced perfusion ofthe active muscles limits oxygen delivery andtherefore the oxygen consumption of the mus-cles. The CHF patient experiences substantialfatigue and dyspnea during exertion, whichlimits the patient’s ability to sustain the physi-cal activity.

Some of the neurohumoral compensatorymechanisms that operate to maintain restingcardiac output in heart failure contribute tolimiting exercise capacity. The chronic in-crease in sympathetic activity to the heartdown-regulates �1-adrenoceptors, which re-duces the heart’s chronotropic and inotropicresponses to acute sympathetic activation dur-ing exercise. Increased sympathetic activity(and possibly circulating vasoconstrictors) tothe skeletal muscle vasculature limits the de-gree of vasodilation during muscle contrac-tion. This limits oxygen delivery to the work-ing muscle and leads to increased oxygenextraction (increased arterial-venous oxygendifference), enhanced lactic acid production(and a lower anaerobic threshold), and musclefatigue at lower workloads. The increase inblood volume, although helping to maintainstroke volume at rest through the Frank-Starling mechanism, decreases the reserve ca-

pacity of the heart to increase preload duringexercise.


Therapeutic goals in the pharmacologic treat-ment of heart failure include (1) reducing theclinical symptoms of edema and dyspnea; (2)improving cardiovascular function to enhanceorgan perfusion and increase exercise capac-ity; and (3) reducing mortality.

Four pharmacologic approaches are takento achieve these goals. The first approach is toreduce venous pressure to decrease edema andhelp relieve the patient of dyspnea. Diureticsare routinely used to reduce blood volume byincreasing renal excretion of sodium and water.Drugs that dilate the venous vasculature (e.g.,angiotensin-converting enzyme inhibitors) alsocan reduce venous pressure. Judicious use ofthese drugs to decrease blood volume and ve-nous pressure does not significantly reducestroke volume because the Frank-Starlingcurve associated with systolic failure is rela-tively flat at left ventricular end-diastolic pres-sures above 15 mm Hg (see Fig. 9-8).

The second approach is to use drugs thatreduce afterload on the ventricle by dilatingthe systemic vasculature. Drugs such as an-giotensin-converting enzyme inhibitors andangiotensin receptor blockers have proven tobe useful in this regard for patients withchronic heart failure. Decreasing the afterloadon the ventricle can significantly enhancestroke volume and ejection fraction, whichalso reduces ventricular end-diastolic volume(preload). Because arterial vasodilators en-hance cardiac output in heart failure patients,the reduction in systemic vascular resistancedoes not usually lead to an unacceptable fall inarterial pressure.

The third approach is to use drugs thatstimulate ventricular inotropy. A commonlyused drug is digitalis, which inhibits the Na�/K�- ATPase and thereby increases intra-cellular calcium (see Chapter 2). This drug,however, has not been shown to reduce mor-tality associated with heart failure. Drugs that

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stimulate �1-adrenoceptors (e.g., dobutamine)or inhibit cAMP-dependent phosphodi-esterase (e.g., milrinone) are sometimes usedas inotropic agents (see Chapter 3). With theexception of digitalis, inotropic drugs are usedonly in acute heart failure and end-stagechronic failure because their long-term usehas been shown to be deleterious to the heart.

The fourth therapeutic approach involvesusing �-blockers. Although this might seemcounterintuitive, many recent clinical trialshave clearly demonstrated the efficacy ofnewer generation �-blockers (e.g., carvedilol).The mechanism of their efficacy is not clear,but it is known that long-term sympathetic ac-tivation of the heart is deleterious. Therefore,�-blockers probably work by reducing thedeleterious actions of long-term sympatheticactivation. Beta-blockers (as well as an-giotensin-converting enzyme inhibitors) pro-vide long-term benefit through ventricular remodeling (e.g., reducing ventricular hyper-trophy or dilation). Furthermore, �-blockers

such as carvedilol significantly reduce mortal-ity in heart failure.

It should be noted that the therapeutic ap-proaches described above are nearly alwaysused in combination with a diuretic.


• Dynamic exercise such as running is associ-ated with a large fall in systemic vascularresistance owing to metabolic vasodilationin active skeletal muscle (i.e., active hyper-emia). To maintain (and elevate) arterialpressure, sympathetic activation increasescardiac output and constricts blood vesselsin the gastrointestinal tract, nonactive mus-cles, and kidneys. Skin blood flow increasesto facilitate heat loss.

• Adrenal release of catecholamines and ac-tivation of the renin-angiotensin-aldo-sterone system contribute directly or indi-rectly to the cardiac stimulation and


A patient is diagnosed with dilated cardiomyopathy. The echocardiogram shows sub-stantial left ventricular dilation (end-diastolic volume is 240 mL) and an ejection frac-tion of 20%; the arterial pressure is 115/70 mm Hg. Calculate the stroke volume andend-systolic volume. How would combined therapy with an angiotensin-converting en-zyme (ACE) inhibitor and diuretic alter ventricular volumes, ejection fraction, and arte-rial pressure?

Given that the ejection fraction is 20% and the end-diastolic volume is 240 mL, thestroke volume is 48 mL/beat using the following relationship: stroke volume � ejectionfraction x end-diastolic volume. The end-systolic volume is the end-diastolic volume mi-nus the stroke volume, which equals 192 mL. The administration of a diuretic woulddecrease the end-diastolic volume by decreasing blood volume. The ACE inhibitorwould reinforce the effects of the diuretic on the kidney and also cause dilation of re-sistance and capacitance vessels. These actions would further decrease end-diastolicpressure by decreasing venous pressure, and would reduce the afterload. This latter ef-fect enhances stroke volume by decreasing the end-systolic volume and increasing thecardiac output. The increased stroke volume and decreased end-diastolic volume wouldcause the ejection fraction to increase. Although the ACE inhibitor would decrease sys-temic vascular resistance, the increased cardiac output might prevent arterial pressurefrom falling, or at least partially offset the pressure-lowering effect of systemic vasodi-lation.

CASE 9-3

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changes in vascular resistance that occurduring exercise.

• Cardiovascular responses to exercise aresignificantly influenced by the type of exer-cise (dynamic versus static), body posture,physical conditioning, altitude, tempera-ture, age, and gender.

• The skeletal muscle and abdominothoracicpump systems, along with increased ve-nous tone, facilitate venous return duringexercise and prevent preload from fallingas heart rate and inotropy increase, therebyenabling cardiac output to increase.

• Pregnancy is associated with an increase inblood volume and cardiac output and a de-crease in systemic vascular resistance andmean arterial pressure; heart rate graduallyincreases during pregnancy.

• Hypotension is most commonly caused bya reduction in cardiac output, which canresult from heart failure, cardiac arrhyth-mias, hemorrhage, dehydration, or chang-ing from supine to standing position.Impaired baroreceptor reflexes (e.g., auto-nomic dysfunction associated with dia-betes) or reduced systemic vascular resis-tance as occurs in circulatory shock (e.g.,septic shock) can also cause hypotension.

• Negative feedback compensatory mecha-nisms are triggered by hypotension, andthey help to restore arterial pressure.These mechanisms include baroreceptorreflexes, renin-angiotensin-aldosterone sys-tem activation, increased circulating vaso-pressin (antidiuretic hormone), adrenal re-lease of catecholamines, and enhancedcapillary fluid reabsorption.

• Severe hypotension activates positive feed-back mechanisms that can lead to irre-versible shock and death. These mecha-nisms include cardiac depression caused bymyocardial ischemia and acidosis, vascularescape from sympathetic vasoconstriction,autonomic depression resulting from cere-bral ischemia, rheological factors that im-pair organ perfusion, and systemic inflam-matory responses that damage tissues andimpair perfusion.

• Hypertension can result from increases incardiac output or systemic vascular resis-

tance. Impaired sodium and water excre-tion by the kidneys, leading to increases inblood volume and cardiac output, appearsto be a major factor in the development ofessential hypertension, although increasesin systemic vascular resistance occur as thedisease progresses. Conditions causing sec-ondary hypertension include renal arterystenosis, renal disease, primary hyperaldos-teronism, pheochromocytoma, aorticcoarctation, pregnancy, hyperthyroidism,and Cushing’s syndrome.

• Hypertension can be controlled by drugsthat (1) reduce cardiac output (e.g., �-block-ers, calcium-channel blockers); (2) decreasesystemic vascular resistance (e.g., �-adreno-ceptor antagonists, calcium-channel block-ers, angiotensin-converting enzyme in-hibitors, angiotensin receptor blockers); and(3) reduce blood volume (e.g., diuretics).

• Heart failure occurs when the heart is un-able to supply adequate blood flow andthus oxygen delivery to peripheral tissuesand organs, or when it is able to do so onlyat elevated filling pressures. It may involvesystolic dysfunction (depressed ventricularinotropy) or diastolic dysfunction. The lat-ter is associated with reduced ventricularcompliance, often caused by hypertrophyor impaired relaxation; this leads to im-paired filling.

• Heart failure is associated with the follow-ing cardiovascular changes and clinicalsymptoms: reduced stroke volume, re-duced ejection fraction (systolic dysfunc-tion), increased ventricular and atrial fillingpressures, increased blood volume, venouscongestion, pulmonary or systemic edema,increased systemic vascular resistance, hy-potension (depending upon severity),shortness of breath, fatigue, and reducedexercise capacity.

• The following compensatory mechanismsare activated during heart failure: sympa-thetic nervous system, renin-angiotensin-aldosterone system, atrial natriuretic pep-tide, and vasopressin. The overall effect ofthese mechanisms is an increase in bloodvolume and systemic vascular resistance tohelp maintain arterial pressure.

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• Pharmacologic management of heart fail-ure is directed toward the following: (1) re-ducing blood volume, venous congestion,and edema by using diuretics; (2) dilatingthe systemic vasculature to reduce after-load on the ventricle and thereby improvestroke volume and reduce preload; (3)stimulating the heart with positive in-otropic drugs to increase stroke volumeand reduce preload (particularly in acuteheart failure); and (4) reducing the delete-rious effects of chronic sympathetic activa-tion by using �-blockers.

Review Questions

Please refer to appendix for the answers tothe review questions.For each question, choose the one best answer:

1. During a moderate level of whole-bodyexercise (e.g., running),

a. Arterial pulse pressure decreasesowing to the elevated heart rate.

b. Sympathetic-mediated vasoconstric-tion occurs in the skin.

c. Systemic vascular resistance in-creases owing to sympathetic activa-tion.

d. Vagal influences on the sinoatrialnode are inhibited.

2. One important reason why stroke vol-ume is able to increase during runningexercise is that

a. Central venous pressure decreases.b. Heart rate increases.c. The rate of ventricular relaxation de-

creases.d. Venous return is enhanced by the

muscle pump system.

3. Maximal cardiac output during exercisea. Decreases with age because of de-

creased maximal heart rate andstroke volume.

b. Increases by exercise training owingto increased maximal heart rates.

c. Is higher when exercising in a stand-ing than in a supine position.

d. Is higher with static than dynamicexercise.

4. In an exercise study, the subject’s rest-ing heart rate and left ventricularstroke volume were 70 beats/min and80 mL/beat, respectively. While thesubject was walking rapidly on a tread-mill, the heart rate and stroke volumeincreased to 140 beats/min and 100mL/beat, respectively; ejection frac-tion increased from 60% to 75%. Thesubject’s mean arterial pressure in-creased from 90 mm Hg at rest to 110mm Hg during exercise. One can con-clude that

a. Cardiac output doubled.b. Compared to rest, the cardiac out-

put increased proportionately moreduring exercise than systemic vascu-lar resistance decreased.

c. Ventricular end-diastolic volume in-creased.

d. The increase in mean arterial pres-sure during exercise indicates thatsystemic vascular resistance in-creased.

5. During pregnancy,a. Systemic vascular resistance is in-

creased.b. Heart rate is decreased.c. Cardiac output is decreased.d. Blood volume is increased.

6. The baroreceptor reflex in hemorrhagicshock

a. Decreases venous compliance.b. Decreases systemic vascular resis-

tance.c. Increases vagal tone on the SA node.d. Stimulates angiotensin II release

from the kidneys.

7. Long-term recovery of cardiovascularhomeostasis following moderate hemor-rhage involves

a. Aldosterone inhibition of renin re-lease.

b. Enhanced renal loss (excretion) ofsodium.

c. Increased capillary fluid filtration.


Ch09_185-214_Klabunde 4/21/04 11:47 AM

d. Vasopressin-mediated water reab-sorption by the kidneys.

8. A mechanism that may contribute to ir-reversible, decompensated hemorrhagicshock is

a. Diminished sympathetic-mediatedvasoconstriction.

b. Increased capillary fluid reabsorp-tion.

c. Myocardial depression by metabolicalkalosis.

d. Increased renin release by kidneys.

9. Hypertension may result froma. Excessive nitric oxide production by

vascular endothelium.b. Low plasma concentrations of cate-

cholamines.c. Low plasma renin activity.d. Decreased renal sodium excretion.

10. One mechanism by which a �-blockerlowers blood pressure in a patient withessential hypertension is by

a. Dilating the systemic vasculature.b. Increasing plasma renin activity.c. Increasing ventricular preload.d. Reducing heart rate.

11. Left ventricular systolic failure is usuallyassociated with

a. Decreased systemic vascular resis-tance.

b. Increased ejection fraction.c. Increased left ventricular end-

diastolic volume.d. Reduced pulmonary capillary pres-

sures.

12. Compared to the maximal exercise re-sponses of a normal subject, a patientwith moderate-to-severe heart failureduring maximal exercise will have a

a. Lower arterial pressure.b. Lower arterial-venous oxygen extrac-

tion.

c. Higher ejection fraction.d. Similar maximal oxygen consump-

tion.

13. Reducing afterload with an arterial va-sodilator in a patient diagnosed withheart failure

a. Improves ventricular ejection frac-tion.

b. Increases stroke volume by increas-ing preload.

c. Reduces organ perfusion.d. Reduces preload and cardiac output.

SUGGESTED READINGSChapman AB, Abraham WT, Zamudio S, et al. Temporal

relationships between hormonal and hemodynamicchanges in early human pregnancy. Kidney Int1998;54:2056–2063.

Chobanian AV, Bakris GL, Black HR, et al. JointNational Committee on prevention, detection, evalu-ation, and treatment of high blood pressure: TheJNC 7 report. JAMA 2003;289:2560–2572.

Elkayam U. Pregnancy and cardiovascular disease. InBraunwald E, ed. Heart Disease. 5th Ed.Philadelphia: W.B. Saunders Company, 1997.

Janicki JS, Sheriff DD, Robotham JL, Wise RA. Cardiacoutput during exercise: contributions of the cardiac,circulatory, and respiratory systems. In Rowell LB,Shepherd JT, eds. Handbook of Physiology; Exercise:Regulation and Integration of Multiple Systems.New York: Oxford University Press, 1996.

Hall JE. The kidney, hypertension, and obesity.Hypertension 2003;41:625–633.

Laughlin MH, Korthius RJ, Duncker DJ, Bache RJ.Control of blood flow to cardiac and skeletal muscleduring exercise. In Rowell LB, Shepherd JT, eds.Handbook of Physiology; Exercise: Regulation andIntegration of Multiple Systems. New York: OxfordUniversity Press, 1996.

Lilly LS. Pathophysiology of Heart Disease. 3rd Ed.Philadelphia: Lippincott Williams & Wilkins, 2003.

Rowell LB, O’Leary DS, Kellogg DL: Integration of car-diovascular control systems in dynamic exercise InRowell LB, Shepherd JT, eds. Handbook ofPhysiology; Exercise: Regulation and Integration ofMultiple Systems. New York: Oxford UniversityPress, 1996.

Wei JY. Age and the cardiovascular system. N Engl JMed 1992;327:1735–1739.

214 CHAPTER 9

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Supplemental Content Chapter 1 Chapter 2 Ion Permeability and Conductance Reentry Mechanisms Chapter 3 Formation and Physiological Actions of Nitric Oxide Formation and Physiological Actions of Endothelin-1 Formation and Physiological Actions of Metabolites of Arachidonic Acid Chapter 4 Compliance Energetics of Flowing Blood Abnormal Cardiac Pressures and Volumes Caused by Valve Disease Ventricular Hypertrophy Ventricular Stroke Work Chapter 5 Critical Stenosis Valsalva Maneuver Chapter 6 Chapter 7 Angina Chapter 8 Capillary Pressure Interstitial Compliance Osmosis and Osmotic Pressure Chapter 9 Pulmonary Capillary Wedge Pressure Pressure Natriuresis Other Reynolds Number Turbulent Flow

CHAPTER 1

1. The correct answer is “a” because bloodflow carries heat from the deep organswithin the body to the skin where the heatenergy can be given off to the environ-ment. Choice “b” is incorrect because thepulmonary and systemic circulations arein series. Choice “c” is incorrect becausecarbon dioxide is transported from the tis-sues to the lungs. Choice “d” is incorrectbecause blood transports oxygen from thelungs to the tissues.

2. The correct answer is “d” because whenthe volume per beat (stroke volume) ismultiplied by the number of beats perminute (heart rate), the units become vol-ume per minute, which is the flow out ofthe heart (cardiac output). Choice “a” isincorrect because the pulmonary veinsempty into the left atrium. Choice “b” isincorrect because the left ventricle gener-ates much higher pressures than the rightventricle during contraction. Choice “c” isincorrect because the right and left ven-tricles are in series.

3. The correct answer is “a” because when aperson stands up, blood pools in the legs,reducing the filling of the heart, whichleads to a fall in cardiac output and arter-ial pressure. Choice “b” is incorrect be-cause increased blood volume leads to anincrease in cardiac output and arterialpressure. Choice “c” is incorrect becauseincreased cardiac output increases arterialpressure. Choice “d” is incorrect becauseincreases in circulating angiotensin II andaldosterone increase arterial pressure byconstricting systemic blood vessels (an-giotensin II) and by acting on the kidneys

to increase blood volume (angiotensin IIand aldosterone).

CHAPTER 2

1. The correct answer is “d” because the sar-colemmal Na�/K�-ATPase is an electro-genic pump that generates hyperpolariz-ing currents; inhibition of this pumpresults in depolarization. Furthermore,inhibition of the pump leads to an in-crease in intracellular sodium and a de-crease in intracellular potassium, both ofwhich cause depolarization. Choices “a”and “b” are incorrect because decreasedcalcium and sodium conductance reducesthe inward movement of positive chargesthat normally depolarize the membrane.Choice “c” is incorrect because increasedpotassium conductance hyperpolarizesthe membrane (see Equations 2-4 and 2-5).

2. The correct answer is “c” because slowdepolarization leads to closure of the h-gates, which inactivates the fast sodiumchannels. Choice “a” is incorrect becausethe m-gates open at the onset of phase 0,which activates the fast sodium channels.Choice “b” is incorrect because it is theclosure of the h-gates that inactivates thechannel. Choice “d” is incorrect becauseL-type (long-lasting) calcium channelshave a prolonged phase of activation be-fore they become inactivated.

3. The correct answer is “d” because themembrane potential during phase 4 is pri-marily determined by the high potassiumconductance. Choices “a,” “b,” and “c” areincorrect because the overall potassiumconductance is reduced during phases 0

A P P E N D I X

Answers to Review Questions

215

App_215-224_Klabunde 4/21/04 11:50 AM Page 215

through 2, and it begins to recover onlyduring early phase 3.

4. The correct answer is “a” because one ef-fect of �1-adrenoceptor activation is to in-crease If, which enhances the rate ofspontaneous depolarization. Choice “b” isincorrect because fast sodium channelsare inactivated in SA nodal cells; inwardcalcium currents are responsible forphase 0. Choice “c” is incorrect becausepotassium conductance is lowest duringphase 0. Choice “d” is incorrect becausevagal stimulation reduces pacemaker fir-ing rate, in part, by decreasing the slopeof phase 4.

5. The correct sequence of activation andconduction within the heart is choice “a”.

6. The correct answer is “b” because acetyl-choline released by the vagus nerve bindsto M2 receptors, which decreases conduc-tion velocity. Removal of vagal tonethrough the use of a muscarinic receptorantagonist (e.g., atropine) leads to an in-crease in conduction velocity. Choice “a”is incorrect because blocking �1-adreno-ceptors would decrease the influence ofsympathetic nerves on the AV node andlead to a decrease in conduction velocity.Choice “c” is incorrect because depolar-ization of the AV node, which occurs dur-ing hypoxic conditions, decreases conduc-tion velocity. Choice “d” is incorrectbecause L-type calcium channel blockers(e.g., verapamil) reduce conduction ve-locity by decreasing the rate of calciumentry into the cells during depolarization,which decreases the slope of phase 0 inAV nodal cells.

7. The correct answer is “c” because the Twave represents repolarization of the ven-tricular muscle. Choice “a” is incorrectbecause the normal P-R interval is be-tween 0.12 and 0.20 seconds. Choice “b”is incorrect because the duration of theventricular action potential is most closelyassociated with the Q-T interval. Choice“d” is incorrect because the duration ofthe QRS complex is normally less than 0.1seconds.

8. The correct answer is “a” because thepositive electrode is on the left arm andthe negative electrode in on the right armfor lead I. Choices “b” and “d” are incor-rect because lead II and aVF have the pos-itive electrode on the left leg. Choice “c”is incorrect because the positive electrodeis on the right arm for aVR.

9. The correct answer is “a” because whenlead II is biphasic, the mean electrical axismust be perpendicular to that lead, andtherefore it is either –30º or �150º.Because aVL is positive, the mean electri-cal axis must be –30º because that is theaxis for aVL. All the other choices aretherefore incorrect.

10. The correct answer is “c” because a com-plete dissociation between P waves andQRS complexes indicates a complete(third-degree) AV nodal block. Fur-thermore, the rate of ventricular depolar-izations and the normal shape and dura-tion of the QRS complexes suggest thatthe pacemaker driving ventricular depo-larization lies within the AV node or bun-dle of His so that conduction follows nor-mal ventricular pathways. Choice “a” isincorrect because a first-degree AV nodalblock increases only the P-R interval.Choice “b” is incorrect because some ofthe QRS complexes would still be pre-ceded by a P wave in a second-degreeblock. Choice “d” is incorrect becausepremature ventricular complexes nor-mally have an irregular discharge rhythmand the QRS is abnormally shaped andhas a longer-than-normal duration.

CHAPTER 3

1. The correct answer is “b” because myosinlight chain kinase is involved in myosinphosphorylation in both types of muscle.Choice “a” is incorrect because densebodies are specialized regions found onlywithin vascular smooth muscle cellswhere bands of actin filaments are joinedtogether. Choices “c” and “d” are incor-rect because these structures are found in

216 APPENDIX


cardiac muscle cells, not smooth musclecells.

2. The correct answer is “b” because myosinis the major component of the thick fila-ment. Choices “a,” “c,” and “d” are incor-rect because they are all components ofthe thin filament.

3. The correct answer is “c” because amyosin binding site is exposed on theactin after calcium binds to TN-C.Choices “a” and “b” are incorrect becausecalcium binds to TN-C, not myosin orTN-I. Choice “d” is incorrect becauseSERCA pumps calcium back into the sar-coplasmic reticulum.

4. The correct answer is “d” because phos-phorylation of the L-type calcium chan-nels by protein kinase A increases the per-meability of the channel to calcium,thereby permitting more calcium to enterthe cell during depolarization, which trig-gers the release of calcium by the sar-coplasmic reticulum. Choice “a” is incor-rect because Gi-protein activationdecreases cAMP formation, thereby de-creasing inotropy. Choice “b” is incorrectbecause calcium binding to TN-C en-hances inotropy. Choice “c” is incorrectbecause it is the calcium that is releasedby the terminal cisternae of the sarcoplas-mic reticulum that binds to TN-C leadingto contraction.

5. The correct answer is “d” because �2-adrenoceptor activation in vascular smoothmuscle increases cAMP, which inhibitsphosphorylation of myosin light chains bymyosin light chain kinase. Choice “a” is in-correct because activation of myosin lightchain kinase leads to myosin phosphoryla-tion and contraction. Choice “b” is incor-rect because �2-adrenoceptor activationcauses smooth muscle relaxation. Choice“c” is incorrect because �2-adrenoceptoractivation increases cAMP.

6. The correct answer is “c” because an-giotensin II receptors (AT1) are coupledto the Gq-protein and phospholipase C,which increases IP3 when activated.Choice “a” is incorrect because an-

giotensin II activates the Gq-protein.Choice “b” is incorrect because the Gq-protein stimulates IP3 formation, notcAMP. Choice “d” is incorrect becausethe increase in IP3 stimulates calcium re-lease from the sarcoplasmic reticulum.

7. The correct answer is “b” because en-dothelin-1 (ET-1) acts through the Gq-protein pathway to increase IP3, whichleads to contraction. Choices “a” and “c”are incorrect because increased nitric ox-ide stimulates the formation of cGMP,which leads to relaxation. Choice “d” is in-correct because prostacyclin (PGI2)causes smooth muscle relaxation by actingthrough the Gs-protein and stimulatingthe formation of cAMP.

CHAPTER 4

1. The correct answer is “c” because the mi-tral valve is open throughout ventricularfilling. Choice “a” is incorrect because S4,when heard, is associated with atrial con-traction and frequently is heard in hyper-trophied hearts. Choice “b” is incorrectbecause the aortic valve is open only dur-ing ventricular ejection. Choice “d” is in-correct because the ventricular pressureis higher than aortic pressure only duringthe phase of rapid ejection.

2. The correct answer is “c” because moretime is available for filling at reducedheart rates (diastole is lengthened); there-fore, preload is increased at reducedheart rates. Choices “a,” “b,” and “d” areincorrect because decreased atrial con-tractility, blood volume, and ventricularcompliance lead to reduced ventricularfilling and therefore reduced preload.

3. The correct answer is “a” because in-creased preload causes length-dependentactivation of actin and myosin, which in-creases active tension development. Thisis the basis for the Frank-Starling mecha-nism. Choice “b” is incorrect becausechanges in inotropy are independent of sarcomere length. Choice “c” is incor-rect because an increase in preload, by

ANSWERS TO REVIEW QUESTIONS 217


definition, is an increase in sarcomerelength. Choice “d” is incorrect because anincrease in preload increases the velocityof shortening by shifting the force-velocity curve to the right.

4. The correct answer is “d” because ven-tricular hypertrophy reduces ventricularcompliance, which results in elevatedend-diastolic pressures when the ventri-cle fills. Choice “a” is incorrect becausedecreased afterload leads to a reductionin end-systolic volume, which results in asecondary fall in end-diastolic volume andpressure. Choice “b” is incorrect becausedecreased venous return decreases ven-tricular filling, which decreases ventricu-lar end-diastolic volume and pressure.Choice “c” is incorrect because increasedinotropy reduces end-systolic volume,which results in a secondary fall in end-diastolic volume and pressure.

5. The correct answer is “a” because de-creased inotropy diminishes the ability ofthe ventricle to develop pressure andeject blood. Choice “b” is incorrect be-cause increased venous return increasesstroke volume by the Frank-Starlingmechanism. Choice “c” is incorrect be-cause reduced afterload enhances theability of the ventricle to eject blood andtherefore increases stroke volume.Choice “d” is incorrect because a reducedheart rate provides more time for filling,which increases preload and stroke vol-ume by the Frank-Starling mechanism.

6. The correct answer is “c” because a de-crease in inotropy causes a reduction instroke volume, which increases the end-systolic volume. Choice “a” is incorrectbecause a sudden increase in aortic pres-sure increases the afterload on the ventri-cle, which reduces stroke volume and in-creases end-systolic volume. Choice “b” isincorrect because end-diastolic volume,by definition, is the ventricular volume atthe end of filling, whereas the end-systolicvolume is that which is left in the ventri-cle after ejection. Choice “d” is incorrectbecause increasing preload alone does notchange end-systolic volume.

7. The correct answer is “a” because �1-adrenoceptors are coupled to the Gs-pro-tein, which increases cAMP (see Chapter3). Choice “b” is incorrect because an in-crease in heart rate leads to an increase ininotropy (Bowditch effect), probably ow-ing to an increase in intracellular calcium.Choice “c” is incorrect because calciummovement into the cell during the actionpotential triggers the release of calciumfrom the sarcoplasmic reticulum, whichleads to contraction (see Chapter 3).Therefore, decreased calcium entry intothe cell results in less calcium release bythe sarcoplasmic reticulum and decreasedinotropy. Choice “d” is incorrect becausevagal activation decreases inotropy.

8. The correct answer is “b” because an in-crease in inotropy increases stroke vol-ume, which is the width of the pressure-volume loop. Choice “a” is incorrectbecause increased inotropy increasesstroke volume and reduces the end-systolic volume. Choice “c” is incorrectbecause increased inotropy causes a sec-ondary reduction in end-diastolic volumebecause of the reduced end-systolic vol-ume. Choice “d” is incorrect because in-creased inotropy shifts the force-velocitycurve to the right so that for any given af-terload, an increase in muscle fiber short-ening velocity occurs.

9. The correct answer is “b”. Choices “a”and “c” are incorrect because increas-ing afterload decreases ejection velocityand stroke volume, which leads to an increase in end-systolic volume.Choice “d” is incorrect because Vmax,which is the y-intercept of the force-velocity relationship, changes only whenthere are changes in inotropy.

10. The correct answer is “b” because an in-crease in end-diastolic volume will in-crease stroke volume; however, strokevolume changes are about one-fourth aseffective in changing myocardial oxygenconsumption as are changes in heart rate,mean arterial pressure, or ventricular ra-dius because of the relationships betweenoxygen consumption, wall stress, ventric-

218 APPENDIX


ular pressure, and ventricular radius. Forthis reason, choices “a,” “c,” and “d” areincorrect.

CHAPTER 5

1. The correct answer is “c” because thesevessels are the most permeable to fluid.Choice “a” is incorrect because capillar-ies, not arterioles, have the highest indi-vidual resistance because of their smalldiameter. Choice “b” is incorrect becausethe large number of parallel capillaries re-duces their overall resistance as a group ofvessels. Choice “d” is incorrect becausethe small arteries and arterioles are theprimary sites for pressure and flow regu-lation.

2. The correct answer is “a” because any fac-tor that reduces stroke volume will de-crease pulse pressure. Choice “b” is in-correct because increased inotropyincreases stroke volume, which increasespulse pressure. Choice “c” is incorrect be-cause aortic compliance decreases withage. Choice “d” is incorrect because theperfusion pressure for the systemic circu-lation is aortic pressure minus right atrialpressure.

3. The correct answer is “c;” “a” and “b” areincorrect because reducing heart rate by10% without changing stroke volume de-creases cardiac output by 10%. Becausemean arterial pressure is also reduced by10% and mean arterial pressure equalscardiac output times systemic vascular re-sistance (when central venous pressure iszero), systemic vascular resistance is notchanged. Choice “d” is incorrect becausesystemic vascular resistance changes if thesystemic vasculature dilates.

4. The correct answer is “d” because a 50%increase in diameter will increase flow byabout five-fold because flow is propor-tional to radius (or diameter) to the fourthpower in a single vessel segment (assum-ing that the pressure gradient does notchange appreciably). Choice “a” is incor-rect because decreasing temperature in-creases blood viscosity, which decreases

flow. Choice “b” is incorrect because in-creasing perfusion pressure by 100% in-creases flow by about 100%. Choice “c” isincorrect because flow is inversely relatedto blood viscosity.

5. The correct answer is “a” because sys-temic vascular resistance equals arterialminus venous pressure (mm Hg) dividedby cardiac output (mL/min).

6. The correct answer is “b” because the re-nal artery is the distributing artery to thekidney, which is in series with the renalartery. Although decreasing the diameterby 50% increases the resistance of the re-nal artery sixteen-fold, the total renal re-sistance increases only about 15% be-cause the renal artery resistance is about1% of total renal resistance. Therefore,flow will decrease about 13%.

7. The correct answer is “a” because aforced expiration against a closed glottis(Valsalva maneuver) increases in-trapleural pressure, which compressesthe vena cava and increases central ve-nous pressure. Choice “b” is incorrect be-cause increasing cardiac output decreasesvenous blood volume, which decreasescentral venous pressure. Choice “c” is in-correct because increasing venous com-pliance decreases venous pressure.Choice “d” is incorrect because gravita-tional forces associated with standingcauses blood to pool in the legs, which de-creases central venous volume and pres-sure.

8. Choice “d” is correct because inspirationreduces intrapleural pressure, which ex-pands the right atrium, lowers its pres-sure, and thereby enhances venous re-turn. Choice “a” is incorrect because anincrease in cardiac output must increasevenous return because the circulatory sys-tem is closed. Choice “b” is incorrect be-cause decreased sympathetic activation ofthe veins causes them to relax, which in-creases their compliance. This reducespreload on the heart, which leads to a re-duction in cardiac output and venous re-turn. Choice “c” is incorrect because aValsalva maneuver increases intrapleural



pressure, compresses the vena cava, andreduces venous return.

9. Choice “a” is correct because decreasedvenous compliance shifts the systemicfunction curve to the right, which in-creases the mean circulatory filling pres-sure (value of the x-intercept). Choice “b”is incorrect because changes in systemicvascular resistance alter the slope of thesystemic function curve, but not its x-in-tercept. Choice “c” is incorrect because adecrease in blood volume causes a paral-lel shift in the systemic function curve tothe left, which decreases mean circulatoryfilling pressure. Choice “d” is incorrectbecause mean circulatory filling pressure,by definition, is the intravascular pressurewhen cardiac output is zero, and there-fore it is independent of cardiac output.

10. The correct answer is “b” because a de-crease in systemic vascular resistance in-creases the slope of the systemic functioncurve. Choices “a” and “d” are incorrectbecause decreased blood volume and in-creased venous compliance decrease rightatrial pressure and cardiac output bycausing a leftward parallel shift in the sys-temic function curve. Choice “c” is incor-rect because increased heart rate in-creases cardiac output a small amountand decreases right atrial pressure.

CHAPTER 6

1. The correct answer is “c” because this re-gion of the brainstem contains cell bodiesfor both sympathetic and parasympatheticneurons; choices “a” and “b” are thereforeincorrect. Choice “d” is incorrect becausethe nucleus tractus solitarius is the regionin the medulla that receives afferentfibers from peripheral sensors (e.g.,baroreceptors) and then sends excitatoryor inhibitory fibers to sympathetic andparasympathetic neurons within themedulla.

2. The correct answer is “b” because norepi-nephrine binds to �1-adrenoceptors locatedon vascular smooth muscle to stimulatevasoconstriction. Choice “a” is incorrect be-cause norepinephrine preferentially binds

to �1-adrenoceptors in the heart. Choice“c” is incorrect because prejunctional �2-adrenoceptors facilitate norepinephrine re-lease (prejunctional �2-adrenoceptors in-hibit release). Choice “d” is incorrectbecause norepinephrine stimulates reninrelease through �1-adrenoceptors.

3. The correct answer is “d” because the va-gus nerve is parasympathetic cholinergicand therefore releases acetylcholine.Choice “a” is incorrect because efferentright vagal stimulation primarily affectsthe sinoatrial node and has no significantdirect effects on the systemic vasculature.Choice “b” is incorrect because vagalstimulation decreases atrial inotropy.Choice “c” is incorrect because right vagalstimulation reduces heart rate by decreas-ing the slope of phase 4 of the pacemakeraction potential.

4. The correct answer is “c” because in-creased carotid artery pressure stimulatesthe firing of carotid sinus baroreceptors(therefore, choice “a” is incorrect), whichleads to a reflex activation of vagal effer-ents to slow the heart rate (therefore,choice “d” is incorrect). Choice “b” is in-correct because the baroreceptor reflexwould attempt to reduce arterial pressureby withdrawing sympathetic tone on thesystemic vasculature.

5. The correct answer is “b” because in-creased blood pCO2 stimulates chemore-ceptors, which activate the sympatheticnervous system to constrict the systemicvasculature and raise arterial pressure.Choice “a” is incorrect because submerg-ing the face in cold water elicits the “div-ing reflex,” which causes bradycardia.Choice “c” is incorrect because increasedcarotid sinus firing (usually caused by ele-vated arterial pressure) causes a reflex decrease in heart rate brought about byvagal activation and sympathetic with-drawal. Choice “d” is incorrect becausethe vasovagal reflex causes vagal activa-tion and bradycardia.

6. The correct answer is “d” because thisdose of epinephrine binds to both �2 and�1-adrenoceptors on blood vessels.Therefore, if the �2-adrenoceptors (which

220 APPENDIX


produce vasodilation) are blocked, the �1-adrenoceptors can produce vasoconstric-tion unopposed by the �2-adrenoceptors.Choice “a” is incorrect because the unop-posed �-adrenoceptor activation in-creases arterial pressure. Choice “b” is in-correct because epinephrine binds toboth � and �-adrenoceptors. Choice “c” isincorrect because the increase in arterialpressure will cause a reflex bradycardia.

7. The correct answer is “c” because acetyl-choline dilates blood vessels, which low-ers arterial pressure and causes a barore-ceptor-mediated increase in heart ratebrought about by sympathetic activation.Choice “a” is incorrect because stimula-tion of muscarinic receptors on the sinoa-trial node induces bradycardia. Choice“b” is incorrect because the hypotensioncauses decreased carotid sinus firing.Choice “d” is incorrect because reflex sys-temic vasodilation can occur only if arte-rial pressure is elevated and baroreceptorfiring increases.

8. The correct answer is “b” because in-creased angiotensin II acts directly on thekidney and indirectly by increasing aldo-sterone secretion (therefore, choice “c” isincorrect) to increase sodium reabsorption,which leads to an increase in blood volume.Choice “a” is incorrect because angiotensinII enhances sympathetic activity by facili-tating the release of norepinephrine fromsympathetic nerves and decreasing norepi-nephrine re-uptake. Choice “d” is incorrectbecause angiotensin II stimulates the re-lease of atrial natriuretic peptide.

9. The correct answer is “c” because atrialnatriuretic peptide is counter-regulatoryto the renin-angiotensin-aldosterone sys-tem (therefore, choices “a” and “b” are in-correct). Choice “d” is incorrect becausedepression of the renin-angiotensin-aldosterone system leads to enhancedsodium loss, hypovolemia, and a subse-quent reduction in cardiac output.

CHAPTER 7

1. The correct answer is “c.” Choice “a” isincorrect because elevated pCO2 causes

vasodilation in most organs; therefore decreased pCO2 would cause vasocon-striction. Choice “b” is incorrect becauseincreased tissue pO2 causes vasoconstric-tion. Choice “d” is incorrect because en-dothelin-1 is a vasoconstrictor.

2. The correct answer is “a” because in re-sponse to a reduction in perfusion pres-sure and blood flow, the kidney undergoesautoregulation through dilation of the af-ferent arterioles. Choice “b” is incorrect.When the pressure is first reduced, bloodflow will fall by about 30%, but after 2minutes the blood flow will be near nor-mal owing to the autoregulation. Choice“c” is incorrect because afferent arteriolarvasodilation reduces renal vascular resis-tance. Choice “d” is incorrect because au-toregulation, by maintaining blood flow,protects the kidney against ischemia andhypoxia.

3. The correct answer is “c” because the in-crease in flow (reactive hyperemia) fol-lowing release of the occlusion causes aflow-dependent release of nitric oxide bythe vascular endothelium, which furthercontributes to the increase in blood flow.Choice “a” is incorrect because active hyperemia is associated with increasedtissue metabolic activity and not withpostischemic hyperemia. Choice “b” is in-correct because vasodilation occurs dur-ing ischemia. Choice “d” is incorrect be-cause increased interstitial adenosinedilates coronary arterioles.

4. The correct answer is “c.” Choice “a” isincorrect because the brain responds littleto sympathetic activation. Although thecoronary vasculature in the heart (choice“b”) is capable of responding to sympa-thetic activation, concurrent stimulationof heart rate and inotropy lead to meta-bolic vasodilation. Choice “d” is incorrectbecause sympathetic control of the skincirculation is primarily related to ther-moregulation; therefore, the barorecep-tor reflex associated with standing has lit-tle influence on cutaneous blood flow.

5. The correct answers are “f” and “i”.6. The correct answers are “b” and “d”.7. The correct answer is “e”.



8. The correct answer is “c”.9. The correct answer is “a”.

10. The correct answer is “g”.

CHAPTER 8

1. The correct answer is “a” because this isthe mechanism by which fluid and ac-companying electrolytes move throughcapillary intercellular junctions. Choice“b” is incorrect because diffusion, al-though an important mechanism of ex-change, is quantitatively less importantthan bulk flow. Choice “c” is incorrect be-cause osmosis concerns the movement ofwater. Choice “d” is incorrect becausevesicular transport is primarily for thetransport of large macromolecules.

2. The correct answer is “c” because de-creased tissue pO2 increases the concen-tration gradient for oxygen diffusion fromthe blood into the tissue. Choice “a” is in-correct because decreased arteriolar flowreduces capillary pO2, which lowers theconcentration gradient for diffusion out ofthe blood. Choice “b” is incorrect becausedecreased arteriolar pO2 decreases capil-lary pO2 and therefore the oxygen gradi-ent between the blood and tissue. Choice“d” is incorrect because a decrease in thenumber of flowing capillaries decreasesthe surface area available for oxygen ex-change.

3. The correct answer is “a” because capil-lary plasma oncotic pressure opposes fil-tration, therefore decreasing this pressureenhances filtration. Choice “b” is incor-rect because decreasing venous pressurereduces capillary hydrostatic pressure,thereby decreasing filtration. Choice “c”is incorrect because increased precapil-lary resistance decreases capillary hydro-static pressure and reduces filtration.Choice “d” is incorrect because increasedtissue hydrostatic pressure opposes filtra-tion.

4. The correct answer is “b” because the netdriving force, calculated from the givenvalues, is –2 mm Hg, which causes reab-sorption. Choices “a” and “c” are incor-

rect because the net driving force is anegative value.

5. The correct answer is “a” because in-creased filtration results in more fluid be-ing taken up by the lymphatics and re-moved from the tissue. Choice “b” isincorrect because increased capillary fil-tration increases filtration fraction.Choice “c” is incorrect because histamineincreases the capillary filtration constant,thereby increasing filtration. Choice “d” isincorrect because increased filtration in-creases interstitial fluid volume, which in-creases interstitial fluid pressure.

6. The correct answer is “d” because lym-phatic obstruction prevents the normalremoval of excess filtration from the tis-sue. Choice “a” is incorrect because in-creased arteriolar resistance decreasescapillary hydrostatic pressure, which de-creases filtration. Choice “b” is incorrectbecause increased plasma protein con-centration enhances reabsorption. Choice“c” is incorrect because reduced venouspressure decreases capillary pressure andfiltration.

CHAPTER 9

1. The correct answer is “d” because heartrate is increased during exercise throughactivation of sympathetic adrenergicnerves and inhibition of vagal (parasym-pathetic) nerves on the sinoatrial node.Choice “a” is incorrect because arterialpulse pressure increases during moderateexercise because of the increase in strokevolume. Choice “b” is incorrect becausecutaneous vasodilation occurs during ex-ercise to facilitate heat loss from the body.Choice “c” is incorrect because systemicvascular resistance falls owing to vasodila-tion in the active skeletal muscle.

2. The correct answer is “d” because themuscle pump system facilitates venous re-turn, which maintains or elevates ventric-ular filling pressures. Choice “a” is incor-rect because a decrease in central venouspressure would decrease stroke volume.Choice “b” is incorrect because an in-

222 APPENDIX


crease in heart rate, with no other com-pensatory changes, decreases stroke vol-ume. Choice “c” is incorrect because therate of ventricular relaxation (lusitropy)increases during exercise owing to sympa-thetic influences, which aids ventricularfilling and enhances stroke volume.

3. The correct answer is “a” because themaximal rate of sinoatrial node firing de-creases with age, and stroke volume de-creases because of a decline in inotropicresponsiveness and decreased ventricularcompliance. Choice “b” is incorrect be-cause exercise training does not signifi-cantly change maximal heart rate, al-though it improves inotropic responses.Choice “c” is incorrect because body pos-ture does not significantly affect maximalcardiac output, although it influences therelative changes in heart rate and strokevolume. Choice “d” is incorrect becausestatic exercise, unlike dynamic exercise,does not enhance venous return by themuscle pump.

4. The correct answer is “b” because arterialpressure increased; therefore, cardiacoutput must have increased more thansystemic vascular resistance decreased.Choice “a” is incorrect because cardiacoutput (the product of heart rate andstroke volume) increased from 5.6 to 14.0liters/min (i.e., it more than doubled).Choice “c” is incorrect because stroke vol-ume increased by 25% (from 80 to 100mL/beat), and the ejection fraction in-creased by 25% (from 60% to 75%).Therefore, end-diastolic volume couldnot have changed because ejection frac-tion equals stroke volume divided by end-diastolic volume. Choice “d” is incorrectbecause the percent change in cardiacoutput is much greater than the percentchange in arterial pressure; the systemicvascular resistance can be approximatedfrom the arterial pressure divided by thecardiac output.

5. The correct answer is “d” because activa-tion of the renin-angiotensin-aldosteronesystem during pregnancy increases bloodvolume. Choice “a” is incorrect because

systemic vascular resistance decreasesduring pregnancy owing to the develop-ing uterine circulation. Choices “b” and“c” are incorrect because heart rate andcardiac output increase during pregnancy.

6. The correct answer is “a” because thebaroreceptor reflex activates sympatheticadrenergic nerves that constrict arterialand venous vessels. Choice “b” is incor-rect because sympathetic activation in-creases systemic vascular resistance.Choice “c” is incorrect because sympa-thetic activation is accompanied by with-drawal of vagal tone on the heart. Choice“d” is incorrect because renin, not an-giotensin II, is released from the kidneys.

7. The correct answer is “d” because long-term recovery from hypovolemia requiresrenal retention of water, which is partiallyregulated by vasopressin. Choice “a” is in-correct because increased renin releaseand subsequent formation of angiotensinII and aldosterone contribute to renal re-absorption of sodium and water. Choice“b” is incorrect because sodium reabsorp-tion, not loss, is enhanced following hem-orrhage. Choice “c” is incorrect becauseincreased capillary fluid filtration woulddecrease blood volume and not serve as acompensatory mechanism following hem-orrhage.

8. The correct answer is “a” because organsbecome ischemic and hypoxic followingintense sympathetic activation, and theirvasculature eventually escape the sympa-thetic-mediated vasoconstriction. Choice“b” is incorrect because capillary fluid re-absorption functions as a compensatorymechanism. Choice “c” is incorrect be-cause myocardial depression in hemor-rhagic shock occurs in response to meta-bolic acidosis, not alkalosis. Choice “d” isincorrect because increased renin releaseand subsequent angiotensin II and aldos-terone formation is a compensatorymechanism.

9. The correct answer is “d” because de-creased sodium excretion leads to an in-crease in blood volume, which increasespressure. Choice “a” is incorrect because



nitric oxide is a vasodilator; therefore, ex-cessive production causes hypotension,not hypertension. Choice “b” is incorrectbecause high levels of circulating cate-cholamines produce hypertension.Choice “c” is incorrect because high reninlevels cause hypertension through the ac-tions of angiotensin II and aldosterone onthe vasculature and kidneys.

10. The correct answer is “d” because �-blockers antagonize sympathetic effectson the sinoatrial node, which decreasesheart rate and cardiac output. Choice “a”is incorrect because blocking �2-adreno-ceptors on blood vessels increases sympa-thetic vascular tone owing to unopposed�-adrenoceptor stimulation. Choice “b” isincorrect because �-blockers antagonizesympathetic-stimulated release of reninby the kidneys. Although depressing car-diac function increases ventricular pre-load, choice “c” is incorrect because in-creased preload does not contribute tolowering arterial pressure.

11. The correct answer is “c” because loss ofinotropy in systolic failure decreasesstroke volume and increases end-systolicvolume, which leads to a compensatoryincrease in end-diastolic volume. Choice“a” is incorrect because neurohumoral ac-tivation in heart failure increases systemicvascular resistance. Choice “b” is incor-rect because ejection fraction decreases

because of the decrease in stroke volumeand increase in end-diastolic volume.Choice “d” is incorrect because systolicfailure increases end-diastolic pressure,which is transmitted back into the pul-monary circulation.

12. The correct answer is “a” because cardiacoutput is unable to increase sufficiently tomaintain arterial pressure as systemic vas-cular resistance falls during exercise.Choice “b” is incorrect because reducedorgan perfusion increases oxygen extrac-tion from the arterial blood. Choice “c” isincorrect because impaired inotropic re-sponses during exercise reduces ejectionfraction. Choice “d” is incorrect becausethe heart failure patient achieves lowermaximal oxygen consumption becausemaximal cardiac output is reduced.

13. The correct answer is “a” because reduc-ing afterload increases stroke volume andreduces ventricular end-diastolic volume;these changes enhance ejection fraction.Choice “b” is incorrect because the arte-rial vasodilator, by reducing afterload andenhancing stroke volume, decreases ven-tricular preload in the failing heart.Choice “c” is incorrect because the arte-rial dilator decreases systemic vascular re-sistance and increases cardiac output;these changes increase organ perfusion.Choice “d” is incorrect for the reasonsgiven above.

224 APPENDIX


cv cardiovascular physiology concepts klabunde

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