ganong wf. cardiovascular homeostasis in health and disease

7/31/2019 Ganong WF. Cardiovascular Homeostasis in Health and Disease

1/30

I NTRODUCTI ON: CARDI OVASCULAR HOMEOSTASI S I N

HEALTH & DI SEASE

The compensatory adjustments of the cardiovascular system to the challenges

faced by the circulation normally in everyday life and abnormally in disease illustrate

the integrated operation of the cardiovascular regulatory mechanisms described in thepreceding chapters. The adjustments to gravity, exercise, inflammation, wound

healing, shock, fainting, hypertension, and heart failure are considered in this chapter.

Page 1 of 1

5/19/2012mhtml:mk:@MSITStore:C:\Users\deag1\Desktop\Review of Medical Physiology - Ganon...


2/30

COMPENSATI ONS FOR GRAVI TATI ONAL EFFECTS

In the standing position, as a result of the effect of gravity on the blood (see Chapter

30: Dynamics of Blood & Lymph Flow), the mean arterial blood pressure in the feet of

a normal adult is 180200 mm Hg and venous pressure is 8590 mm Hg. The arterial

pressure at head level is 6075 mm Hg, and the venous pressure is zero. If theindividual does not move, 300500 mL of blood pools in the venous capacitance

vessels of the lower extremities, fluid begins to accumulate in the interstitial spaces

because of increased hydrostatic pressure in the capillaries, and stroke volume is

decreased. Symptoms of cerebral ischemia develop when the cerebral blood flow

decreases to less than about 60% of the flow in the recumbent position. If no

compensatory cardiovascular changes occurred, the reduction in cardiac output due to

pooling on standing would lead to a reduction of cerebral flow of this magnitude, and

consciousness would be lost.

The major compensations on assuming the upright position are triggered by the drop

in blood pressure in the carotid sinus and aortic arch. The heart rate increases,

helping to maintain cardiac output. Relatively little venoconstriction occurs in the

periphery, but there is a prompt increase in the circulating levels of renin and

aldosterone. The arterioles constrict, helping to maintain blood pressure. The actual

blood pressure change at heart level is variable, depending on the balance between

the degree of arteriolar constriction and the drop in cardiac output (Figure 331).

Figu r e 3 31 .

Page 1 of 5



3/30

In the cerebral circulation, additional compensatory changes take place. The arterial

pressure at head level drops 2040 mm Hg, but jugular venous pressure falls 58 mm

Hg, reducing the drop in perfusion pressure (arterial pressure minus venous

pressure). Cerebral vascular resistance is reduced because intracranial pressure falls

as venous pressure falls, decreasing the pressure on the cerebral vessels. The decline

in cerebral blood flow increases the partial pressure of CO2 (PCO2) and decreases thePO

2and the pH in brain tissue, further actively dilating the cerebral vessels. Because

of the operation of these autoregulatory mechanisms, cerebral blood flow declines

only 20% on standing. In addition, the amount of O2

extracted from each unit of

blood increases, and the net effect is that cerebral O2

consumption is about the same

in the supine and the upright positions.

Prolonged standing presents an additional problem because of increasing interstitial

fluid volume in the lower extremities. As long as the individual moves about, the

Effect on the cardiovascular system of rising from the supine to the upright position.

Figures shown are average changes. Changes in abdominal and limb resistance and in

blood pressure are variable from individual to individual. (Redrawn and reproduced, with

permission, from Brobeck JR [editor]: Best and Taylor's Physiological Basis of Medical

Practice, 9th ed. Williams & Wilkins, 1973.)

Page 2 of 5



4/30

operation of the muscle pump (see Chapter 30: Dynamics of Blood & Lymph Flow)

keeps the venous pressure below 30 mm Hg in the feet, and venous return is

adequate. However, with prolonged quiet standing (eg, in military personnel standing

at attention for long periods), fainting may result. In a sense, the fainting is a

"homeostatic mechanism," because falling to the horizontal position promptly restores

venous return, cardiac output, and cerebral blood flow to adequate levels.

The effects of gravity on the circulation in humans depend in part upon the blood

volume. When the blood volume is low, these effects are marked; when it is high,

they are minimal.

The compensatory mechanisms that operate on assumption of the erect posture are

better developed in humans than in quadrupeds even though these animals have

sensitive carotid sinus mechanisms. Quadrupeds tolerate tilting to the upright position

poorly. Of course, giraffes are an exception. These long-legged animals do not develop

ankle edema despite the very large increment in vascular pressure in their legs due to

gravity because they have tight skin and fascia in the lower legsin a sense a built-in

antigravity suit (see below)and a very effective muscle pump. Perfusion in the head

is maintained by a high mean arterial pressure. When giraffes lower their heads to

drink, blood is pumped up their jugular veins to the chest, presumably by rhythmic

contractions of the muscles of the jaws.

Pos tu ra l Hypo tens ion

In some individuals, sudden standing causes a fall in blood pressure, dizziness,

dimness of vision, and even fainting. The causes of this o r t hos t a t i c pos t u ra l

hypo t ens i on are multiple. It is common in patients receiving sympatholytic drugs. It

also occurs in diseases such as diabetes and syphilis, in which there is damage to the

sympathetic nervous system. This underscores the importance of the sympathetic

vasoconstrictor fibers in compensating for the effects of gravity on the circulation.

Another cause of postural hypotension is p r i m a r y a u t o n o m i c f a i lu r e (Table 331).

Autonomic failure occurs in a variety of diseases. One form is caused by a congenital

deficiency of dopamine -hydroxylase (see Chapter 4: Synaptic & Junctional

Transmission) with little or no production of norepinephrine and epinephrine.

Baroreceptor reflexes are also abnormal in patients with primary hyperaldosteronism.

However, these patients generally do not have postural hypotension, because their

blood volumes are expanded sufficiently to maintain cardiac output in spite of changes

in position. Indeed, mineralocorticoids are used to treat patients with postural

hypotension.

Tab le 331 . Ma jo r Form s o f Pr im ary Au to nom ic Fa i lu re .

Bradbu ry -Egg l es ton synd rom e ( i d i opa th i c o r thos ta t i c hypo tens i on )

Onset late in life

Sympathetic and parasympathetic failure

Absent or minimal other neurologic involvement

Plasma norepinephrine/dopamine ratio greater than 1

Page 3 of 5



5/30

Ef fec ts o f Acce lera t ion

The effects of gravity on the circulation are multiplied during acceleration or

deceleration in vehicles that in modern civilization range from elevators to rockets.

Force acting on the body as a result of acceleration is commonly expressed in gunits,

1 gbeing the force of gravity on the earth's surface. "Positive g" is force due to

acceleration acting in the long axis of the body, from head to foot; "negative g" is

force due to acceleration acting in the opposite direction. During exposure to positive

g, blood is "thrown" into the lower part of the body. Arterial pressure in the head is

reduced, but so are venous pressure and intracranial pressure, and this reduces the

decrease in arterial blood flow that would otherwise occur (see Chapter 32: Circulation

Through Special Regions). Cardiac output is maintained for a time because blood is

drawn from the pulmonary venous reservoir and because the force of cardiac

contraction is increased. At accelerations producing more than 5 g, however, vision

fails ("blackout") in about 5 seconds and unconsciousness follows almost immediately

thereafter. The effects of positive gare effectively cushioned by the use of antigravity

"gsuits," double-walled pressure suits containing water or compressed air and

regulated in such a way that they compress the abdomen and legs with a force

proportionate to the positive g. This decreases venous pooling and helps maintain

venous return (Figure 331).

Sh y - D r a g er s y n d r o m e ( m u l t i p l e sy s t e m a t r o p h y )

Onset in mid to late life

Sympathetic and parasympathetic failure

Other neurologic involvement (extrapyramidal, cerebellar, etc)


Ril ey -Day synd rom e ( fam i l i a l dysau tonom i a )

Congenital onset and premature mortality

Ashkenazi Jewish extraction

Sympathetic and parasympathetic involvement

Emotional lability


Dopami ne -hyd rox y l ase de f i c iency

Congenital onset

Sympathoadrenomedullary failure (orthostatic hypotension)Intact sweating

Parasympathetic sparing

Plasma norepinephrine/dopamine ratio much less than 1

Reproduced, with permission, from Robertson D et al: Dopamine -hydroxylase

deficiency: A genetic disorder of cardiovascular regulation. Hypertension 1991;18:1.

By permission of the American Heart Association, Inc.

Page 4 of 5



6/30

Negative gcauses increased cardiac output, a rise in cerebral arterial pressure,

intense congestion of the head and neck vessels, ecchymoses around the eyes, severe

throbbing head pain, and, eventually, mental confusion ("redout"). In spite of the

great rise in cerebral arterial pressure, the vessels in the brain do not rupture,

because generally there is an increase in intracranial pressure and their walls are

supported (see Chapter 32: Circulation Through Special Regions). The tolerance for g

forces exerted across the body is much greater than it is for axial g. Humans tolerate

11 gacting in a back-to-chest direction for 3 minutes and 17 gacting in a chest-to-

back direction for 4 minutes. Astronauts are therefore positioned to take the g forces

of rocket flight in the chest-to-back direction. The tolerances in this position are

sufficiently large to permit acceleration to orbital or escape velocity and deceleration

back into the earth's atmosphere without ill effects.

Ef fec ts o f Zero Grav i ty on t he Card iovascu lar Sys tem

From the data available to date, cardiovascular function is maintained for up to 14

months of weightlessness, though there is some disuse atrophy of the mechanisms

that withstand gravity on earth. On return to earth, astronauts have postural

hypotension, but this disappears and readaptation to gravity appears to be complete

in 47 weeks. Of course, longer exposure to weightlessness might be a bigger

problem.

Other Ef fec ts o f Zero Grav i ty

Muscular effort is much reduced when objects to be moved are weightless, and the

decrease in the extensive normal proprioceptive input due to the action of gravity on

the body leads to flaccidity and atrophy of skeletal muscles. A program of regular

exercises against resistance, eg, pushing against a wall or stretching a heavy rubberband, appears to decrease the loss of muscle. However, the compensation is

incomplete.

Other changes produced by exposure to space flight include space motion sickness

(see Chapter 9: Hearing & Equilibrium), a problem that has proved to be of greater

magnitude than initially expected; loss of plasma volume, probably because of

headward shift of body fluids, with subsequent diuresis; loss of muscle mass; steady

loss of bone mineral, with increased Ca2+ excretion; loss of red-cell mass; and

alterations in plasma lymphocytes. The loss of body Ca2+ is equivalent to 0.4% of the

total body Ca2+ per month, and although some evidence suggests that the loss tapers

off during prolonged space flight, loss at this rate might create problems of

appreciable magnitude if continued for more than 14 months. A high-calcium diet

helps overcome this problem, but no totally effective treatment has yet been

developed. The psychological problems associated with the isolation and monotony of

prolonged space flight are also a matter of concern.

Page 5 of 5



7/30

EXERCI SE

Exercise is associated with very extensive alterations in the circulatory and respiratory

systems. For convenience, the circulatory adjustments are considered in this chapter

and the respiratory adjustments in Chapter 37: Respiratory Adjustments in Health &

Disease. However, it should be emphasized that they occur together in an integratedfashion as part of the homeostatic responses that make moderate to severe exercise

possible.

Muscle Blood Flow

The blood flow of resting skeletal muscle is low (24 mL/100 g/min). When a muscle

contracts, it compresses the vessels in it if it develops more than 10% of its maximal

tension (Figure 332); when it develops more than 70% of its maximal tension, blood

flow is completely stopped. Between contractions, however, flow is so greatly

increased that blood flow per unit of time in a rhythmically contracting muscle is

increased as much as 30-fold. Blood flow sometimes increases at or even before the

start of exercise, so the initial rise is probably a neurally mediated response. Impulses

in the sympathetic vasodilator system (see Chapter 31: Cardiovascular Regulatory

Mechanisms) may be involved. The blood flow in resting muscle doubles after

sympathectomy, so some decrease in tonic vasoconstrictor discharge may also be

involved. However, once exercise has started, local mechanisms maintain the high

blood flow, and there is no difference in flow in normal and sympathectomized

animals.

Figu r e 3 32 .

Page 1 of 7



8/30

Local mechanisms maintaining a high blood flow in exercising muscle include a fall in

tissue PO2, a rise in tissue PCO2, and accumulation of K+ and other vasodilatormetabolites (see Chapter 31: Cardiovascular Regulatory Mechanisms). The

temperature rises in active muscle, and this further dilates the vessels. Dilation of the

arterioles and precapillary sphincters causes a 10- to 100-fold increase in the number

of open capillaries. The average distance between the blood and the active cellsand

the distance O2

and metabolic products must diffuseis thus greatly decreased. The

dilation increases the cross-sectional area of the vascular bed, and the velocity of flow

therefore decreases. The capillary pressure increases until it exceeds the oncotic

pressure throughout the length of the capillaries. In addition, the accumulation of

osmotically active metabolites more rapidly than they can be carried away decreases

the osmotic gradient across the capillary walls. Therefore, fluid transudation into the

interstitial spaces is tremendously increased. Lymph flow is also greatly increased,

limiting the accumulation of interstitial fluid and in effect greatly increasing its

turnover. The decreased pH and increased temperature shift the dissociation curve for

hemoglobin to the right, so that more O2

is given up by the blood. The concentration

of 2,3-DPG in the red blood cells is increased, and this further decreases the O2

affinity of hemoglobin (see Chapter 27: Circulating Body Fluids and Chapter 35: Gas

Transport between the Lungs & the Tissues). The net result is an up to threefold

increase in the arteriovenous O2

difference, and the transport of CO2

out of the tissue

Blood flow through a portion of the calf muscles during rhythmic contraction.

(Reproduced, with permission, from Barcroft H, Swann HJC: Sympathetic Control of

Human Blood Vessels. Arnold, 1953.)

Page 2 of 7



9/30

is also facilitated. All of these changes combine to make it possible for the O2

consumption of skeletal muscle to increase 100-fold during exercise. An even greater

increase in energy output is possible for short periods during which the energy stores

are replenished by anaerobic metabolism of glucose and the muscle incurs an O2

debt

(see Chapter 3: Excitable Tissue: Muscle). The overall changes in intermediary

metabolism during exercise are discussed in Chapter 17: Energy Balance, Metabolism,

& Nutrition.

K+ dilates arterioles in exercising muscle, particularly during the early part of

exercise. Muscle blood flow increases to a lesser degree during exercise in K+-

depleted individuals, and there is a greater tendency for severe disintegration of

muscle ( exe r t i ona l r habdomyo l ys i s ) to occur.

System ic Ci rcu la t ory Chan ges

The systemic cardiovascular response to exercise depends on whether the muscle

contractions are primarily isometric or primarily isotonic with the performance of

external work. With the start of an isometric muscle contraction, the heart rate rises.This increase still occurs if the muscle contraction is prevented by local infusion of a

neuromuscular blocking drug. It also occurs with just the thought of performing a

muscle contraction, so it is probably the result of psychic stimuli acting on the medulla

oblongata. The increase is largely due to decreased vagal tone, although increased

discharge of the cardiac sympathetic nerves plays some role. Within a few seconds of

the onset of an isometric muscle contraction, systolic and diastolic blood pressures

rise sharply. Stroke volume changes relatively little, and blood flow to the steadily

contracting muscles is reduced as a result of compression of their blood vessels.

The response to exercise involving isotonic muscle contraction is similar in that there

is a prompt increase in heart rate but different in that a marked increase in stroke

volume occurs. In addition, there is a net fall in total peripheral resistance (Figure 33

3) due to vasodilation in exercising muscles (Table 332). Consequently, systolic

blood pressure rises only moderately, whereas diastolic pressure usually remains

unchanged or falls. The difference in response to isometric and isotonic exercise is

explained in part by the fact that the active muscles are tonically contracted during

isometric exercise and consequently contribute to increased total peripheral

resistance. In addition, there is a general increase in muscle sympathetic nerve

activity, apparently because of a signal from the contracted muscle. However since

cholinergic sympathetic vasodilation occurs in the inactive skeletal muscles, the

significance of this increase is unclear.

Tab le 33 2 . Card iac Outp u t and Reg iona l B lood Flow in a

Sedenta ry Man.a

Quie t Stand in g Exercise

Cardiac output 5900 24,000

Blood flow to:

Page 3 of 7



10/30

Heart 250 1000

Brain 750 750

Active skeletal muscle 650 20,850

Inactive skeletal muscle 650 300

Skin 500 500

Kidney, liver, gastrointestinal tract, etc. 3100 600

aValues are mL min at rest and durin isotonic exercise at maximal ox en u take.

Figu r e 3 33 .

Page 4 of 7



11/30

Cardiac output is increased during isotonic exercise to values that may exceed 35

L/min, the amount being proportionate to the increase in O2

consumption. The

mechanisms responsible for this increase are discussed above and in Chapter 29: The

Heart As a Pump. The maximal heart rate achieved during exercise decreases with

age. In children, it rises to 200 or more beats per minute; in adults it rarely exceeds

195 beats per minute, and in elderly individuals the rise is even smaller.

A great increase in venous return takes place, although the increase in venous return

is not the primary cause of the increase in cardiac output. Venous return is increased

by the great increase in the activity of the muscle and thoracic pumps; by mobilization

of blood from the viscera; by increased pressure transmitted through the dilated

arterioles to the veins; and by noradrenergically mediated venoconstriction, which

decreases the volume of blood in the veins. The amount of blood mobilized from the

splanchnic area and other reservoirs may increase the amount of blood in the arterial

portion of the circulation by as much as 30% during strenuous exercise.After exercise, the blood pressure may transiently drop to subnormal levels,

presumably because accumulated metabolites keep the muscle vessels dilated for a

short period. However, the blood pressure soon returns to the preexercise level. The

heart rate returns to normal more slowly.

Tem pera tu re Regu la t i on

The quantitative aspects of heat dissipation during exercise are summarized in Figure

334. In many locations, the skin is supplied by branches of muscle arteries, so that

some of the blood warmed in the muscles is transported directly to the skin, where

some of the heat is radiated to the environment. There is a marked increase in

ventilation (see Chapter 37: Respiratory Adjustments in Health & Disease), and some

heat is lost in the expired air. The body temperature rises, and the hypothalamic

centers that control heat-dissipating mechanisms are activated. The temperature

increase is due at least in part to the inability of the heat-dissipating mechanism to

handle the great increase in heat production. Sweat secretion is greatly increased, and

vaporization of this sweat is the major path for heat loss. The cutaneous vessels also

dilate. This dilation is primarily due to inhibition of vasoconstrictor tone, although local

release of vasodilator polypeptides may also contribute (see Chapter 31:

Cardiovascular Regulatory Mechanisms).

Effects of different levels of isotonic exercise on cardiovascular function. (Reproduced,

with permission, from Berne RM, Levy MN: Cardiov ascular Physiology, 5th ed. Mosby,

1986.)

Figu r e 3 34 .

Page 5 of 7



12/30

Tra in ing

Both at rest and at any given level of exercise, trained athletes have a larger stroke

volume and lower heart rate than untrained individuals (see Chapter 29: The Heart As

a Pump), and they tend to have larger hearts. Training increases the maximal oxygen

consumption (VO2max

) that can be produced by exercise in an individual. VO2max

averages about 38 mL/kg/min in active healthy men and about 29 mL/kg/min in

active healthy women. It is lower in sedentary individuals. VO2max

is the product of

maximal cardiac output and maximal O2

extraction by the tissues, and both increase

with training.

The changes that occur in skeletal muscles with training include increases in the

number of mitochondria and the enzymes involved in oxidative metabolism. The

number of capillaries increases, with better distribution of blood to the muscle fibers.

The net effect is more complete extraction of O2

and consequently, for a given work

load, less increase in lactate production. The increase in blood flow to muscles is less

and, because of this, less increase in heart rate and cardiac output than in an

untrained individual. This is one of the reasons that exercise is of benefit to patients

with heart disease.

Relat io n t o Card iovascu lar Disease

Energy exchange in muscular exercise. The shaded area represents the excess of heat

production over heat loss. The total energy output equals the heat production plus the

work done.

Page 6 of 7



13/30

It is said that the internist's mantra for cardiovascular health is, "Stop smoking, lose

weight, and get more exercise." The beneficial effects of a program of regular isotonic

exercise are well established in terms of helping patients to feel better, have less

severe heart attacks when they have them, and avoid heart attacks in the first place.

Regular exercise improves coronary perfusion apparently because the exercise

through shear stress improves the production of prostacyclin and NO by the

endothelium of the coronary vessels.

On the other hand, it is also true that the incidence of heart attacks increases during

and up to 30 minutes after heavy exercise, particularly in individuals leading

sedentary lives. The cause of the increase is unknown but may be related to increased

rupture of atherosclerotic plaques. The long-term benefits of exercise probably

outweigh the short-term dangers, but it is important to start an exercise program

gradually and not let it become too strenuous.

Page 7 of 7



14/30

I NFLAMMATI ON & W OUND HEALI NG

Loc al I n j u r y

Inflammation is a complex localized response to foreign substances such as bacteria

or in some instances to internally produced substances. It includes a sequence of

reactions initially involving cytokines, neutrophils, adhesion molecules, complement,

and IgG. PAF, an agent with potent inflammatory effects (see Chapter 27: Circulating

Body Fluids), also plays a role. Later, monocytes and lymphocytes are involved.

Arterioles in the inflamed area dilate, and capillary permeability is increased (see

Chapter 31: Cardiovascular Regulatory Mechanisms and Chapter 32: Circulation

Through Special Regions). When the inflammation occurs in or just under the skin

(Figure 335), it is characterized by redness, swelling, tenderness, and pain.

Elsewhere, it is a key component of asthma, ulcerative colitis, and many other

diseases.

Figu r e 3 35 .

Page 1 of 4



15/30

Evidence is accumulating that a transcription factor, n u cl ea r f ac t or - B , plays a key

role in the inflammatory response. NF- B is a heterodimer that normally exists in the

cytoplasm of cells bound to I B , which renders it inactive. Stimuli such as cytokines,

viruses, and oxidants separate NF- B from I B , which is then degraded. NF- B

moves to the nucleus, where it binds to the DNA of the genes for numerous

inflammatory mediators, resulting in their increased production and secretion.

Glucocorticoids inhibit the activation of NF- B by increasing the production of I B ,

and this is probably the main basis of their antiinflammatory action (see Chapter 20:

The Adrenal Medulla & Adrenal Cortex).

Sys tem ic Response to I n j u r y

Cytokines produced in response to inflammation and other injuries also produce

systemic responses. These include alterations in plasma acu t e phase p ro t e i ns ,

defined as proteins whose concentration is increased or decreased by at least 25%

following injury. Many of the proteins are of hepatic origin and are listed in Table 27

9. A number of them are shown in Figure 336. The causes of the changes in

concentration are incompletely understood, but it can be said that many of the

changes make homeostatic sense. Thus, for example, an increase in C-reactive

protein activates monocytes and causes further production of cytokines.

Cutaneous wound 3 days after injury, showing the multiple cytokines and growth factors

affecting the repair process. VEGF, vascular endothelial growth factor. For other

abbreviations, see Appendix. Note the epidermis growing down under the fibrin clot,

restoring skin continuity. (Modified from Singer AJ, Clark RAF: Cutaneous wound healing.

N Engl J Med 1999;341:738.)

Figu r e 3 36 .

Page 2 of 4



16/30

Other changes that occur in response to injury include somnolence, negative nitrogen

balance, and fever.

Wou nd Heal i ng

When tissue is damaged, platelets adhere to exposed matrix via integrins that bind to

collagen and laminin (Figure 335). Blood coagulation produces thrombin, whichpromotes platelet aggregation and granule release. The platelet granules generate an

inflammatory response. White blood cells are attracted by selectins and bind to

integrins on endothelial cells, leading to their extravasation through the blood vessel

walls. Cytokines released by the white blood cells and platelets up-regulate integrins

on macrophages, which migrate to the area of injury, and on fibroblasts and epithelial

cells, which mediate wound healing and scar formation. Plasmin aids healing by

removing excess fibrin. This aids the migration of keratinocytes into the wound to

restore the epithelium under the scab. Collagen proliferates, producing the scar.

Time course of changes in some major acute phase proteins. C3, C3 component of

complement. (Modified and reproduced with permission, from Gitlin JD, Colten HR:

Molecular biology of acute phase plasma proteins. In Pick F et al [editors]. Lymphokines,

vol 14, pages 123153. Academic Press, 1987.)

Page 3 of 4



17/30

Wounds gain 20% of their ultimate strength in 3 weeks and later gain more strength,

but they never reach more than about 70% of the strength of normal skin.

Page 4 of 4



18/30

SHOCK

Genera l Considerat ions

Shock is a syndrome about which there has been a great deal of confusion and controversy. Part of the difficulty lies

in the loose use of the term by physiologists and physicians as well as laymen. Electric shock and spinal shock, for

example, bear no relation to the condition produced by hemorrhage and related cardiovascular abnormalities. Shock

in the restricted sense of "circulatory shock" is still a collection of different entities that share certain common

features. However, the feature that is common to all the entities is inadequate tissue perfusion with a relatively orabsolutely inadequate cardiac output. The cardiac output may be inadequate because the amount of fluid in the

vascular system is inadequate to fill it ( h y p o v o l e m i c s h o c k ) . Alternatively, it may be inadequate in the relative

sense because the size of the vascular system is increased by vasodilation even though the blood volume is normal

(d is t r ibu t ive , vasogen ic , or l ow - res is tance shock ). Shock may also be caused by inadequate pumping action of

the heart as a result of myocardial abnormalities ( ca rd iogen ic shock) , and by inadequate cardiac output as a

result of obstruction of blood flow in the lungs or heart ( o b s t r u c t i v e s h o c k ) . These forms of shock are listed in

Table 333, along with examples of the disease processes that can cause them.

Hypovo lemic Shock

Hypovolemic shock is also called "cold shock." It is characterized by hypotension; a rapid, thready pulse; a cold,

pale, clammy skin; intense thirst; rapid respiration; and restlessness or, alternatively, torpor. None of these

findings, however, are invariably present. The hypotension may be relative. A hypertensive patient whose blood

pressure is regularly 240/140, for example, may be in severe shock when the blood pressure is 120/90.

Hypovolemic shock is commonly subdivided into categories on the basis of cause. The use of terms such as

"hemorrhagic shock," "traumatic shock," "surgical shock," and "burn shock" is of some benefit because, although

these various forms of shock have similarities, there are important features that are unique to each.

Hemorr hag ic Shock

It is useful to consider the effects of hemorrhage in some detail because they illustrate the features of a major form

of hypovolemic shock and the multiple compensatory reactions that come into play to defend ECF volume. The

principal reactions are listed in Table 334.

Table 333 . Types o f Shock , w i th Exam ples o f Condi t ions or D iseases That Can Cause

Each Typ e.

Hypovo lemic shock (decreased b lood vo lume)

Hemorrhage

Trauma

Surgery

Burns

Fluid loss due to vomiting or diarrhea

Dis t r ibu t ive shock (mar ked vasod i la t ion ; a lso ca l led vasogen ic o r low- res is tance shock)

Fainting (neurogenic shock)

Anaphylaxis

Sepsis (also causes hypovolemia due to increased capillary permeability with loss of fluid into tissues)

Card iogen ic shock ( inadequa t e ou tpu t by a d iseased hear t )

Myocardial infarction

Congestive heart failure

ArrhythmiasO b st r u c t i v e s h o c k ( o b s t r u c t i o n o f b l o o d f l o w )

Tension pneumothorax

Pulmonary embolism

Cardiac tumor

Cardiac tamponade

Page 1 of 6



19/30

The decline in blood volume produced by bleeding decreases venous return, and cardiac output falls. The heart rate

is increased, and with severe hemorrhage, a fall in blood pressure always occurs. With moderate hemorrhage (515

mL/kg body weight), pulse pressure is reduced but mean arterial pressure may be normal. The blood pressure

changes vary from individual to individual, even when exactly the same amount of blood is lost. The skin is cool and

pale and may have a grayish tinge because of stasis in the capillaries and a small amount of cyanosis. Respiration israpid, and in patients whose consciousness is not obtunded, intense thirst is a prominent symptom.

In hypovolemic and other forms of shock, the inadequate perfusion of the tissue leads to increased anaerobic

glycolysis, with the production of large amounts of lactic acid. In severe cases, the blood lactate level rises from the

normal value of about 1 mmol/L to 9 mmol/L or more. The resulting l ac t i c ac idos is depresses the myocardium,

decreases peripheral vascular responsiveness to catecholamines, and may be severe enough to cause coma.

Rapid Compensatory React ions

When blood volume is reduced and venous return is decreased, the arterial baroreceptors are stretched to a lesser

degree and sympathetic output is increased. Even if there is no drop in mean arterial pressure, the decrease in pulse

pressure decreases the rate of discharge in the arterial baroreceptors, and reflex tachycardia and vasoconstriction

result. It is interesting that with more severe blood loss, tachycardia is replaced by bradycardia; this occurs while

shock is still reversible (see below). With even greater hemorrhage, the heart rate rises again. The bradycardia is

presumably due to unmasking a vagally mediated depressor reflex, and the response may have evolved as a

mechanism for stopping further blood loss.

The vasoconstriction is generalized, sparing only the vessels of the brain and heart. The vasoconstrictor innervation

of the cerebral arterioles is probably insignificant from a functional point of view, and the coronary vessels are

dilated because of the increased myocardial metabolism secondary to the increase in heart rate (see Chapter 32:

Circulation Through Special Regions). Vasoconstriction is most marked in the skin, where it accounts for the

coolness and pallor, and in the kidneys and viscera.

Hemorrhage also evokes a widespread reflex venoconstriction that helps maintain the filling pressure of the heart,

although the receptors that initiate the venoconstriction are unsettled. The intense vasoconstriction in the splanchnic

area shifts blood from the visceral reservoir into the systemic circulation. Blood is also shifted out of the

subcutaneous and pulmonary veins. Contraction of the spleen discharges more "stored" blood into the circulation,

although the volume mobilized in this way in humans is small.

In the kidneys, both afferent and efferent arterioles are constricted, but the efferent vessels are constricted to a

greater degree. The glomerular filtration rate is depressed, but renal plasma flow is decreased to a greater extent,

so that the filtration fraction (glomerular filtration rate divided by renal plasma flow) increases. Na+ retention is

marked, and the nitrogenous products of metabolism are retained in the blood (a z o t e m i a or u r e m i a ). Especially

when the hypotension is prolonged, renal tubular damage may be severe ( a c u t e r e n a l f a i l u r e ) .

Hemorrhage is a potent stimulus to adrenal medullary secretion (see Chapter 20: The Adrenal Medulla & Adrenal

Cortex). Circulating norepinephrine is also increased because of the increased discharge of sympathetic

noradrenergic neurons. The increase in circulating catecholamines probably contributes relatively little to the

generalized vasoconstriction, but it may lead to stimulation of the reticular formation (see Chapter 11: Alert

Behavior, Sleep, & the Electrical Activity of the Brain). Possibly because of such reticular stimulation, some patients

in hemorrhagic shock are restless and apprehensive. Others are quiet and apathetic, and their sensorium is dulled,

probably because of cerebral ischemia and acidosis. When restlessness is present, increased motor activity and

T ab l e 334 . Comp ensa to ry React i ons A c t i va ted by Hemor r hage .

Vasoconstriction

Tachycardia

Venoconstriction

Tachypnea increased thoracic pumping

Restlessness increased skeletal muscle pumping (in some cases)

Increased movement of interstitial fluid into capillaries

Increased secretion of norepinephrine and epinephrine

Increased secretion of vasopressin

Increased secretion of glucocorticoids

Increased secretion of renin and aldosterone

Increased secretion of erythropoietin

Increased plasma protein synthesis

Page 2 of 6



20/30

increased respiratory movements increase the muscular and thoracic pumping of venous blood.

The loss of red cells decreases the O2-carrying power of the blood, and the blood flow in the carotid and aortic

bodies is reduced. The resultant anemia and stagnant hypoxia (see Chapter 37: Respiratory Adjustments in Health &

Disease), as well as the acidosis, stimulate the chemoreceptors. Increased activity in chemoreceptor afferents is

probably the main cause of respiratory stimulation in shock. Chemoreceptor activity also excites the vasomotor

areas in the medulla, increasing vasoconstrictor discharge. In fact, in hemorrhaged dogs with arterial pressures of

less than 70 mm Hg, cutting the nerves to the carotid baroreceptors and chemoreceptors may cause a further fall in

blood pressure rather than a rise. This paradoxic result occurs because no baroreceptor discharge takes place at

pressures below 70 mm Hg, and activity in fibers from the carotid chemoreceptors is driving the vasomotor area

beyond the maximal rate produced by release of baroreceptor inhibition.

The increase in the level of circulating angiotensin II produced by the increase in plasma renin activity during

hemorrhage causes thirst by an action on the subfornical organ (see Chapter 32: Circulation Through Special

Regions), and ingestion of fluid helps restore the ECF volume. The increase in angiotensin II also helps to maintain

blood pressure. The blood pressure fall produced by removal of a given volume of blood is greater in animals infused

with drugs that block angiotensin II receptors than it is in controls. Vasopressin also raises blood pressure when

administered in large doses in normal animals, but infusion of doses that produce the same plasma vasopressin

levels produced by hemorrhage causes only a small increase in blood pressure because a compensatory decrease in

cardiac output occurs (see Chapter 31: Cardiovascular Regulatory Mechanisms). However, blood pressure falls when

peptides that antagonize the effects of vasopressin are injected following hemorrhage. Thus, it appears that

vasopressin also plays a significant role in maintaining blood pressure. The increases in circulating angiotensin II

and ACTH levels increase aldosterone secretion, and the increased circulating levels of aldosterone and vasopressin

cause retention of Na+ and water, which helps reexpand the blood volume. However, aldosterone takes about 30

minutes to exert its effect, and the initial decline in urine volume and Na+ excretion is certainly due for the most

part to the hemodynamic alterations in the kidney.

When the arterioles constrict and the venous pressure falls because of the decrease in blood volume, a drop in

capillary pressure takes place. Fluid moves into the capillaries along most of their course, helping to maintain the

circulating blood volume. This decreases interstitial fluid volume, and fluid moves out of the cells.

Long-Term Compensa to r y React ions

After a moderate hemorrhage, the circulating plasma volume is restored in 1272 hours (Figure 337). Preformed

albumin also enters rapidly from extravascular stores, but most of the tissue fluids that are mobilized are protein-

free. They dilute the plasma proteins and cells, but when whole blood is lost, the hematocrit may not fall for several

hours after the onset of bleeding. After the initial influx of preformed albumin, the rest of the plasma protein losses

are replaced, presumably by hepatic synthesis, over a period of 34 days. Erythropoietin appears in the circulation,

and the reticulocyte count increases, reaching a peak in 10 days. The red cell mass is restored to normal in 48

weeks. However, a low hematocrit is remarkably well tolerated because of various compensatory mechanisms. One

of these is an increase in the concentration of 2,3-BPG in the red blood cells, which causes hemoglobin to give more

O2 to the tissues (see Chapter 27: Circulating Body Fluids). In long-standing anemia in otherwise healthy

individuals, exertional dyspnea is not observed until the hemoglobin concentration is about 7.5 g/dL. Weakness

becomes appreciable at about 6 g/dL; dyspnea at rest appears at about 3 g/dL; and the heart fails when the

hemoglobin level falls to 2 g/dL.

Fi gu re 337 .

Changes in red cell volume (dark color), plasma volume (light color), and total plasma protein following hemorrhage in a

Page 3 of 6



21/30

Refractory Shock

Depending largely on the amount of blood lost, some patients die soon after hemorrhage and others recover as the

compensatory mechanisms, aided by appropriate treatment, gradually restore the circulation to normal. In an

intermediate group of patients, shock persists for hours and gradually progresses to a state in which no response to

vasopressor drugs takes place and in which, even if the blood volume is returned to normal, cardiac output remains

depressed. This is known as r e f r a c t o r y s h o c k . The condition is not unique to hemorrhagic shock but occurs in

other forms as well. It used to be called i r revers ib le shock , and patients still do die despite vigorous treatment.

However, more and more patients are saved as understanding of the pathophysiologic mechanisms increases and

treatment improves. Therefore, refractory shock seems to be a more appropriate term.

Various positive feedback mechanisms contribute to the production of refractory shock. For example, severe

cerebral ischemia leads eventually to depression of the vasomotor and cardiac areas of the brain, causing

vasodilation and reduction of the heart rate. These both make the blood pressure drop further, with a further

reduction in cerebral blood flow and further depression of the vasomotor and cardiac areas.

Another important example of this type of positive feedback is myocardial depression. In severe shock, the coronary

blood flow is reduced because of the hypotension and tachycardia (see Chapter 32: Circulation Through Special

Regions), even though the coronary vessels are dilated. The myocardial failure makes the shock and the acidosis

worse, and this in turn leads to further depression of myocardial function. If the reduction is marked and prolonged,

the myocardium may be damaged to the point where cardiac output cannot be restored to normal in spite of

reexpansion of the blood volume.A late complication of shock that can be fatal is pulmonary damage with the production ofacu te resp i ra to ry

d i s t r e s s s y n d r o m e (ARDS, adu l t resp i ra to ry d is t r ess syndrom e; see Chapter 37: Respiratory Adjustments in

Health & Disease). This syndrome is characterized by acute respiratory failure with a high mortality, and it can be

triggered not only by shock but also by sepsis, lung contusion, other forms of trauma, and other serious conditions.

The common feature seems to be damage to capillary endothelial cells and alveolar epithelial cells, with release of

cytokines.

Other Forms o f Hypovo lemic Shock

Traumat ic shock develops when muscle and bone are severely damaged. This is the type of shock seen in battle

casualties and automobile accident victims. Frank bleeding into the injured areas is the principal cause of the shock,

although some plasma also enters the tissue. The amount of blood which can be lost into an injury that appears

relatively minor is remarkable; the thigh muscles can accommodate 1 L of extravasated blood, for example, with an

increase in the diameter of the thigh of only 1 cm.Breakdown of skeletal muscle ( r h a b d o m y o l y s i s ) is a serious additional problem when shock is accompanied by

extensive muscle crushing ( c r u s h s y n d r o m e ) . Kidney damage is also common in the crush syndrome. It is due to

accumulation of myoglobin and other products from reperfused tissue in kidneys in which glomerular filtration is

already reduced by shock. The products damage and clog the tubules, frequently causing anuria, which may be

fatal.

Surg ica l shock is due to the combination in various proportions of external hemorrhage, bleeding into injured

tissues, and dehydration.

In b u r n s h o c k , the most apparent abnormality is loss of plasma as exudate from the burned surfaces. Since the

loss in this situation is plasma rather than whole blood, the hematocrit rises and h e m o c o n c e n t r a t i o n is a

prominent finding. Burns also cause complex, poorly understood metabolic changes in addition to fluid loss. For

example, the metabolic rate of nonthyroidal origin rises by 50%, and some burned patients develop hemolytic

anemia. Because of these complications, plus the severity of the shock and the problems of sepsis and kidney

damage, the mortality rate when third-degree burns cover more than 75% of the body is still close to 100%.Hypovolemic shock is a complication of various metabolic and infectious diseases. For example, although the

mechanism is different in each case, adrenal insufficiency, diabetic ketoacidosis, and severe diarrhea are all

characterized by loss of Na+ from the circulation. The resultant decline in plasma volume may be severe enough to

precipitate cardiovascular collapse.

Dis t r ibu t i ve Shock

As noted above, distributive shock occurs when the blood volume is normal but the capacity of the circulation is

increased by marked vasodilation. It is also called "warm shock" because the skin is not cold and clammy, as it is in

hypovolemic shock. A good example is anaphy lac t ic shock , a rapidly developing, severe allergic reaction that

normal human subject.

Page 4 of 6



22/30

sometimes occurs when an individual who has previously been sensitized to an antigen is reexposed to it. The

resultant antigenantibody reaction releases large quantities of histamine, causing increased capillary permeability

and widespread dilation of arterioles and capillaries.

Sept ic Shock

Septic shock is a common and serious condition in which infections, usually due to gram-negative bacteria, cause

shock which has both distributive and hypovolemic features. Endotox ins , the cell wall lipopolysaccharides produced

by some bacteria, cause vasodilation and increased capillary permeability, with loss of plasma in the tissues. Theyalso initiate a complex series of cytokine and coagulant reactions that can lead eventually to multiple organ failure.

The mortality of the condition is 3050%, and numerous drugs designed to inhibit the inflammatory response,

including glucocorticoids have failed to lower this figure. However, promising results have been obtained with

ac t iva ted p ro t e in C, which has anticoagulant activity (see Chapter 27: Circulating Body Fluids).

Fa in t ing

A third type of distributive shock is neurogenic shock, in which a sudden burst of autonomic activity produces

vasodilation, pooling of blood in the extremities, and fainting. These are called vasovagal attacks, and they are

short-lived and benign. Other forms of syncope include pos tu ra l syncope , fainting due to pooling of blood in the

dependent parts of the body on standing. Mic tu r i t ion syncope , fainting during urination, occurs in patients with

orthostatic hypotension. It is due to the combination of the orthostasis and reflex bradycardia induced by voiding in

these patients. Pressure on the carotid sinus, produced, for example, by a tight collar, can cause such marked

bradycardia and vasodilation that fainting results ( ca ro t id s inus syncope) . Rarely, vasodilation and bradycardia

may be precipitated by swallowing (deg lu t i t ion syncope) . Cough syncope occurs when the increase in

intrathoracic pressure during straining or coughing is sufficient to block venous return. Ef fo r t syncope is fainting on

exertion as a result of inability to increase cardiac output to meet the increased demands of the tissues and is

particularly common in patients with aortic or pulmonary stenosis.

Syncope can also be due to more serious abnormalities. About 25% of syncopal episodes are of cardiac origin and

are due to either transient obstruction of blood flow through the heart or sudden decreases in cardiac output owing

to various cardiac arrhythmias. Fainting due to bradycardia, heart block, or sinus arrest is called neurocard iogen ic

syncope . In addition, fainting is the presenting symptom in 7% of patients with myocardial infarctions. Thus, all

cases of syncope should be investigated to determine the cause.

Card iogenic & Obstruct ive Shock

When the pumping function of the heart is impaired to the point that blood flow to the tissues is no longer adequate

to meet resting metabolic demands, the condition that results is called cardiogenic shock. It is most commonly dueto extensive infarction of the left ventricle, but it can also be caused by other diseases that severely compromise

ventricular function. The symptoms are those of shock plus congestion of the lungs and viscera because the heart

fails to put out all the venous blood returned to it. Consequently, the condition is sometimes called "congested

shock." The incidence of this shock in patients with myocardial infarction is about 10%, and it has a mortality of 60

90%.

The picture of congested shock is also seen in obstructive shock. When the obstruction is due to tension

pneumothorax with kinking of the great veins (see Chapter 37: Respiratory Adjustments in Health & Disease) or

bleeding into the pericardium with external pressure on the heart ( c a r d i a c t a m p o n a d e ) , prompt surgical

intervention is required to prevent death.

Trea tmen t o f Shock

The treatment of shock should be aimed at correcting the cause and helping the physiologic compensatory

mechanisms to restore an adequate level of tissue perfusion. In hemorrhagic, traumatic, and surgical shock, forexample, the primary cause of the shock is blood loss, and the treatment should include early and rapid transfusion

of adequate amounts of compatible whole blood. Saline is of limited temporary value. The immediate goal is

restoration of an adequate circulating blood volume, and since saline is distributed in the ECF, only 25% of the

amount administered stays in the vascular system. In burn shock and other conditions in which there is

hemoconcentration, plasma is the treatment of choice to restore the fundamental defect, the loss of plasma.

"Plasma expanders," solutions of sugars of high molecular weight and related substances that do not cross capillary

walls, have some merit. Concentrated human serum albumin and other hypertonic solutions expand the blood

volume by drawing fluid out of the interstitial spaces. They are valuable in emergency treatment but have the

disadvantage of further dehydrating the tissues of an already dehydrated patient.

In anaphylactic shock, epinephrine has a highly beneficial and almost specific effect that must represent more than

Page 5 of 6



23/30

just constriction of the dilated vessels.

Page 6 of 6



24/30

HYPERTENSI ON

Hyper t ens i on is a sustained elevation of the systemic arterial pressure. Pu l m ona ry

hype r t ens i on also occurs, but the pressure in the pulmonary artery (see Chapter

34: Pulmonary Function) is relatively independent of that in the systemic arteries.

Exper im enta l Hyper tens ion

The arterial pressure is determined by the cardiac output and the peripheral

resistance (pressure = flow x resistance; see Chapter 30: Dynamics of Blood &

Lymph Flow). The peripheral resistance is determined by the viscosity of the blood

and, more importantly, by the caliber of the resistance vessels. Hypertension can be

produced by elevating the cardiac output, but sustained hypertension is usually due

to increased peripheral resistance. Some of the procedures that have been reported

to produce sustained hypertension in experimental animals are listed in Table 335.

For the most part, the procedures involve manipulation of the kidneys, the nervous

system, or the adrenals. In addition a number of strains of rats develop hypertension

either spontaneously (SHR rats) or when fed a high-sodium diet (Dahl salt-sensitive

rats).

Tab le 33 5 . P rocedures Tha t P roduce Sus ta ined Hyp er tens ion in

Exper imenta l An ima ls .

I n t e r f e r en c e w i t h r e n a l b l oo d f l o w ( r e n a l h y p e r t e n si o n )

Constriction of one renal artery; other kidney removed (one-clip, one-kidney

Goldblatt hypertension)

Constriction of one renal artery; other kidney intact (one-clip, two-kidneyGoldblatt hypertension)

Constriction of aorta or both renal arteries (two-clip, two-kidney Goldblatt

hypertension)

Compression of kidney by rubber capsules, production of perinephritis, etc

I n t e r r up t i ons o f a f f e ren t i npu t f r om a r t e r i a l ba ro recep t o rs (neu rogen i c

hype r t ens i on )

Denervation of carotid sinuses and aortic arch

Bilateral lesions of nucleus of tractus solitarius

T reat m en t w i t h co r t i cost e ro i ds

Deoxycorticosterone and salt

Other mineralocorticoids

Par t i a l ad rena lect om y ( ad rena l r egene ra t i on hype r t ens i on )

Genet i c

Spontaneous hypertension in various strains of rats

Salt-induced hypertension in genetically sensitive rats

Page 1 of 4



25/30

The hypertension that follows constriction of the renal arterial blood supply or

compression of the kidney is called rena l hype r t ens i on . As noted in Chapter 24:

Endocrine Functions of the Kidneys, Heart, & Pineal Gland, some animals with renalhypertension have elevated plasma renin activity, whereas others do not. In general,

one-clip, two-kidney Goldblatt hypertension (Table 335) is renin-dependent,

whereas one-clip, one-kidney Goldblatt hypertension is not. An additional factor that

probably contributes to renal hypertension is decreased ability of the constricted

kidney to excrete Na+.

Neurogenic hypertension is discussed in Chapter 31: Cardiovascular Regulatory

Mechanisms. Provided that salt intake is normal or high, deoxycorticosterone causes

hypertension which may persist after treatment is stopped. The hypertension is more

severe in unilaterally nephrectomized animals.

H y per t ens i on i n H um ans

Hypertension is a very common abnormality in humans. It can be produced by many

diseases (Table 336). It causes a number of serious disorders. When the resistance

against which the left ventricle must pump (afterload) is elevated for a long period,

the cardiac muscle hypertrophies. The initial response is activation of immediate-

early genes in the ventricular muscle, followed by activation of a series of genes

involved in growth during fetal life. Left ventricular hypertrophy is associated with a

poor prognosis. The total O2

consumption of the heart, already increased by the

work of expelling blood against a raised pressure (see Chapter 29: The Heart As a

Pump), is increased further because there is more muscle. Therefore, any decreasein coronary blood flow has more serious consequences in hypertensive patients than

it does in normal individuals, and degrees of coronary narrowing that do not produce

symptoms when the size of the heart is normal may produce myocardial infarction

when the heart is enlarged. The incidence of atherosclerosis increases in

hypertension, and myocardial infarcts are common even when the heart is not

enlarged. Eventually, the ability to compensate for the high peripheral resistance is

exceeded, and the heart fails. Hypertensive individuals are also predisposed to

thromboses of cerebral vessels and cerebral hemorrhage. An additional complication

is renal failure. However, the incidence of heart failure, strokes, and renal failure can

be markedly reduced by active treatment of hypertension, even when the

hypertension is relatively mild.

Endothelial NOS gene knockout in mice

Various types of transgenic animals

Tab le 33 6 . Es t im ated F requency o f Var ious Forms o f

Hyper t ens ion in t he Genera l Hyper tens ive Popu la t ion .

Percen t age o f

Popu la t i on

Essential hypertension 88

Page 2 of 4



26/30

Mal ignan t Hyper tens ion

Chronic hypertension can enter an accelerated phase in which necrotic arteriolar

lesions develop and there is a rapid downhill course with papilledema, cerebral

symptoms, and progressive renal failure. This syndrome is known as m al i gnan t

hype r t ens i on , and without treatment it is fatal in less than 2 years. However, its

progression can be stopped, and it can be reversed by appropriate antihypertensive

therapy.

Essent ia l Hyper ten s ion

In about 88% of patients with elevated blood pressure, the cause of the

hypertension is unknown, and they are said to have essen t i a l hype r t ens i on .

At present, essential hypertension is treatable but not curable. Effective lowering of

the blood pressure can be produced by drugs that block -adrenergic receptors,

either in the periphery or in the central nervous system; drugs that block -

adrenergic receptors; drugs that inhibit the activity of angiotensin-converting

enzyme; and calcium channel blockers that relax vascular smooth muscle.

Essential hypertension is probably polygenic in origin, and environmental factors are

also involved.

Other Form s o f Hyper t ens ion

In other, less common forms of hypertension, the cause is known. A review of these

is helpful because it emphasizes ways disordered physiology can lead to disease.

Pathology that compromises the renal blood supply leads to rena l hype r t ens i on . So

does narrowing (coa rc t a t i on) of the thoracic aorta, which both increases renin

secreation and increases peripheral resistance. Pheoch rom ocy t om as , adrenal

Renal hypertension

Renovascular 2

Parenchymal 3

Endocrine hypertension

Primary aldosteronism 5

Cushing's syndrome 0.1

Pheochromocytoma 0.1

Other adrenal forms 0.2

Estrogen treatment ("pill hypertension") 1

Miscellaneous (Liddle's syndrome, coarctation of

the aorta, etc)0.6

Reproduced, with permission, from McPhee SJ, Lingappa V, Ganong WF.

Pathophysiology of Disease, 4th ed. McGraw-Hill, 2003.

Page 3 of 4



27/30

medullary tumors that secrete norepinephrine and epinephrine, can cause sporadic

or sustained hypertension (see Chapter 20: The Adrenal Medulla & Adrenal Cortex).

Estrogens increase angiotensinogen secretion, and contraceptive pills containing

large amounts of estrogen cause hypertension (p i l l hype r t ens i on ) on this basis

(see Chapter 24: Endocrine Functions of the Kidneys, Heart, & Pineal Gland).

Increased secretion of aldosterone or other mineralocorticoids causes renal Na+

retention, which leads to hypertension. A primary increase in plasma

mineralocorticoids inhibits renin secretion. For unknown reasons, plasma renin is also

low in 1015% of patients with essential hypertension and normal circulating

mineralocortical levels (l ow ren i n hype r t ens i on ).

Mutations in a number of single genes are known to cause hypertension. These cases

ofm on ogen i c hype r t ens i on are rare, but informative. One of these is

g l ucoco r t i co i d - rem ed iab l e a l dos t e ren i sm (GRA), in which a hybrid gene encodes

an ACTH-sensitive aldosterone synthase, with resulting hyperaldosterenism (see

Chapter 20: The Adrenal Medulla & Adrenal Cortex). El ev e n- h y d r ox y l as e

def i c iency also causes hypertension by increasing the secretion of

deoxycorticosterone (see Chapter 20: The Adrenal Medulla & Adrenal Cortex).

Normal blood pressure is restored when ACTH secretion is inhibited by administering

a gluccocorticoid. Mutations that decrease 1 1 - h y d r ox y s t er o id d eh y d r og en a se

cause loss of specificity of the mineralocorticoid receptors (see Chapter 20: The

Adrenal Medulla & Adrenal Cortex) with stimulation of them by cortisol and in

pregnancy, by the elevated circulation levels of progesterone.

Finally, mutations of the genes for ENaCs that disrupt their or subunits increase

ENaC activity and lead to excess renal Na+ retention and hypertension (L idd le 's

s y n d r o m e; see Chapter 38: Renal Function & Micturition).

Page 4 of 4



28/30

HEART FAI LURE

Pathogenes is

Heart failure occurs when the heart is unable to put out an amount of blood that is

adequate for the needs of the tissues. It can be acute and associated with sudden

death, or chronic. The failure may involve primarily the right ventricle (cor

pulmonale), but much more commonly it involves the larger, thicker left ventricle or

both ventricles.

In ch ron i c hea r t f a i l u re ( conges t i ve hear t f a i l u re ) , cardiac output is initially

inadequate during exercise but adequate at rest (Figure 338). As the disease

progresses, the output at rest also becomes inadequate. There are two types of

failure, systolic and diastolic. In systo l i c fa i l u re , stroke volume is reduced because

ventricular contraction is weak. This causes an increase in the end-systolic

ventricular volume, so that the e j ec t i on f r ac t i on the fraction of the blood in the

ventricle that is ejected during systolefalls from 65% to as low as 20%. The initial

response to failure is activation of the genes that cause cardiac myocytes tohypertrophy, and thicken of the ventricular wall (ca rd i ac rem ode l i ng). The

incomplete filling of the arterial system leads to increased discharge of the

sympathetic nervous system and increased secretion of renin and aldosterone, so

Na+ and water are retained. These responses are initially compensatory, but

eventually the failure worsens and the ventricales dilate.

Figu r e 3 38 .

Decreased cardiac output in congestive heart failure. R, rest; E, maximal exercise. Note

that with moderate failure, resting cardiac output is normal and only the portion going to

skeletal muscle during exercise is reduced. As failure progresses, resting cardiac output

is also reduced. (Modified and reproduced, with permission, from Zelis R et al:

Page 1 of 3



29/30

In d ias to l i c fa i l u re , the ejection fraction is initially maintained but the elasticity of

the myocardium is reduced so filling during diastole is reduced. This leads to

inadequate stroke volume and the same cardiac remodeling and Na+ and water

retention that occur in systolic failure.

It should be noted that the inadequate cardiac output in failure may be relative

rather than absolute. When a large arterior venous fistula is present, in

thyrotoxicosis, and in thiamine deficiency, cardiac output may be elevated in

absolute terms but still be inadequate to meet the needs of the tissues (h i g h - o u t p u t

f a i l u re).

The principal symptoms and signs of congestive failure include cardiac enlargement

and the symptoms and signs listed in Table 337.

T rea t m en t

Treatment of congestive heart failure is aimed at improving cardiac contractility,

treating the symptoms, and decreasing the load on the heart. Currently, the most

effective treatment in general use is inhibition of the production of angiotensin II

with angiotensin-converting enzyme inhibitors. Blockade of the effects of angiotensin

II on AT1

receptors with nonpeptide antagonists is also of value. Angiotensin II

Vasoconstrictor mechanisms in congestive heart failure, Part I. Mod Concepts Cardiovasc

Dis 1989;58:7. By permission of the American Heart Association, Inc.)

Tab le 337 . Sim p l i f i ed Sum m ary o f Pa thogenes is o f Ma jo r

Find ing s in Cong est ive Hear t Fa i lure .

A bno rma l i t y Cause

Weakness, exercise

intolerance, fatigueLeft ventricle; output inadequate to perfuse muscles;

especially, failure of output to rise with exercise.

Ankle, sacral edema Increased peripheral venous pressure increased fluidtransudation.

Hepatomegaly Increased peripheral venous pressure increased resistanceto portal flow.

Pulmonary congestion Increased pulmonary venous pressure pulmonary venousdistention and transudation of fluid into air spaces.

Dyspnea on exertion Failure of left ventricular output to rise during exerciseincreased pulmonary venous pressure.

Paroxysmal dyspnea,

pulmonary edemaProbably sudden failure of left heart output to keep up with

right heart output acute rise in pulmonary venous andcapillary pressure transudation of fluid into air spaces.

Orthopnea Normal pooling of blood in lungs in supine position added toalready congested pulmonary vascular system; increased

venous return not put out by left ventricle. (Relieved by

sitting up, raising head of bed, lying on extra pillows.)

Cardiac dilation Greater ventricular end-diastolic volume.

Page 2 of 3



30/30

appears to have direct effects on the heart, although these are controversial.

Blocking the production of angiotensin II or its effects also reduces the circulating

aldosterone level and decreases blood pressure, reducing the afterload against which

the heart pumps. The effects of aldosterone can be further reduced by administering

aldosterone receptor blockers, and these have shown promise in recent trials.

Reducing venous tone with nitrates or hydralazine increases venous capacity so that

the amount of blood returned to the heart is reduced, lowering the preload. Diuretics

reduce the fluid overload. Drugs that block -adrenergic receptors have been shown

to decrease mortality and morbidity. Digitalis derivatives such as digoxin have

classically been used to treat congestive failure because of their ability to increase

intra-cellular Ca2+ and hence exert a positively inotropic effect (see Chapter 3:

Excitable Tissue: Muscle), but they are now used in a secondary role to treat systolic

dysfunction and slow the ventricular rate in patients with atrial fibrillation (see

Chapter 28: Origin of the Heartbeat & the Electrical Activity of the Heart).

Page 3 of 3

ganong wf. cardiovascular homeostasis in health and disease

Documents