REGULATION OF CVS

BY

DOCTOROID

INTRODUCTION : A) FUNCTIONS OF CVS :• I) Primary >(i) Distribution to tissues(ii) Collection from tissues & carry to ex. organs

• II) Secondary > Contribution in ---

(i)Thermoregulation(ii) Compartmental balance of body-fluids

B) NEED FOR CARDIOVASCULAR REGULATION:• (i) Increase blood supply to active tissues• (ii) Redistribution of blood to ↓/↑ heat loss• (iii) Make circulatory adjustments during

routine CV stresses• (iv) Maintenance of adequate blood flow to

the vital organs (BHK) , all the times including emergencies even at the expense of circulation to rest of the body

C) CV REG.MECHS MEET THESE REQUIREMENTS PRIMARILY BY CONTROLLING FOLLOWING PARAMETERS:• I) Cardiac Performance > by altering CO ,in terms of one or more of the 4

tropic (chrono-, ino-, dromo-, bathmo-) actions• II) Vascular Performance> by altering---(i)Diameter of resistance vessels thus Cap.

Hydrostatic Pressure(ii)Blood storage in capacitance vessels thus

venous return

D) DIVISION OF CARDIOVASCULAR REGULATORY MECHANISMS: 3 arbitrary groups --• I) Neural Control Mechanisms• II) Humoral Control Mechanisms• III) Local Control Mechanisms

These are integrated & inter-dependent.

I) NEURAL CONTROL MECHS. : systemic regulation – respond within

seconds Consists of 3 components :• A) Autonomic Innervation of CVS• B) Medullary Cardiovascular Control

Centres• C) Afferent Impulses to Medullary

Cardiovascular Control Centres

A) Autonomic Innervation of CVS: 1) Autonomic Innervation of Heart : SYMPATHETIC SUPPLY:Spinal Sympathetic Centre >> formed by neurons in IML horn of T1 - L2 can spontaneously generate impulses even if

higher centre-control is cut-off. Sympathetic Preganglionic Fibres >>IML of T1-T5 Symp. Trunk (to 3 cervical

ganglia)

Sympathetic Postganglionic Fibres >>leave ganglia via 3 cardiac symp. Nerves

supply nodal tissues & muscles release NAd Epicardial Differential distribution of Rt. & Lt. side Effects of Symp. Stimulation >> all 4 +ve tropic effects. “cardio-acceleratory centre”

PARASYMPATHETIC SUPPLY:Parasympathetic Preganglionic Fibres >>Medulla(NA , DNV & NTS) travel along vagi

through their cardiac branches synapse in ganglia(in both cardiac plexus)

Parasympathetic Postganglionic Fibres >>leave ganglia supply release Ach Endocardial & Diff. distribution Effects of Parasymp. Stimulation >> all –ve but Ino- & Bathmo- in atria only Normally vagal tone is predominant

AUTONOMIC INNERVATION OF HEART

2) Autonomic Innervation of Blood Vessels : Vasomotor tone & control Acc. to the effects produced, 2 sets of nerves – VASOCONSTRICTORS : Symp. Vasoconstrictor Fibres – most imp. Thoracolumbar (T1-L2) outflow Symp. Trunk

spinal nerves supplying blood vessels Nad & sometimes Neuropeptide Y Adrenergic show tonic discharge @ 1-2 impulse/sec aka

‘sympathetic tone’ checked by VMC in medulla

Result of Stimulation of symp.vasoconstrictors--

(a) Vasoconstriction ↑ PR ↑ DBP(b) Venoconstriction ↓ venous capacity ↑

venous return ↑EDV ↑CO ↑SBP When symp.stimulation is cut-off (e.g.) opposite

effects in most tissues by ↓ / ≠ of symp.tone

Influence of adrenergic symp. vasoconstrictors is on almost all of the vascular system, except—

(a) Cerebral & coronary blood vessels(b) true capillaries

VASODILATORS : Symp. Cholinergic Vasodilator Fibres >>

Additional supply to the vessels of some organs (sk.muscles, heart, kidney, uterus, lungs etc)

NT released – Ach & sometimes VIP cerebral cortex relay in Ant. Hypothalamus &

midbrain reach spinal symp. Centre Not tonically active get activated only during

biologically stressful situations (e.g. syncope during intense emotional conditions)

Parasymp. Vasodilator Fibres >> come through cranio-sacral outflow of ANS supply blood vessels of salivary glands, GI glands,

Ext.genitalia, anal canal etc. NT released – Ach, Vaso-inhibitory Peptide (VIP) not tonically active activation only contributes to

pleasure & fulfilling imp. biological funtions

Vasodilators acting via Axon Reflex >>

Stimulation of skin in a particular area afferent impulses are conducted antidromically through collaterals(supplying blood vessels of adjacent

area) release of Substance P ,Ach & histamine-like substances local cutaneous vasodilatation & ↑capillary permeability.

B) Medullary CV Control Centres:• 1) VASOMOTOR CENTRE: ‘Medullary Sympathetic Centre’Groups of neurons situated b/l in reticular sub. of

medulla @ the floor of 4th ventricle– constituted by 2 diff. areas with some anatomical overlapping

Pressor Area>> in RVLM – glutaminergic neuronsAlways activetonic excitatory drive to ‘spinal

symp.centre’ Ж stimulation ↑symp.activity Depressor Area>> in CVLM stimulation inhibition of tonically discharging

impulses by Pressor area ↓ symp.activity

MEDULLARY SYMPATHETIC

NEURONS NTS

CVLM

RVLM

IML grey column

Bulbospinal pathway

Preganglionic symp.fibres

• 2) CARDIAC VAGAL CENTRE (CVC):‘Medullary Parasympathetic Centre’ ¤ “CIC”(DMN + NA) neurons not tonically activeReceive afferents via NTS & send inhibitory

pathways in the form of ‘vagi’ to the heart

• 3) MEDULLARY RELAY STATION : NTS receives most cardio-respiratory afferents

relays to VMC & CVC also inhibits VMC via local inhibitory interneuronsStimulation↓symp. & ↑parasymp. activities

ARRANGEMENT OF MEDULLARY PARASYMPATHETIC NEURONS

C) Afferent Impulses to Medullary Cardiovascular Control Centres

• 1) FROM HIGHER CENTRES :

CEREBRAL CORTEX :descending tracts from limbic cortex to VMC –that

relay into hypothalamus Examples of such influence— during sudden emotional shock in anticipation of flight or physical defence

HYPOTHALAMUS : integrate many somatic & autonomic responses. e.g. Temp. Changes effect on cutaneous vessels Emotional Stresses effect on HR & CO

• 2) FROM RESPIRATORY CENTRES :Effect on CVC change in vagal tone alterations

in HR ≈ ‘Sinus Arrhyrthmia’ @ forced breathing during Inspiration ↑ HRduring expiration ↓ HR

3) FROM NOCICEPTIVE STIMULI : Afferents carrying pain sensations affect VMC – Somatic pain (unmyelinated C) Pressor effectVisceral pain (thin myelinated) Depressor effect

4) DIRECTLY ACTING ON VMC : locally produced hypoxia & hypercapnia ~ max.

excitation of VMC strong symp.stimulation. e.g.- CNS ischaemic response (when BP<60 mm

hg)--last corrective attempt before irreversible shock Cushing Reflex (when ↑ICP)—f/b reflex ↓HR

• 5) CARDIOVASCULAR REFLEX MECHS: a group of imp. Short term mechs, swiftly operating

to maintain the BP within a physiological range—

BARORECEPTOR REFLEX : Baroreceptors > stretch-sensitive ,spray type

nerve endings in walls of heart & blood vessels2 Functional types – High pressure & Low pressure2 Anatomical types– Arterial & Cardiac Innervation – Carotid (by Hering’s nerve ∞ CN IX) &

all others (by CN X)

o Reflex Response > first,foremost & life-saving ↑BP distension of locating stuctures activation

of baroreceptors ↑firing of IX & X excitation of NTS 2 projections (i)inhibitory effect on VMC(↓symp.) & (ii) stimulatory effect on CVC (↑parasymp.) ↓HR, ↓CO, ↓PR ↓BP

BP Range > ~ 50 -200 (linear relation @ ~ 70 -140) Normal BP levels > baro-afferents discharge @low

rates even a slight BP change marked increase Response-type > both to change of PP & MAP More to rapid change than a sustained changeResetting—no role in long-term regulation of BP

CARDIOPULMONARY STRETCH REFLEX:↑ECF volume ↑pressure in the low-pressure areas

of circulation sensed by CP-stretch receptors elicit reflexes parallel to those of high-pressure receptors (baro-reflex)more potent control of BP

VOLUME REFLEX:Vol. overload activation of atrial stretch receptors- reflex dilatation of glom.afferent arterioles↑GFR signal to hypothal. ↓ADH↓water reabsorpn. ANP release ↑diuresis 3 combined effects indirectly@‘Pressure controller’

CHEMORECEPTOR REFLEX : Peripheral > Carotid(via IX) & Aortic(via X) bodies Chemosensitive to > ↓PO2, ↑PCO2, ↓pH of bloodAfferents Projection > medullary resp. & CV centresStimulation has 2 phase effects---1⁰ & 2⁰ stimulation of CIC & VMC↓HR & ↑PR ‘initial hypoxia’-induced Pul.hyperventilation &

↑catechol. release from ad.medulla ↑HR Net Effect –no change/slight ↑HR & ↑PR ↑BP BP Range of operation 40-70 mm Hg

CORONARY CHEMOREFLEX :Inj. Of chemicals(serotonin,capsaicin)into

Coronary arteries supplying lt.ventricle stimulation of ventricular stretch receptors(with vagal afferents) reflex apnoea f/b hyperventilation , ↓HR & ↓BP

aka “Bezold-Jarisch reflex”Uncertain physiological significance ---

persistent hypotension in some AMI patients

BAINBRIDGE REFLEX :Rapid infusion of saline/blood(with initially

low HR)↑atrial filling activation of TPAR (at veno-atrial jn.)tachycardia competes with the ↓HR by baroreceptor reflex d/t volume expansion

response abolished following vagotomy mediated by vagi

2)HUMORAL CONTROL MECHS. : Consists of 2 components :A)By Circulating VasodilatorsB)BY Circulating Vasoconstrictors

A) VASODILATORS:(a)KININS >> 2 physiologically imp. forms—(i)Bradykinin nonapeptide – in plasma(ii)Lysyl-bradykinin decapeptide – in body tissuesFormed from ‘Kininogens’(circulating α-2 globulin)

by action of proteolytic enzymes ‘Kallikreins’.M/A relaxes VSM via NO regulate blood flow

esp. in skin,salivary glands & GI glands.

(b) ATRIAL NATRIURETIC PEPTIDE >> ↑venous return ↑atrial filling stretchANP

release from atrial myocytes produce natriuresis & vasodilatation ↓BP

(c) ADRENOMEDULIN >>from Adrenal medulla first discovered from

Pheochromocytoma cells ↓BP by ---(i) Vasodilatation d/t ↑NO synthesis(i) Inhibit Aldosterone secretion

B) VASOCONSTRICTORS:(a) CATECHOLAMINES >>Released on sympathetic stimulation– Include 2- Epinephrine: stimulates both receptors α- mediated vasoconstriction (skin & splanchnic) β –mediated vasodilatation (sk.muscle,liver,

coronary arteries) © Though net effect = α < β Norepinephrine: negligible β-action –net cons.

(b) RENIN-ANGIOTENSIN SYSTEM>>↓BP Renin from JGcellsAngiotensinogen(plasma)

Ag I by ACE (lungs,kidney)Ag II

Ag II ↑ECF volume & thereby BP by—(i) potent vasoconstriction(ii)↑ synthesis & secretion of Aldosterone(iii) stimulates thirst to ↑water intake.

(c) VASOPRESSIN (ADH) >>Restores blood vol. & BP in demanding situations by

—(i)↑water reabsorption (in CD & DCT) via V 2(ii)Vasoconstriction (in supraphysiological doses) via V

1A receptors

3) LOCAL CONTROL MECHS. : Consists of 2 components :A)Acute control of local blood flowB)Long-term control of local blood flow

A) ACUTE CONTROL OF LOCAL BLOOD FLOW:Within secs-mins through constriction or

dilatation of arterioles, meta-arterioles, precapillary sphincters.

Different mechanisms involved----

(a) AUTOREGULATION >>• Ability of a tissue/organ to adjust its vascular

resistance & maintain a constant blood flow over a wide range of systemic arterial pressure.

• Well developed in BHK, sk.muscle, mesentery • 3 theories put forward to explain this phenomena—Myogenic: VSM responds to wall tension d/t ↑BPMetabolic : ↑Blood flow wash out local metabolites Tissue Perfusion: ↑ BP ↑CHP ↑fluid escape to

interstitium compressing effect on capillaries

• Fails @ extremes of systemic pressure variations

(b) BY LOCAL VASODILATOR METABOLITES & FACTORS >>• ↑metabolism ↑accumulation ↑blood flow• Most Important are—↓in PO2 & pH : in most ↑ in PCO2 & Osmolality : esp. in skin & brain↑ Temp : any active tissue d/t heat of metabolism K+ & Lactate : esp. in sk.muscles Histamine : in injured tissues & allergic reactionsAdenosine : in cardiac ms., inhibits NAd release• Hyperaemia : Active & Reactive

(c) BY LOCAL VASOCONSTRICTORS>• Serotonin & TxA2: by platelets in injured tissues• ↓Temp. : regulatory response to cold

(d) BY ENDOTHELIUM-RELEASED VASOACTIVE SUBSTANCES>>

PGI2 : inhibits platelet agg. & promote vasodilatation balance with TxA2 required

EDRF : identified to be NO major endogenous vasodilator mediating effect of many humoral agents help VSM to receive messages from

endothelium & nerve endings. Synthesis & M/A of NO :

(d) BY ENDOTHELINS (ET)>>• Family of 3 similar polypeptides (ET-1,2,3) one of

most potent vasoconstrictors yet isolated• Stimulators of release: hypoxia, AgII, Catechols,

insulin, some growth factors , shear stess• Inhibitors of release: NO, ANP, PGE, PGI2• ET-1 paracrine action via ‘ET-A’ on VSM• ETs autocrine via ‘ET-B’ on endotheliumEDRF

in-built check on ET-induced vasoconstriction UROTENSIN-II >> in human CV tissues – one of the

most potent mammalian vasoconstrictors known – pathophysiologic role till now of research-interest.

(e) BY SPECIAL MECHANISMS >>• For control of blood flow in certain specific areas• e.g. ‘Tubuloglomerular Feedback Mechanism’ >>fluid-composition in EDT sensed by macula densa if

↑filtrate through glomerulus feedback signals to aff.arteriolesconstriction↓RBF & GFR

B) LONG-TERM CONTROL OF LOCAL BLOOD FLOW:

over days-months—to meet metabolic needsfor tissues--ischaemic,rapidly growing,↑hyperactive by↑in vascular size/no. (VEGF,FGF,Angiogenin)