Reflex Control of the Peripheral Francois

M. Abboud,

Donald

D. Heistad,

T

HE purpose of the circulation is perfusion of tissues, and the major role of blood vessels in determining tissue perfusion must be appreciated. Knowledge of cardiovascular reflexes and neurohumoral control of the peripheral circulation has exploded in recent years. Despite the complexity of the control mechanisms, a greater understanding of their influence on the circulation in physiologic and in some pathologic states has been achieved. Reflex control of the peripheral circulation encompasses the neurohumoral regulation of every segment of the vascular tree. Its understanding requires knowledge of central nervous system (CNS) autonomic functions, of the coupling of the CNS with the various components and segments of the peripheral circulation, and of the modification of neurohumoral control of the circulation by local metabolic factors in the tissues. Central nervous system control is achieved through the autonomic system with its sympathetic and parasympathetic branches. The neural discharge from autonomic CNS neurons on the circulation is defined by three factors: (1) The continuous influx of afferent neural impulses that originate in the cardiovascular system as well as in other tissues and other parts of the CNS. The integration of these multiple inputs and their impact on the autonomic neurons are complex but important in the moment-to-moment regulation of vasomotor tone and the peripheral circulation. (2) The selectivity and nonuniformity of activation of the different efferent nerves of the autonomic system. Contrary to the old belief, efferent impulses *The references are examples of work done to support the statements and do not represent a complete listing of the contributions in each area. Figures ae reproduced with permission of the authors and publishers. From the Cardiovascular Center and the Division of Cardiovascular Diseases, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa. Supported by U.S. Public Health Service Grants HL 14388, HL 16149, and HL 16066. Reprint requests should be addressed to Francois M. Abboud, Division of Cardiovascular Diseases, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242. 0 1976 by Grune & Stratton, Inc.

Progress

in Cardiovascular

Diseases,

Vol.

XVIII,

No.

5 (March/April),

Allyn

L. Mark,

Circulation* and

Phillip

G. Schmid

generatedin the CNS are targeted to specific vascular beds and possibly specific segmentsof a vascular bed. Definition of reflex responsesin terms of “pressor” or “depressor” patterns is inadequatein light of today’s knowledge. It is possiblethat in the absence of any change in arterial pressure, significant changesin vascular resistancemay take place in various organsand modify blood flow and tissue perfusion. Differential rather than uniform responsesof the various parts of the circul.ation would be and indeed are more effective in satisfying the requirements of different physiologic and behavioral stimuli such as exercise, eating, diving, or running. (3) The direct or indirect regulation by the CNS of secretion of various hormonessuch as vasopressin,angiotensin, aldosterone and prostaglandins. These hormones alter vascular tone, affect sodium and water retention and the distribution of blood volume, and may modulate the neural activity and releaseof neurotransmitters. Another important aspect of this topic is the coupling of the CNS with various vascular segments that have different functions, different innervation, and that respond differently to the same stimuli. Blood vesselshave five different functions: (1) large arteries provide an impedance function that dampensthe pulsatile flow but also contributes to cardiac afterload; (2) the arterioles develop the critical resistancethat regulates the magnitude of blood flow to each organ; (3) the precapillary sphincters determine the total exchangecapillary surface area; (4) the venulesregulate postcapillary resistance, capillary filtration, and intravascular volume; (5) the large veins subserve a capacitance function that can influence cardiac filling pressureand cardiac output. Each of these segmentsin each vascular bed is coupled to the CNS in a specific manner and is under fine selective central control. It is possible, for example, that the activation of cardiopulmonary and arterial baroreflexes during hemorrhagemight causea selectiveincreasein splanchnic venous tone before an increasein splanchni8cresistance. In contrast, an increase in vascular resistanceof skeletalmusclemight be noted without an increasein venoustone in muscle.

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A third important and controversial aspect of this topic revolves around the relative importance of neurohumoral versus metabolic factors in the final determination of tissue perfusion. Continuous reflex adjustments in cardiac output, vascular resistance, and venous tone are integrated to maintain arterial pressure and perfusion of organs. These adjustments become crucial during acute stresses. On the other hand, the regulation of arteriolar resistance and precapillary sphincters in certain organs such as the heart or the exercising skeletal muscle may be determined predominantly by the metabolic demands of the organ and the elaboration of local vasoactive tissue factors. In addition, structural changes in vessel walls may accentuate the influence of neurohumoral factors, such as those seen in hypertension. CNS

CONTROL

OF

THE

CIRCULATION

The preganglionic autonomic neurons that may regulate almost every part of the circulatory system are modulated by a multitude of afferent impulses. The important components of this CNS network may be described under the following headings: (1) Medullary centers and efferent pathways; (2) Afferent neural stimuli; (3) Central integration of reflexes; (4) Modulation of neural control by humoral factors. Medullary

Centers

and

Efferent

Pathways

Stimulation of neurons in the rostrolateral areas of the medulla causes hypertension. The neural output from this pressor area is modulated by an inhibitory influence from an adjacent depressor area.l The output from the pressor area is carried along efferent fibers through the spinal cord, reaches sympathetic preganglionic cells in the lateral horn, and exits with motor nerves in the ventral root of spinal cord segments between T-l and L-2. The fibers synapse in the paravertebral sympathetic ganglia in the sympathetic chain or in separate ganglia, such as the celiac ganglia. Postganglionic fibers travel as discrete nerves, such as the cardiac and splanchnic nerves, or rejoin the motor roots and are distributed to blood vessels in the peripheral nerve trunks. The medulla also contains the vagus nuclei, which provide the parasympathetic outflow.

ET

AL.

Sympathetic Adrenergic Pathways The sympathetic adrenergic fibers mediate reflex vasoconstriction. Sympathetic tone is a function of neural discharge rate and can be evaluated by measurement of norepinephrine turnover or plasma levels of dopamine beta hydroxylase.’ Norepinephrine, the neurotransmitter, is located in vesicles in the adrenergic nerve endings. Release of norepinephrine may activate vasoconstrictor alpha receptors in vascular smooth muscle or excitatory betaadrenergic receptors in the heart and sino-atria1 (SA) node. The action of released norepinephrine is terminated by its uptake by the adrenergic nerves or by its metabolism through the catechol-o-methyltransferase and monamine oxidase (MAO) enzymes. The uptake of norepinephrine by adrenergic terminals is of clinical significance because it may be interrupted by drugs such as the tricarboxylic antidepressants (e.g., imipramine) and by guanethidine. When inactivation of norepinephrine through the uptake mechanism is prevented, excessive quantities of the neurotransmitter would be available to activate receptor sites and cause hypertension. The simultaneous administration of drugs that have different effects on the release and uptake of norepinephrine may have significant clinical side effects. For example, simultaneous administration of an MAO inhibitor and imipramine causes coma, hyperpyrexia, and convulsions, and the administration of imipramine to a hypertensive patient receiving guanethidine may prevent a hypotensive effect of guanethidine and cause hypertension. The distribution of the adrenergic fibers to various vascular segments as well as to various regions of the heart is not uniform. Reflex responses in both animals and man cause selective effects in different vascular beds. Stimulation of sympathetic nerves to various vascular beds elicits responses that differ widely in magnitude; for example, vasoconstriction is greater in the kidney than in the forelimb of the dog and is negligible in the coronaries and in the brain. This differential effect is important in determining the distribution of blood flow during stresses. Randall and his co-workers have shown that stimulation of sympathetic nerves to the heart may cause highly localized alterations in contractile force; for example, a separate influence of sympathetic nerve activity on the control of right and left ventricular contractility has been shown dur-

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373

CONTROL

ing exercise and emotional responses3 Such a differential response to activation of the nodal tissue may be important in the genesis of cardiac arrhythmias.4 In addition to the release of norepinephrine from nerve terminals, sympathetic activation releases epinephrine and norepinephrine from the adrenal medulla and renin from the juxtaglomerular apparatus5 Renin is released by the kidney during sympathetic stimulation as a result of changes in perfusion pressure in juxtaglomerular arterioles, changes in sodium concentration in the distal tubule (macula densa), and a direct effect, independent of pressure and sodium, but mediated through beta receptors. Low level sympathetic stimulation of the renal nerves may induce sodium retention even in the absence of an effect on intrarenal blood flow distribution.6 After attaching to receptors in cardiac or vascular muscle, the catecholamines activate the enzyme adenylcyclase and catalyze the formation of cyclic 3’-5’-AMP, which mediates contractile responses in the heart and vasodilator responses. Cyclic guanosine monophosphate may mediate alpha-receptor responses such as vasoconstriction.

also in normal man after adrenergic blockader2 and in patients with autonomic neuropathy12-l4 during the valsalva maneuver12”3 or simulated diving by apneic facial immersion.14 These reflexes cause vasoconstriction in normal subjects. In animals, direct stimulation of efferent sympathetic nerves following adrenergic blockade may induce vasodilatation. Several agents are thought to mediate active reflex vasodilatation. The dilatation is choline@ in skeletal muscle but is noncholinergic in other vascular beds; e.g., the paw of dog. This noncholinergic vasodilator pathway may be involved in mediating certain reflex respons,es.” Non-neuronal histamine may also indirectly mediate a vasodilator response in skeletal muscle during stimulation of baroreceptors.16 The release of bradykinin from salivary or sweat glands during sympathetic stimulation may mediate a significant vasodilator response. Prostaglandins are heavily concentrated in the renal cortex and may be released during renal nerve stimulationr7 and participate in feedback regulation of sympathetic tone.

Sympathetic

Parasympathetic nerves supply not only the SA node, atrial structures, and conduction system but also the ventricles.” The parasympathetic control of the ventricles exerts a negative inotropic effect through a muscarinic action blocked by atropine.” Acetylcholine is the inhibitory mediator of parasympathetic activity in the heart. Parasympathetic nerves also supply the coronary vessels and may participate in reflex regulation of coronary resistance.20’21 The action of acetylcholine is complex and may involve direct activation of muscarinic receptors, stimulation of nicotinic receptors, modulation of the release of norepinephrine, membrane effects, and formation of cyclic guanosine monophosphate.

Vasodilator Pathways

In experimental animals, during the defense reaction in response to hypothalamic stimulation, there is an active vasodilatation in skeletal muscle that is mediated through sympathetic cholinergic fibers. This cholinergic vasodilator pathway7 originates in the frontal cortex, passes through synaptic relays in hypothalamic and collicular nuclei, and runs through the ventral medulla to the spinal cord. The fibers innervate predominantly larger arteriolar resistance vessels of skeletal muscle. There has been some question regarding the importance of this system in the subhuman primate or in man. Schramm et aL8” have demonstrated in the primate a nonchohnergic sympathetic vasodilator system by stimulating loci along the route of the lateral spinothalamic tract. This noncholinergic sympathetic vasodilator pathway may be analogous to the cholinergic pathway identified in cats and in dogs. In man, active vasodilatation occurs during emotional stress,” suggesting that the defense reaction of hypothalamic stimulation in animals may have important physiologic counterparts in man (Fig. l).‘op’l Active reflex vasodilatation occurs

Efferent Parasympathetic Pathways

Afferent

Neural

Stimuli

The medullary neurons are constantly barraged by afferent impulses that originate from the arterial system, the cardiac and pulmonary regions, the chemoreceptors, skeletal muscle, and from areas of the central nervous system-particularly the hypothalamus and the cerebellum. Each afferent impulse has a selective influence on the medullary centers, and in many clinical situations, afferent

ABBOUD

ET AL.

ICE

I

$:iml P t is 8 Iml 3

0 Control Arm 0 Exprrimardol m Mean Arhriol 1-I Std. Error

P

-I

-2 t

Arm Rururs

I

-

I tI

Phcnlolomine

Fig. 1. Cholinergic vasodilatation in the forearm of man. (A) The left panel shows that severe emotional stress induced by the suggestion to the subject that he was suffering from severe blood loss caused tachycardia and marked vasodilatation in the forearm (solid dots) but not in the hand (circles). The right panel indicates that this dilatation is in part cholinergic: A, period of stress; 0, flow to normal forearm; l O-, flow to atropinized forearm; 6, vasodilator response after arrest of circulation to both forearms for 2 minutes (reproduced from Blair DA et al, Journal of Physiology (London) 146633, 1959). (6) Left panels: the tracings represent plethysmographic flow curves. Application of ice to the forehead caused vasodilatation in the forearm after intra-arterial guanethidine, which blocked adrenergic neurovasconstriction: the response in the opposite control arm was the expected vasoconstriction. Right panel: the reflex vasodilatation in the experimental arm was blocked in part by intra-arterial atropine. (Reprinted from Abboud FM, E&stein JW: Circulation Research 16 & 19:96, 1966.)

impulsesoriginating from different receptor areas converge simultaneously on the medullary centers. The net responseof the peripheral circulation and the heart does not reflect simply the algebraic summation of these individual reflexes but is the resultant of synergistic or inhibitory interactions between the various afferent impulses. Heretofore, the classicexperimental approachto

the study of reflex responseshas been to control activation of all receptor sites except the one under study. Such an approach yields limited information when one considersthat the circulatory adjustment in the intact organism results from integrated responses.Recently, the responsesto simultaneousactivation of two or more receptor siteswere studied.

REFLEX

CONTROL

There are four major areas that contribute afferent impulses. Two appear to trigger primarily inhibitory cardiovascular responses, and these are the arterial and cardiac baroreceptors. Two other sources of afferent impulses seem to mediate excitatory responses, and these are the chemoreceptors and the somatic afferents. Arterial Baroreceptors Mechanoreceptors or stretch receptors are located in the adventitia and media of the arch of the aorta and in the adventitia of the carotid arteries in the carotid sinus regions. Increases in afferent nerve activity are caused by stretch or distension of baroreceptors.22 Chronic hypertension is associated with a decrease in sensitivity of baroreceptor function that may result from structural changes in the aorta and carotid vessels.23 This “resetting” of baroreceptors is in part responsible for maintaining hypertension. A rise in arterial pressure causes an increase in afferent nerve activity from carotid and aortic baroreceptors and triggers a reflex reduction in peripheral resistance, in heart rate, and in myocardial contractility. This is achieved primarily through withdrawal of sympathetic vasoconstrictor tone and increases in activity of parasympathetic vagal efferent pathways to the heart. Activation of sympathetic vasodilator pathways and inhibition of cardiac sympathetic activity may also participate in this circulatory adjustment, but to a much lesser degree. In contrast, a fall in arterial pressure triggers reflex vasoconstriction, tachycardia, and an increase in cardiac output through activation of sympathetic excitatory efferent pathways. The activation of sympathetic and parasympathetic pathways as well as their inhibition are not generalized phenomena. For example, during carotid sinus nerve stimulation in man, reflex bradycardia and hypotension were demonstrated, but there was no evidence of venodilatationz4 In studies using lower body negative pressure to simulate blood loss and produce systemic hypotension, we have demonstrated reflex tachycardia and vasoconstriction in the forearm, but there was little or no evidence of an increase in venous tone in the extremities (Figs. 2, 3, and 17).25 Hemorrhage, however, appears to induce an increase in splanchnit venous tone.26 This selective modulation of efferent autonomic

Fig. 2. Schematic diagram of “lower body suction” and “neck suction.” “Lower body suction” is produced by creating negative pressure with a commercial vacuum cleaner and a box applied around the lower half of the body. The negative pressures may range from -5 to -80 mm Hg and may cause significant pooling of blood with a rapid reduction in central venous pressure. Low levels of suction may be used to activate the cardiopulmonary reflex without causing a change in systemic arterial pressure. Similarly, the “neck suction” is induced by creating negative pressure in the box placed around the neck to activate carotid stretch receptors and trigger reflex bradycardia and hypotension. Changes in forearm blood flow are measured with a strain gauge plethysmograph. Intra-arterial and central venous pressures are recorded continuously. Activation of the cardiopulmonary reflex and the carotid reflex may be induced separately or simultaneously.

pathways to parts of the cardiovascular system has also been demonstrated during activation of carotid sinus mechanoreceptors by applying negative pressure to the neck in man to simulate hypertension (Fig. 2).27. Reflex bradycardia and hypo-’ tension were induced without significant vasodilatation in the forearm or any increase in forearm flow (Fig. 4). In contrast, increase in forearm flow can be demonstrated readily during elevation of the legs, a maneuver that increases central venous pressure and may activate cardiac mechanoreceptors (Fig. 15)” The carotid sinus reflex was considered to exert a significant restraint on heart rate and myocardial contractility, 29 but more recent observations in conscious dogs by Vatner and his collaborators indicate that the suppression of myocardial contractility by carotid sinus stimulation is a relatively minor factor in the circulatory adjustments to this reflex.30

376

ABBOUD

LBS

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Fig. 21. Effect of hypoxemia in resting and contracting gracilis muscle at constant blood flow. Responses to three doses of norepinephrine were compared when the poZ of the blood perfusing the resting and contracting gracilis muscle was 100 mm Hg (left panel) and 29 mm Hg (right panel). Contraction at normal pot or hypoxemia in the absence of contraction had a slight effect on the constrictor response to norepinephrine, whereas a combination of hypoxemia and contraction antagonized the vasoconstriction. (Reproduced from Heistad DD, Abboud FM, Mark AL, et al: Journal of Pharmacology and Experimental Therapeutics 193:941-950, 1975.)

ABBOUD

396

in vessel walls is increased during stretch, causing spontaneous smooth muscle contraction and an increase in resistance. Hence, the flow in arterial pressure rises. This has been generally referred to as the Bayliss response, characterizing a contraction of smooth muscle during stretch. Another theory is that the rate of oxygen delivery to arterioles and precapillary sphincters, as well as the rate of accumulation of metabolites around these vessels might regulate the smooth muscle tone when flow is either increased or decreased. Hypoxia and accumulation of metabolites would tend to produce arteriolar vasodilatation and relaxation of precapillary sphincters, and would favor restoration of flow and perfusion to the microcirculation. The third theory is that an increase in perfusion pressure might increase capillary filtration and tissue pressure, and secondarily increase resistance to flow by compressing arterioles and precapillary sphincters. Hemorrhage and Shock The response to hemorrhage may be considered as an exaggerated response to pooling of blood in the lower extremities, which would cause constriction of arterioles in muscle, skin, splanchnic, and renal beds. An increase in sympathoadrenal discharge also causes tachycardia and an increase in myocardial contractility. In man, hemorrhage causes a rapid contraction of capacitance vessels, predominantly in the splanchnic bed.26 The neurogenie response of veins of the extremities is negligible, however, but the humoral factors released during sustained hypotension and shock (such as vasopressin, angiotensin, norepinephrine and epinephrine released from the adrenal gland) would all tend to increase venous tone and cause a reduction in the capacitance of the forearm vessels, particularly the cutaneous veins in shock.95 One may postulate that warming subjects in hemorrhagic shock would eliminate venoconstrictor adaptation and might have a detrimental effect. In prolonged shock, the associated acidosis may cause a reduction in precapillary resistance, while its effect on postcapillary resistance would be negligible. This increase in post- over precapillary resistance might cause a further loss of intravascular fluid by capillary filtration. The administration of an alpha blocker may eliminate the venoconstrictor response to adrenergic stimuli more completely than the arteriolar constrictor responses and

ET

AL.

ther-eby reverse the loss of intravascular volume. 167g168Information concerning venous responses in man during hemorrhagic and cardiogenic shock is lacking. Orthostatfc

Hypotension

A dramatic fall in arterial pressure occurs during upright tilt in patients who have orthostatic hypotension on the basis of autonomic denervation, such as patients with peripheral neuropathy, diabetes, and Shy-Drager Syndrome. This is caused primarily by an absence of reflex vasoconstriction.12-14 In patients with idiopathic orthostatic hypotension or diabetic neuropathy, the failure of vasoconstriction is probably related to the loss of adrenergic innervation of blood vesseIs.13 On the other hand, in patients with Shy-Drager Syndrome, failure of the reflex response is probably related to a CNS defect. 16’ In the patients with peripheral autonomic neuropathy, the Valsalva maneuver or the apneic facial immersion result in active vasodilatation of forearm vessels.‘*-r4 Thus, instead of the normal vasoconstrictor response, these patients exhibit a vasodilator response in the extremities, which is detrimental in that it will tend to accentuate the hypotension and redistribute the cardiac output towards the skeletal muscle and extremities, thus depriving the cerebral circulation from an adequate flow and contributing to the syncope. The mediator of this vasodilatation is not clear. Attempts to reverse this response with increased salt intake, the administration of fluorohydrocortisone and adrenergic vasoconstrictors, and possibly of propranolol should be considered. In addition to the defect in the adrenergic control of blood vessels, the baroreceptor reflex also seems to be attenuated in this disease. The application of ice on the forehead, which ordinarily causes a rise in arterial pressure and bradycardia, increases pressure in these patients significantly, but without inducing reflex bradycardia.‘* Instead, there is an increase in heart rate with the application of ice to the forehead, suggesting that the innervation to the heart is intact, whereas the autonomic constrictor innervation to the blood vessels is defective, as well as the baroreceptor reflex. It is possible that norepinephrine biosynthesis in the CNS, possibly at the level of the brain stem, may also be involved and may modulate the baroreceptor reflex.

REFLEX

CONTROL

It is important to remember that there are other causes of postural hypotension that are unrelated to dysautonomia. Patients with severe anemia or patients with extensive varices of the lower extremities may have postural hypotension despite the presence of an adequate sympathoadrenal system; the failure is simply due to the severity of the stimulus, requiring an excessive compensatory adjustment that cannot be fully met. One can simply evaluate at the bedside the adequacy of the autonomic response by asking the subject to perform a Valsalva maneuver to determine the presence or absence of post-Valsalva overshoot. The peripheral circulation in heart failure is discussed separately in this symposium by Dr. Mason. Brief reference to the topic is made here. Congestive Heart Failure Because of the decreased cardiac output, particularly during exercise, an excessive sympathoadrenal discharge directed at the splanchnic, renal, or skeletal muscle and cutaneous beds will tend to limit blood flow to these organs and may actually decrease it during stress to favor the distribution of flow to the coronary and cerebral vessels.1”>171 Baroreceptor reflexes are impaired in heart failure; there is less bradycardia during the rise in arterial pressure. 172,173 However, this does not appear to be due to a decreased synthesis of the cholinergic transmitter nor to a decreased sensitivity of cholinergic r-eceptors in the SA node.‘74Y’75 It has also been suggested that the exaggerated renal sympathetic tone that may contribute to sodium retention in heart failure may be in part caused by a failure of the inhibitory impulses originating from stretch of the pulmonary left atria1 region. One may speculate that one of the mechanisms of action of digitalis might be to restore the integrity of these reflexes and cause a withdrawal of renal sympathetic tone, which would then favor natriuresis. Digitalis also may increase the sensitivity of arterial baroreceptors. The elevated venous pressure in heart failure is caused in part by hypervolemia, reduction in ventricular compliance, and increased venous tone. Splanchnic blood volume increases. This increase may be partly passive and related to the high central venous pressure. Wood et a1.‘76 found that venous tone in the forearm of patients with cardiac failure is greater than in normal subjects and in patients with compensated heart failure; he also dem-

397

onstrated that in cardiac failure, the venoconstrictor response to exercise is exaggerated. It is proposed that the increases in arteriolar and venous tone in heart failure might not only represent an increase in sympathoadrenal activity, but also some structural changes in the vessel wall, possibly related to sodium and water retention. The decrease in venous capacity in the cutaneous bed might limit the ability of cardiac patients to dissipate heat properly during mild exercise and would exaggerate their intolerance.“’ In heart failure, postural changes in peripheral blood flow are opposite those seen in normal subjects. In the upright position, there is an increase in forearm blood flow instead of a decrease.“’ Similarly, the response to Valsalva maneuver is atypical and does not include the post-Valsalva overshoot. The reasons for these abnormalities are not clear. Am-tic Stenosis and Myocardial Infarction As mentioned earlier, the stretch of ventricular mechanoreceptors results in activation of nonmedullated C fibers that mediate an inhibitory response in the cardiovascular system, resulting in hypotension, vasodilatation, and possibly bradycardia. A few years ago, we proposed that stretch of these ventricular receptors in patients with aortic stenosis who are subjected to moderate or heavy exercise might contribute to the syncope by preventing the reflex sympathetic vasoconstriction that occurs in the nonactive organs and muscles during exercise. This hypothesis was proven by demonstrating that during leg exercise, patients with aortic stenosis have an increase in forearm blood flow, whereas normal subjects and patients with mitral stenosis have a decrease in forearm blood flow (Fig. 22). 53 In dogs, brief inflation of a balloon in the aorta could cause a fall in systemic arterial pressure with an abrupt rise in left ventricular pressure and dilatation in skeletal muscle.44 Clearly, the sympathetic inhibition induced by left ventricular stretch was sufficient to mask the anticipated sympathetic vasoconstrictor response from the arterial baroreceptors as arterial pressure fell precipitously. The vasodilator response of muscle was caused by withdrawal of sympathetic tone rather than activation of vasodilator fibers. After acute myocardial infarction, the hypotension might be in part related to activation of ventricular stretch mechanoreceptors in the dyskinetic

398

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ischemic myocardium, which would be inhibitory (Fig. 23). Toubes and Brody5’ demonstrated that following acute myocardial infarction in dogs, peripheral resistance increased only slightly despite hypotension; but when bilateral vagotomy was performed, there was a marked rise in peripheral resistance and arterial pressure. The findings strongly suggest the presence of an inhibitory cardiac afferent activity mediated through the vagi and originating in the ischemic myocardium.50 Differential effects on muscle and paw were reported after coronary occlusion in dogs by Hanley et a.l.17’ Hypertension

and Hyperkinetic

0

Stenosis and Syncope

mart Disease

-.

Fig. 22. Effect of leg exercise in aortic stenosis. The reflex vasoconstrictor response seen in the normal subjects and in patients with mitral stenosis is replaced by a vasodilator response in aortic stenosis. (Reprinted from Mark AL, Kioschos JM, Abboud FM . . ,. et al: Journal Ot clinical /I?vestigations 52:1138-1146, 1973.)

be activated. The similarity in circulatory adjustment raises the possibility that in early labile hypertension, a hypothalamic drive may be a factor in maintaining the high output and may possibly trigger an autoregulatory adjustment of the circu-

Ref Iex Sympcthetic Stimulation

State

It is known that in some patients with early labile hypertension, peripheral resistance may not be increased, and the elevated blood pressure may be caused by a high cardiac output.“’ In this condition, however, the regional circulations may show abnormalities.181 There may be an increase in skeletal muscle flow and a decrease in splanchnic, cutaneous, and possibly renal blood flow, The higher output and the distribution of blood flow is reminiscent of the circulatory adjustments seen with hypothalamic stimulation or during the defense reaction. In some patients with the hyperkinetic state, similar circulatory abnormalities may be observed, lending support to the view that in the hyperkinetic state, the defense reaction may also

Venlricular Recepfors

>

Reflex Sympathetic Inhibition

Myocardial Infarction Hypotension Fig. 23. Schematic representation of two reflexes in acute myocardial infarction. The stretch of the dyskinetic ventricular myocardium activates the inhibitory cardiopulmonary reflex, whereas the systemic hypotension and the decrease iq the stretch of the carotid and aortic baroreceptors will trigger the excitatory reflex from the arterial barorecaptors. The net circulatory response results from the interaction of these two reflexes. Often the inhibitory cardiac reflex overrides and results in sustained hypotension.

REFLEX

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lation involving structural changes in the arterioles. Such structural changes will increase the wall/ lumen ratio and augment vascular reactivity and vasoconstrictor responses, thus creating a state of positive feedback. 182 Furthermore, the hypothalamic drive may be inhibitory to the baroreceptor reflex and would thus prevent the restoration of arterial pressure through the baroreflex mechanism.71 Although speculative, these are potential contributing factors to the pathogenesis of hypertension. These aspects are discussed in greater detail in the chapter by Drs. Brody and Zimmerman. CLOSING

COMMENTS

This overview and all the recent investigative work in this area should bring into focus several important concepts in circulatory control. Their

application to clinical situations and to disease states is difficult but challenging. Some of these concepts include: the significant role of cardiopulmonary afferents in man; the complex CNS contributions to reflex control; the importance of m-examining reflex control asa “closed loop” system with interacting and nonuniformity of activation of efferent componentsof the autonomic system; the differential control of each component of the vasculartree aseachsubservesa different function. The complexity of the system is overwhelming and its sophistication is staggering.Our attempt to dealwith it shouldhopefully serveasa framework, a starting base,for the student of circulatory control. The need and opportunities for future investigation are limitless and the applicability to clinical statesis extremely relevant.

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