Integration of Reflex Responses in the Control of Blood Pressure and Vascular Resistance
FRANCOIS M. ABBOUD, MD lowa city, lowa
From the Cardiovascular Center; the Cardiovascular Division, Department of internal Medicine; and the Department of Physiology, University of Iowa College of Medicine, Iowa City, Iowa. The experimental work referred to in this presentation was carried out in collaboration with Drs. Allyn L. Mark, Donald D. Heistad, Marc D. Thames, Phillip G. Schmid, John Walker, Manuel Calvelo, James Hackett and Sidney Klopfenstein. This study was supported by Grants HL 14388, HL 16 149, and HL 16066 from the U. S. Public Health Service, Bethesda, Maryland. Manuscript received July 31, 1979, accepted August 3. 1979. Address for reprints: Francois M. Abboud, MD. Department of Internal Medicine, Cardiovascular Center, University of Iowa Collegeof Medicine,
IowaCity,Iowa52242.
This overview presents four important concepts related to integration of cardiovascular reflexes. (1) Activation of sympathetic efferent activity to various organs is nonuniform. Simultaneous activation of both sympathetic and parasympathetic efferent pathways may occur. These effects are evident in the responses to diving and stimulation of chemoreceptors. Both diving and stimulation of chemoreceptors decrease heart rate and myocardial oxygen demand and cause intense peripheral vasoconstriction, which limits oxygen delivery to the periphery. Stimulation of chemoreceptors also causes active coronary vasodilatation favoring an optimal distribution of blood flow to the heart. 2. When two groups of sensory afferents that cause opposing responses are activated simultaneously, the effect of one sensory afferent system will override the other. During hypotension caused by occlusion of the circumflex coronary artery, the reflexes originating in cardiac vagal afferents are inhibitory and reverse the effect of unloading of arterial baroreceptors. The net effect is not simply blockade of sympathetic vasoconstrictor effects, but withdrawal of sympathetic tone. Thus, the cardiac “reflex” overrides the effects of arterial hypotension. 3. The reflex response to activation of one group of sensory afferents may be dependent on the input from other groups of afferents to the medullary neurons. At low carotid sinus pressure, the “gains” of the chemoreceptor and somatic reflexes are augmented. The cardiopulmonary vagal afferents modulate the arterial baroreceptor reflex as well as the chemoreceptor and somatic reflexes. The cardiopulmonary vagal afferents, when activated, suppress the sympathetic excitatory response to arterial hypotension, to chemoreceptor stimulation and to somatic afferent stimulation. Another important interaction is that of the thermal receptors which, when activated by heat, suppress the vasoconstrictor response to arterial hypotension in cutaneous more than in muscular beds. 4. Stimulation of sensory afferent receptors may be modified by drugs or humoral factors acting on the receptor itself or on the chemical and mechanical characteristics of the tissues surrounding the receptor. Acetylstrophanthidin injected into the circumflex coronary artery potentiates the sympathetic inhibitory response to activation of cardiac sensory afferents (vagal afferents) by volume loading and by occlusion of the circumflex. The sensitization may explain in part the action digitalis has on the peripheral circulation in heart failure. The clinical implications of these four important physiologic concepts are discussed.
An understanding of reflex regulation of vascular resistance and blood pressure requires the ability to integrate responses observed in several organs and vascular beds during activation of more than one type of sensory afferent. There are two reasons for this: (1) Reflex responses in various vascular beds are different and this difference determines the
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optimal distribution of blood flow. (2) In the intact animal or human being, particularly in abnormal states, several groups of sensory afferents are activated simultaneously and the net reflex response cannot be deduced from knowledge of responses to activation of each group of afferents separately. For example, in hemorrhagic shock, arterial and cardiopulmonary baroreceptor reflexes as well as chemoreceptor reflexes are activated simultaneously when patients are hypotensive, hypoxic and acidotic. The net response does not equal the algebraic sum of responses observed when each reflex is activated alone. This nonlinear summation implies an “interaction of reflexes” that is important in circulatory control. The experiments selected for presentation emphasize four concepts in the study of integrated control of the circulation: (1) selectivity and nonuniformity; (2) simultaneous activation of opposing reflexes; (3) interaction of reflexes; and (4) “sensitization” of afferent receptors. Selectivity
and Nonuniformity Activity
of Sympathetic
Sympathetic neural activity to various vascular beds and even to segments of the same vascular bed is modulated in a nonuniform manner. The different components of the circulation are controlled selectively.*~2 Furthermore, activation of the sympathetic outflow is not always accompanied by inhibition of the parasympathetic outflow and vice versa. There are reflex responses that include activation of the sympathetic and parasympathetic efferents simultaneously. The foollowing are several examples of selectivity and nonuniformity of neural control: Differential responses of various vascular beds: Stimulation of chemoreceptors causes neurogenic vasoconstriction in skeletal muscle and in splanchnic and renal vessels, and vasodilatation in the coronary circulation, but there is no neurogenic influence on cerebral vessels.“-6 The coronary vasodilatation is caused by activation of vagal parasympathetic efferents5 and the constriction in other vessels is caused by activation of sympathetic adrenergic efferents. Thus, the neurogenie adjustment to stimulation of chemoreceptors favors the distribution of blood flow toward organs critically dependent on oxygen for their integrity and away from those relatively less dependent on oxygen. Simultaneous activation of sympathetic and parasympathetic efferents: Diving and stimulation of chemoreceptors activate sympathetic efferents to the peripheral circulation causing intense vasoconstriction and parasympathetic efferents to the hearts7 Marked bradycardia is seen during diving and during stimulat.ion of chemoreceptors if the hyperventilatory response is prevented by artificial ventilation of the experimental animal. Peripheral vasoconstriction favors “oxygen delivery” to the coronary circulation and, when this is coupled with a reduction in myocardial oxygen demand as a result of bradycardia, the protective effect of the reflex is optimal. Recently, deBurgh Daly et aL8 demonstrated that sustained bradycardia in the diving seal
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is caused by activation of the chemoreceptor reflex and Blix et a1.g showed that the diving bradycardia is sustained in the duck by activation of cardiac vagal afferents as a result of intense peripheral vascular constriction and a shift of blood volume toward the cardiopulmonary region. Differential responses to activation of two “inhibitory” reflexes in human beings: The stretch of arterial baroreceptors during hypertension and of atria1 and ventricular receptors during hypervolemia increases their activity. Afferent impulses originating in these regions inhibit sympathetic vasomotor neurons and activate vagal nuclei. Conversely, a decrease in arterial blood pressure and hypovolemia or hemorrhage unload these receptors and cause a reflex increase in sympathetic and a decrease in vagal efferent activity. Although the afferent nerves from these two receptor regions project to the nucleus tractus solitarius, the physiologic responses to their activation or unloading are not identical, suggesting that they do not converge on the same neurons in the medulla. We are able to evaluate the role of cardiopulmonary afferents and that of carotid baroreceptor afferents separately in hunian beings by applying “lower body negative pressure” using a suction box placed around the lower limbs to the level of the iliac crest. Suction with a commercial vacuum cleaner allows negative pressures of -5, -10, -20 and -40 mm Hg in the box. Progressive pooling of blood in the lower limbs during graded suction reduces central venous pressure and cardiac size. During minimal levels of lower body negative pressure (-5 and -10 mm Hg) central venous pressure decreases by 3 to 5 mm Hg but without a change in arterial pressure or heart rate; thus the signal sensed by the arterial baroreceptors is unchanged. Nevertheless, significant reflex vasoconstriction of forearm blood vessels and a reduction in forearm blood flow occur. The increase in forearm vascular resistance without a change in arterial pressure and without tachycardia (on occasions a decrease in heart rate of 2 to 3 beats/min is seen) suggests that the reflex is not caused by inhibition or unloading of arterial baroreceptors, but rather by unloading of cardiopulmonary baroreceptors1° (Fig. 1). When lower body negative pressure is applied at -40 mm Hg, arterial pressure decreases and pulse pressure narrows. Excessive pooling invokes the arterial baroreceptor reflex in addition to the cardiopulmonary reflex and the resulting response includes tachycardia, a slightly greater increase in forearm resistarlce (Fig. 1) and significant splanchnic vasoconstriction.‘lJ13 The results suggest that in human beings arterial baroreceptors regulate significantly heart rate and splanchnic resistance vessels but not forearm vessels, whereas the cardiopulmonary receptors regulate predominantly resistance of forearm vessels. In order to evaluate more directly the role of carotid baroreceptors in man, a suction device is applied around the neck and the negative pressure increases carotid transmural distending pressure. Reflex bradycardia and hypotension occur but there is no significant
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POOLING
LBNP 40mmHg
LBNP IOmmHg II Central Venous Pressore (mmtig)
OL Systemic Arterial
Pressure (mmliq)
Heart Rote (beots/min) 180 ,-u”-,-“_r.
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Forearm Vosculor Resistance +
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FIGURE 1. Activation of cardiopulmonary baroreceptor reflex in man. Minimal lower body suction with a lower body negative pressure (LBNP) of - 10 mm Hg causes constriction of vessels of the forearm withput any change in arterial pressure, pulse pressure or first derivative’of pressure (dP/dt); there is no tachycardia. This reflex (left half of figure), which is thought to be mediated through low pressure cardiopulmonary receptors, as indicated by the decrease in central venous pressure, differs from the reflex induced during excessive pooling at LBNP of -40 mm Hg, which causes systemic hypotension and tachycardia but no vasoconstriction (right half of figure).
Venous (LENP
Neck
Poolinp
(NNP
40mmHg)
Nsgohvc
Pressure
and
Venous (LBNP
Pooling 40mmHg)
+
+ Neck
Suction 40mmHp)
(mmHg)
Or
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FIGURE 2. Comparison of the role of cardiopulmonary baroreceptors and carotid baroreceptors in the regulation of circulation in man. High levels of lower body negative pressure (LBNP) caused the decrease in central venous pressure, hypotension, reflex tachycardia and forearm vasoconstriction. When lower body negative pressure at high levels (LBNP 40 mm Hg) was applied simultaneously with carotid neck suction (NNP 40 mm Hg) (the latter to inhibit the input from the carotid baroreceptor reflex), the interaction resulted in a disappearance of the reflex bradycardia, but the reflex vasoconstrictor response was sustained.
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causing ischemia of the posterior wall of the ventricle,17 or (3) by coronary arteriography.i8 Simultaneously, arterial hypotension reduces the activity of arterial baroreceptors and increases sympathetic drive. The results in these three instances indicate that the net response is inhibition of sympathetic outflow with vasodilatation of the perfused skeletal muscle, decrease in renal nerve activity or bradycardia. Thus, the “cardiac reflex” overrides the effects of arterial hypotension. Figure 3 illustrates the change in renal activity during hypotension induced by transient occlusion of the left anterior descending and circumflex coronary artery sequentially. Occlusion of the left anterior descending coronary artery caused hypotension and an increase in renal nerve activity. In contrast, occlusion of the circumflex coronary artery caused greater hypotension, bradycardia and a reduction in renal nerve activity in more than half of the animals studied despite the hypotension and intact sinoaortic nerves.lg In these animals, the cardiac reflex triggered by circumflex arterial occlusion overrides the effect of inhibition of arterial baroreceptor activity during arterial hypotension. After sinoaortic denervation, the influence of arterial hypotension is minimized and the inhibitory effect of the “cardiac reflex” becomes much more pronounced.lg Although evident with occlusions of both the circumflex and left anterior descending artery, it is more pronounced with circumflex occlusion. The greater inhibitory reflex response during occlusion of the circumflex than during occlusion of the left anterior descending artery reflects a greater density of cardiac sensory receptors with vagal afferents in the posterior wall of the left ventricle. The reflex is mediated through vagal afferents because after bilateral vagotomy there is lesser hypotension and a slight increase in the sympathetic nerve activity during occlusion of both left anterior descending and circumflex arteries.lg
decrease in forearm vascular resistance, thus confirming the belief that carotid baroreceptors do not modulate sympathetic efferents to resistance vessels of the forearm in human beings.zxi4 It is possible, however, that forearm vessels do not dilate during neck suction because sympathetic tone is very low to begin with in these subjects. When sympathetic tone is increased by excessive lower body negative pressure, forearm and splanchnic resistance vessels constrict and heart rate increases. Under these circumstances, simultaneous neck suction suppresses the reflex tachycardia and splanchnic vasoconstriction but the vasoconstriction in the forearm is unalteredl’J” (Fig. 2). These results demonstrate that the two inhibitory reflexes, namely, the carotid and cardiopulmonary reflexes in man, have selective influences on sympathetic efferents to various parts of the circulation. The carotid sinus reflex regulates heart rate and splanchnic resistance and has minimal effect on vessels of the forearm, whereas the cardiopulmonary reflex modulates sympathetic efferents to resistance vessels of the forearm. This situation is different from that in the dog where the same change in muscle resistance is associated with a greater change in renal resistance and heart rate in response to stimulation of cardiac vagal afferents as compared with stimulation of arterial baroreceptor afferents.12 Simultaneous
Activation
of Opposing Reflexes
In pathologic states, several groups of sensory afferents are activated simultaneously and their effects are synergistic. There are instances in which two groups of sensory afferents that cause opposing responses are activated simultaneously. An important question is whether the net effect will be “zero” or whether the effect of one sensory afferent will override the other. Following are three examples of conditions in which opposing reflexes are triggered simultaneously. Cardiac sensory afferents, which reflexly inhibit sympathetic drive, are stimulated (1) by inflation of a balloon in the ascending aorta causing acute left ventricular distension,i6 (2) by occlusion of the circumflex coronary artery
Interaction
The output from neurons in the medullary centers along the sympathetic and parasympathetic efferent
. 1
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The American Journal of CARDIOLOGY
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mm Hg)
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HR(Beats/min)
FIGURE 3. Occlusion of the left circumflex (Cx) and left anterior descending (LAD) coronary arteries causes similar increases in mean left atrial pressure (MLAP) but the decrease in mean arterial pressure (MABP) is greater with left circumflex occlusion. Despite the greater decrease in pressure there are several experiments where renal nerve activity (RNA) and heart rate (HR) decrease during left circumflex occlusion. After sinoaortic denervation, occlusions of the left circumflex and left anterior descending coronary arteries both reduce renal nerve activity and mean left atrial pressure but the reductions are much greater with occlusion of the former. P = probability.
INTEGRATION OF CARDIOVASCULAR REFLEXES-ABBOUD
afferents and their neuronal connections. They are also important in pathophysiologic states where the input from arterial or cardiac receptors may be suppressed, as in hyptertension or heart failure. Under those conditions responses to activation of somatic afferents with exercise or activation of chemoreceptors with hypoxia might be drastically modified. Three examples of important interactions are used to illustrate the concept.
pathways is constantly modulated by afferent input from various sensory receptors in the cardiovascular system and other parts of the body. Sensory afferent impulses originate in baroreceptors such as the arterial or cardiopulmonary baroreceptors or in receptors concerned with oxygen conservation and delivery such as the chemoreceptors, the trigeminal sensory afferents that mediate the “diving reflex,” and the somatic receptors activated during exercise. Other receptors in the skin and in the hypothalamic region are sensitive to temperature. The medullary neurons are also under the control of spinal afferents from various viscera and afferents from various regions of the brain such as the hypothalamus, cerebellum, fastigial nuclei and cortex. These reflexes essentially subserve three functions: (1) maintenance of arterial pressure; (2) delivery of oxygen and nutrients to vital organs or to organs with increasing oxygen demand under stress; and (3) regulation of body temperature. The reflex response to activation of one group of sensory afferents may be dependent on the input from other groups of afferents to the medullary neurons. Several questions may be asked in this context: (1) What is the influence of the tonic input from certain sensory receptors on the reflex response observed when the input from one group of sensory afferents is modified? In other words, if the arterial baroreceptor input is increased or decreased, does that modify the response to chemoreceptor stimulation? (2) Can the input from cardiac vagal afferents modify the effects of changes in the activity of arterial baroreceptors or of chemoreceptors on blood pressure, renin release, antidiuretic hormone release and other variables? These questions have physiologic implications concerning the nature of the central projections of these
MUSCLE PP (mmlig)
pressure, the “gains” of the chemoreceptor and somatic reflexes are augmented. 1. Carotid chemoreceptors: Elevation of carotid sinus pressure in the left carotid artery suppresses the chemoreceptor reflex activated by perfusion of the right carotid artery with hypoxic, hypercapnic blood at constant perfusion pressure (Fig. 4). Conversely, a reduction in arterial pressure induced by hemorrhage augments the vasoconstrictor response to stimulation of chemoreceptors.21 A similar interaction occurs with respect to the hyperventilatory response to chemoreceptor stimulation, which is augmented at low carotid sinus pressure.22 2. Carotid somatic receptors: The reflex response to activation of the somatic reflex is also augmented during carotid sinus hypotension. Activation of somatic afferents (by contraction of skeletal muscle or by electric stimulation of the central end of the cut sciatic nerve at high frequency) causes reflex vasoconstriction in the perfused gracilis muscle, an increase in arterial pressure and tachycardia. The magnitude of this reflex response is augmented significantly when the carotid sinuses are perfused at low pressure and inhibited when the carotid sinuses are perfused at high pressure.23 This interaction is not caused by a change in reactivity of blood vessels
“:t
,[A 9a94’
RIGHT CAROTID Paz (mmlig)
A. Carotid baroreceptors modulate the chemoreceptor and somatic reflexes: At low carotid sinus
l~~~~ 0E
v
-
300 100 E A
v
200 LEFT PP
CAROTID (mml+g) 0E 200
RIGHT CAROTID PP (mmHg1 2:
E
SYSTEMIC ARTERIAL PRESSURE (mmHg)
t 0 t.I
FIGURE
. 101356
4. The carotid chemoreflex caused by perfusion of one carotid with hypoxic hypercapnic blood at normal pressure is suppressed when
the opposite carotid is perfused at high perfusion pressure (PP) demonstrating a central interaction between the carotid baroreceptors and chemoreceptors. POn = oxygen tension.
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in the gracilis muscle to the released neurotransmitter, norepinephrine. When the somatic reflex is augmented at low carotid sinus pressure, the response to intraarterial norepinephrine injected into the perfused gracilis artery is, if anything, lesser than the control response and, conversely, when the somatic reflex response is inhibited at high carotid sinus pressure, the response to norepinephrine tends to be even greater. The change in gain of the somatic reflex is due to neural interactions rather than to a change in the responsiveness of vascular muscle to the released neurotransmitter. The interaction between carotid baroreceptors and somatic afferents has clinical implications. Activation of somatic afferents in hypertensive states is associated with an increased sympathetic outflow to blood vessels. The augmented neural adrenergic response to exercise in hypertensive states may be related to the fact that carotid baroreceptor activity is suppressed in hypertension. B. Interaction of cardiopulmonary vagal afferents with other reflexes: The cardiopulmonary vagal afferents modulate the arterial baroreceptor reflex with respect to changes in vascular resistance, antidiuretic hormone reIease, and renin release. They can also modulate the chemoreceptor and somatic reflexes. 1. Cardiopulmonary arterial baroreceptors: Carotid hypotension increases arterial pressure and vascular resistance in the gracilis muscle in dogs with cut aortic depressor nerves. Bilateral vagotomy augments this reflex.24 It is postulated that the tonic inhibitory input from cardiopulmonary vagal afferents reduces the gain of the baroreceptor reflex, particularly in the lower range of carotid sinus pressures between 120 and 50 mm Hg. 2. Cardiopulmonary chemoreceptors: Similarly, the response to chemoreceptor stimulation is augmented when the vagal afferent input is absent. The reflex
vasoconstrictor response to injections of nicotine or cyanide into the carotid arteries was significantly greater after than before vagotomy in animals in which the aortic depressor nerves had been cut and carotid sinus pressure was maintained constant.24 3. Cardiopulmonary arterial baroreceptors and ADH: Release of antidiuretic hormones (ADH) is under the control of both the arterial sinoaortic baroreceptors as well as the cardiopulmonary vagal afferents. Thames and Schmidz5 showed that when the aortic nerves and carotid sinus nerves are cut sequentially in the presence of the vagi, there are no changes in ADH concentration but, immediately after vagotomy, there is a significant rise. When the order of these interventions is reversed so that vagotomy is carried out first, followed by section of aortic then carotid sinus nerves, there is a progressive rise in vasopressin concentrations after section of each set of nerves. These results emphasize two points. First, that the order of interventions determines in a significant way the nature of the response, suggesting that there are interneuronal connections that modulate the final pathway for the response in a differential way. The second and more important finding is that the cardiopulmonary vagal input is critical and can suppress the influence of the arterial baroreceptors on ADH release. 4. Cardiopulmonary somatic afferents: The central end of the cut sciatic nerve is stimulated electrically in anesthetized dogs to activate somatic afferents and simulate exercise. The resulting decrease in renal blood flow, increase in arterial pressure and tachycardia are measured as indexes of the magnitude of the somatic reflex. During hypervolemia caused by infusion of dextran, the reflex renal response is reduced whereas, immediately after vagotomy, the response is augmented.26 The magnitude of the renal response in these dogs with cut sinoaortic nerves is inversely related to the
.s F
5 f-
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FIGURE 5. The increases in renal vascular resistance during activation of somatic afferents (right panel) are reduced by volume loading with intravenous dextran (5, 10 and 15 ml/kg) and augmented by vagotomy (V). A similar trend is seen for the simultaneous increase in arterial pressure and decrease in renal blood flow (left panel). C = control (before dextran); n = number of experiments; P = probability.
INTEGRATION OF CARDIOVASCUCAR
intensity of cardiopulmonary receptor activity (Fig. 5). This interaction is most evident with respect to the changes in renal vascular resistance, but it is less evident with respect to changes in arterial pressure and it is absent with respect to changes in heart rate. In an attempt to determine whether such tin interaction occurs in human beings, somatic afferents are activated by asking normal subjects to perform isometric exercise of the left arm by compressing a dynamometer. Handgrip pressures of 10 and 20 percent of maximal contraction are sustained over a period of 1.5 minutes. The resulting reflex responses are studied by measuring changes in arterial blood pressure and heart rate. This reflex response is examined in a control state and when the input from the cardiopulmonary afferent is reduced by lower body negative pressure at -5 mm Hg. Lower body negative pressure at this minimal level of suction reduces central venous pressure and causes a slight increase in forearm vascular resistance without a change in arterial pressure or heart rate. The reflex response to lower body negative pressure is ascribed to withdrawal or inhibition of cardiopulmonary baroreceptor activity. When isometric exercise is performed during this low level of lower body negative pressure, the reflex vasoconstrictor response is augmented severalfold.” (Fig. 6). These findings indicate that in animals and human beings, the magnitude of reflex neuroadrenergic drive during exercise is modulated by the input from cardiopulmonary vagal afferents. It is tempting to speculate that augmented neuroadrenergic response to exercise in heart failure, which has been documented in patients as well as in animal models, might be related to the decreased afferent input from the heart. Studies by Greenberg et al.*” and by Zucker et a1.2g demonstrated that the activity of left atria1 stretch receptors with vagal afferents is suppressed in animal models of heart failure. If the large number of unmyelinated inhibitory vagal afferents from the left ventricle were hypoactive in heart failure, one might expect the augmented exercise response on the basis of the interaction we demonstrated in normal animals and human beings. C. Interaction of thermal receptors and baroreceptors in the control of cutaneous blood flow: Thermal receptors in the skin mediate responses that modify vascular tone in cutaneous beds to either increase or decrease heat dissipation. We postulated30 that heating of one forearm in human beings could interfere with reflex vasoconstrictor responses in the cutaneous bed (finger or hand) of the opposite arm. Lower body negative pressure at -40 mm Hg increases sympathetic efferent activity; blood flow to the fingers and fore&m decreases. When one forearm is immersed in warm water, the reflex vasoconstrictor response to lower body negative pressure is markedly inhibited in the contralateral fingers but the forearm response is altered only slightly. When the temperature of the water is cooled to loo to 12O C, the reflex response is increased. Thus, the baroreceptor reflex effect on blood flow to the
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fingers is inhibited when the input from thermoreceptors in the contralateral forearm signals an increase in skin temperature. This interaction does not extend as effectively to vessels of the forearm presumably because the forearm is predominantly skeletal muscle. Input from thermal receptors overrides the input from arterial or cardiopulmonary baroreceptors in the control of blood flow to the fingers. of Aff erent Receptors
Sensitization
Stimulation of sensory afferent receptors may be modified by drugs or humoral factors acting on the receptor itself or on the chemical and mechanical characteristics of the tissues surrounding the receptor. Acetylstrophanthidin activates directly cardiac receptors with vagal afferents and arterial baroreceptors, causing reflex bradycardia and inhibition of sympathetic outflow. This effect is transient and lasts several minutes. We recently”’ tested the possibility that acetylstrophanthidin may sensitize cardiac inhibitory receptors and augment responses to expansion of blood volume or to myocardial ischemia. Injection of acetylstrophanthidin (25 pg) into the circumflex coronary artery of dogs with sinoaortic denervation produces an acute and transient bradycardia with decrease in sympathetic nerve activity. Ten to 15 minutes after the injection, when resting values are back to control levels, occlusion of the circumflex coronary artery causes a greater inhibition of sympathetic nerve traffic. Similarly, volume loading with infusion of dextran causes a
A Forearm
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(+6+_1
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10% LBNP -5 mmlig
(i13fl
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20%
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(-5
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FffiURE 6. The increases in forearm vascular resistance in 11 subjects during combined lower body negative pressure (LBNP) and handgrip exercise at 10 and 20 percent of maximal voluntary contraction are much greater than those noted with handgrip exercise or lower body negative pressure alone. The bare represent mean changes in vascular resistance in arbitrary units (mm Hg/ml per min per 100 ml f 1 standard error).
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“Sensitization”
of Cardiac
Acetyl
Reflex
(Sino-Aorfic Before mmHg 4OOT
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FIGURE 7. Rapid intravenous (I.V.) infusion of dextran causes hypervolemia, This reflex is augmented pressure.
significantly
after intracoronary
a rise in left atrial pressure and reflex reduction in renal nerve activity. (l.c.) injection of acetylstrophanthidin (AS). LV dp/dt = first derivative of left ventricular
greater inhibition of renal sympathetic nerve activity after than before acetylstrophanthidin (Fig. 7). These results suggest that one of the mechanisms of action of acetylstrophanthidin in heart failure might be to sensitize cardiac receptors and thereby result in an inhibition of sympathetic activity. In addition to its direct inotropic effect, sensitization of these baroreceptors which are known to be depressed in heart failure may explain the effect of the drug on the peripheral circulation in heart failure. Conclusions An overview of four important concepts related to integration of cardiovascular reflexes is presented: 1. Nonuniformity of sympathetic efferent activity to various organs and of vagal parasympathetic efferent activity to the heart is emphasized. The reflex control of the circulation is selective and optimal for the necessary adjustments under stress. This is evident in the differential effect on the heart and peripheral circulation in diving and during chemoreceptor stimulation. Optimal oxygen conservation and distribution are achieved by a reduction in heart rate and myocardial oxygen demand as well as coronary vasodilatation and intense peripheral vasoconstriction which limits oxygen delivery to organs that are not as dependent on oxygen as the brain and heart.
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2. Simultaneous activation of two or more sensory afferents is not uncommon in pathologic conditions. One set of reflex responses may override the other. It is difficult to predict which reflex overrides. It appears that cardiac reflexes and reflexes related to oxygen conservation and delivery may override the baroreceptor reflexes when these are activated simultaneously. 3. The input from the cardiopulmonary baroreceptors and the arterial baroreceptors may modify significantly responses to chemoreceptor activation and to activation of somatic afferents. There is a significant augmentation of the somatic reflex at low carotid sinus pressures and when the cardiopulmonary vagal afferents are inhibited. The interaction between somatic and cardiopulmonary vagal afferents can be seen in man and may have implications with respect to the response to exercise in patients with hypertension as well as those with heart failure. 4. Finally, the concept of sensitization of receptors is important. The magnitude of a response to a specific stimulus may be modified several fold in the presence of certain drugs or hormones which alter the sensitivity of the receptors to the stimulus. The cardiopulmonary baroreceptors appear to be sensitized by acetylstrophanthidin. This sensitization may explain in part the action of digitalis on the peripheral circulation in heart failure.
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References 1. Abboud FM: Control of the various components of the peripheral vasculature. Fed Proc 31:1226-1239, 1972 2. Abboud FM, Heisfad DD, Mark AL, Schmid PG: Reflex control of the peripheral circulation. Prog Cardiovasc Dis 16:371-403, 1976 3. Calvelo MG, Abboud FM, Ballard IN?, Abdel-Sayed WA: Reflex vascular responses to stimulation of chemoreceptors with nicotine and cyanide. Circ Res 27:259-276, 1970 4. Little R, Oberg B: Circulatory responses to stimulation of the carotid body chemoreceptors in the cat. Acta Physiol Stand 93:34-51, 1975 5. Hackett JG, Abboud FM, Mark AL, Schmid PG, Heistad DD: Coronary vascular responses to stimulation of chemoreceptors and baroreceptors: evidence for reflex activation of vagal cholinergic innervation. Circ Res 31:6-17, 1972 6. Heistad DD, Marcus ML. Ehrhatdt JC. Abboud FM: Effect of stimulation of carotid chemoreceptors on total and regional blood flow. Circ Res 36:20-25, 1976 7. Heistad DD, Abboud FM, Eckstein JW: Vasoconstrictor response to simulated diving in man. J Appl Physiol 25:542-549, 1966 6. deBurgh Daly M, Elsner R, Angell-James JE: Cariorespiratory control by carotid chemoreceptors during experimental dives in the seal. Am J Physiol 232:H508-H516, 1977 9. Blix AS, Wennergren G, Folkow B: Cardiac receptors in ducks-A link between vasoconstriction and bradycardia during diving. Acta Physiol Stand 97:13-19, 1976 10. Zoller RP, Mark AL, Abboud FM, Schmid PG, Heistad DD: The role of low pressure baroreceptors in reflex vasoconstrictor responses in man. J Clin Invest 51:2967-2972, 1972 11. Abboud FM, Eckberg DL, Johannsen UJ, Mark AL: Carotid and cardiopulmonary baroreceptor control of splanchnic and forearm vascular resistance during venous pooling in man. J Physiol 286:173-184 1979 12. Kendrick E, Oberg B, Wennergren G: Vasoconstrictor fibre discharge on skeletal muscle, kidney, intestine and skin at varying levels of arterial baroreceptor activity in the cat. Acta Physiol Stand 85~464-476, 1972 13. Johnson JA, Moore WW, Segar WE: Small changes in left atrial pressure and plasma antidiuretic hormone sites in dogs. Am J Physiol 217:210-214, 1969 14. Eckberg DL, Cavanaugh MS, Mark AL, Abboud, FM: A simplified neck suction device for activation of carotid baroreceptors. J Lab Clin Med 85167-173, 1975 15. Abboud FM, Mark AL, Heistad DD, Schmid PG: Selectivity of autonomic control of the peripheral circulation in man. Trans Am Clin Climatol Assoc 87:184-197, 1975 16. Mark AL, Abboud FM, Schmid PG, Heistad DD: Reflex vascular responses to left ventricular outflow obstruction and activation of ventricular baroreceptors in dogs. J Clin Invest 52: 1147-l 153, 1973
17. Thames MD, Klopfenstein HS, Abboud, FM, Mark AL, Walker JL: Preferential distribution of inhibitory cardiac receptors with vagal afferents to the inferoposterior wall of the left ventricle activated during coronary occlusion in the dog. Circ Res 43:512-519, 1976 18. Eckberg DL, White CW, Kioschos JM, Abboud FM: Mechanisms mediating bradycardia during coronary arteriography. J Clin Invest 54~1445-1461, 1974 19. Thames MD, Abboud FM: Reflex inhibition of renal sympathetic nerve activity during myocardial ischemia mediated by left ventricular receptors with vagal afferents in dogs. J Clin Invest 63: 395-402, 1979 20. Walker JL, Thames MD, Abboud FM, Mark AL, Klopenfenstein HS: Preferential distribution of inhibitory cardiac receptors in left ventricle of the dog. Am J Rhysiol 235:H188-H192, 1978 21. Heistad DD, Abboud FM, Mark AL, Schmfd PG: Interaction of baroreceptor and chemoreceptor reflexes: Modulation of the chemoreceptor reflex by changes in baroreceptor activity. J Clin Invest 53:1226-1236, 1974 22. Heistad DD, Abboud FM, Mark AL, Schmid PG: Effect of baroreceptor activity on ventilatory response to chemoreceptor stimulation. J Appl Physiol 39:411-416, 1975 23. Mark AL, Koike H, Abboud FMr Inhibition of the somatic pressor reflex by increases in carotid baroreceptor activity. Clin Res 23: 473A, 1975 24. Koike H, Mark AL, Heistad DD, Schmid PG: Influence of cardiopulmonary vagal afferent activity on carotid chemoreceptor and baroreceptor reflexes in the dog. Circ Res 37:422-429, 1975 25. Thames MD, Schmid PG: Cardiopulmonary receptors with vagal afferents tonically inhibit ADH release in the dog. Am J Physiol, in press 26. Thames MD, Abboud FM: Interaction of somatic and cardiopulmonary receptors in control of renal circulation. Am J Physiol, in press 27. Walker JL, Abboud FM, Mark AL, Thames MD: Interaction of cardiopulmonary receptors with somatic receptors in man. Submitted for publication 28. Greenberg lT, Richmond WH, Stocking RA, Gupta PD, Meehan JP, Henry JP: Impaired atrial receptor responses in dogs with heart failure due to tricuspid insufficiency and pulmonary artery stenosis. Circ Res 32~424-433, 1973 29. Zucker IH, Earle AM, Gilmore JP: The mechanism of adaptation of left atrial stretch receptors in dogs with chronic congestive heart failure. J Clin Invest 60.323-331,-1977 30. Heistad DD. Abboud FM. Mark AL, Schmid PG: Interaction of thermal and baroreceptor reflexes ‘in man. J Appl Physiol 35: 581-587, 1973 3 1. Thames MD, Abboud FM, Richter R: Sensitization of cardiac receptors by acetylstrophantidin. Clin Res 27:503A, 1979
October 22, 1979
The American Journal of CARDIOLOGY
Volume 44
911
FRANCOIS M. ABBOUD, MD lowa city, lowa
From the Cardiovascular Center; the Cardiovascular Division, Department of internal Medicine; and the Department of Physiology, University of Iowa College of Medicine, Iowa City, Iowa. The experimental work referred to in this presentation was carried out in collaboration with Drs. Allyn L. Mark, Donald D. Heistad, Marc D. Thames, Phillip G. Schmid, John Walker, Manuel Calvelo, James Hackett and Sidney Klopfenstein. This study was supported by Grants HL 14388, HL 16 149, and HL 16066 from the U. S. Public Health Service, Bethesda, Maryland. Manuscript received July 31, 1979, accepted August 3. 1979. Address for reprints: Francois M. Abboud, MD. Department of Internal Medicine, Cardiovascular Center, University of Iowa Collegeof Medicine,
IowaCity,Iowa52242.
This overview presents four important concepts related to integration of cardiovascular reflexes. (1) Activation of sympathetic efferent activity to various organs is nonuniform. Simultaneous activation of both sympathetic and parasympathetic efferent pathways may occur. These effects are evident in the responses to diving and stimulation of chemoreceptors. Both diving and stimulation of chemoreceptors decrease heart rate and myocardial oxygen demand and cause intense peripheral vasoconstriction, which limits oxygen delivery to the periphery. Stimulation of chemoreceptors also causes active coronary vasodilatation favoring an optimal distribution of blood flow to the heart. 2. When two groups of sensory afferents that cause opposing responses are activated simultaneously, the effect of one sensory afferent system will override the other. During hypotension caused by occlusion of the circumflex coronary artery, the reflexes originating in cardiac vagal afferents are inhibitory and reverse the effect of unloading of arterial baroreceptors. The net effect is not simply blockade of sympathetic vasoconstrictor effects, but withdrawal of sympathetic tone. Thus, the cardiac “reflex” overrides the effects of arterial hypotension. 3. The reflex response to activation of one group of sensory afferents may be dependent on the input from other groups of afferents to the medullary neurons. At low carotid sinus pressure, the “gains” of the chemoreceptor and somatic reflexes are augmented. The cardiopulmonary vagal afferents modulate the arterial baroreceptor reflex as well as the chemoreceptor and somatic reflexes. The cardiopulmonary vagal afferents, when activated, suppress the sympathetic excitatory response to arterial hypotension, to chemoreceptor stimulation and to somatic afferent stimulation. Another important interaction is that of the thermal receptors which, when activated by heat, suppress the vasoconstrictor response to arterial hypotension in cutaneous more than in muscular beds. 4. Stimulation of sensory afferent receptors may be modified by drugs or humoral factors acting on the receptor itself or on the chemical and mechanical characteristics of the tissues surrounding the receptor. Acetylstrophanthidin injected into the circumflex coronary artery potentiates the sympathetic inhibitory response to activation of cardiac sensory afferents (vagal afferents) by volume loading and by occlusion of the circumflex. The sensitization may explain in part the action digitalis has on the peripheral circulation in heart failure. The clinical implications of these four important physiologic concepts are discussed.
An understanding of reflex regulation of vascular resistance and blood pressure requires the ability to integrate responses observed in several organs and vascular beds during activation of more than one type of sensory afferent. There are two reasons for this: (1) Reflex responses in various vascular beds are different and this difference determines the
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optimal distribution of blood flow. (2) In the intact animal or human being, particularly in abnormal states, several groups of sensory afferents are activated simultaneously and the net reflex response cannot be deduced from knowledge of responses to activation of each group of afferents separately. For example, in hemorrhagic shock, arterial and cardiopulmonary baroreceptor reflexes as well as chemoreceptor reflexes are activated simultaneously when patients are hypotensive, hypoxic and acidotic. The net response does not equal the algebraic sum of responses observed when each reflex is activated alone. This nonlinear summation implies an “interaction of reflexes” that is important in circulatory control. The experiments selected for presentation emphasize four concepts in the study of integrated control of the circulation: (1) selectivity and nonuniformity; (2) simultaneous activation of opposing reflexes; (3) interaction of reflexes; and (4) “sensitization” of afferent receptors. Selectivity
and Nonuniformity Activity
of Sympathetic
Sympathetic neural activity to various vascular beds and even to segments of the same vascular bed is modulated in a nonuniform manner. The different components of the circulation are controlled selectively.*~2 Furthermore, activation of the sympathetic outflow is not always accompanied by inhibition of the parasympathetic outflow and vice versa. There are reflex responses that include activation of the sympathetic and parasympathetic efferents simultaneously. The foollowing are several examples of selectivity and nonuniformity of neural control: Differential responses of various vascular beds: Stimulation of chemoreceptors causes neurogenic vasoconstriction in skeletal muscle and in splanchnic and renal vessels, and vasodilatation in the coronary circulation, but there is no neurogenic influence on cerebral vessels.“-6 The coronary vasodilatation is caused by activation of vagal parasympathetic efferents5 and the constriction in other vessels is caused by activation of sympathetic adrenergic efferents. Thus, the neurogenie adjustment to stimulation of chemoreceptors favors the distribution of blood flow toward organs critically dependent on oxygen for their integrity and away from those relatively less dependent on oxygen. Simultaneous activation of sympathetic and parasympathetic efferents: Diving and stimulation of chemoreceptors activate sympathetic efferents to the peripheral circulation causing intense vasoconstriction and parasympathetic efferents to the hearts7 Marked bradycardia is seen during diving and during stimulat.ion of chemoreceptors if the hyperventilatory response is prevented by artificial ventilation of the experimental animal. Peripheral vasoconstriction favors “oxygen delivery” to the coronary circulation and, when this is coupled with a reduction in myocardial oxygen demand as a result of bradycardia, the protective effect of the reflex is optimal. Recently, deBurgh Daly et aL8 demonstrated that sustained bradycardia in the diving seal
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is caused by activation of the chemoreceptor reflex and Blix et a1.g showed that the diving bradycardia is sustained in the duck by activation of cardiac vagal afferents as a result of intense peripheral vascular constriction and a shift of blood volume toward the cardiopulmonary region. Differential responses to activation of two “inhibitory” reflexes in human beings: The stretch of arterial baroreceptors during hypertension and of atria1 and ventricular receptors during hypervolemia increases their activity. Afferent impulses originating in these regions inhibit sympathetic vasomotor neurons and activate vagal nuclei. Conversely, a decrease in arterial blood pressure and hypovolemia or hemorrhage unload these receptors and cause a reflex increase in sympathetic and a decrease in vagal efferent activity. Although the afferent nerves from these two receptor regions project to the nucleus tractus solitarius, the physiologic responses to their activation or unloading are not identical, suggesting that they do not converge on the same neurons in the medulla. We are able to evaluate the role of cardiopulmonary afferents and that of carotid baroreceptor afferents separately in hunian beings by applying “lower body negative pressure” using a suction box placed around the lower limbs to the level of the iliac crest. Suction with a commercial vacuum cleaner allows negative pressures of -5, -10, -20 and -40 mm Hg in the box. Progressive pooling of blood in the lower limbs during graded suction reduces central venous pressure and cardiac size. During minimal levels of lower body negative pressure (-5 and -10 mm Hg) central venous pressure decreases by 3 to 5 mm Hg but without a change in arterial pressure or heart rate; thus the signal sensed by the arterial baroreceptors is unchanged. Nevertheless, significant reflex vasoconstriction of forearm blood vessels and a reduction in forearm blood flow occur. The increase in forearm vascular resistance without a change in arterial pressure and without tachycardia (on occasions a decrease in heart rate of 2 to 3 beats/min is seen) suggests that the reflex is not caused by inhibition or unloading of arterial baroreceptors, but rather by unloading of cardiopulmonary baroreceptors1° (Fig. 1). When lower body negative pressure is applied at -40 mm Hg, arterial pressure decreases and pulse pressure narrows. Excessive pooling invokes the arterial baroreceptor reflex in addition to the cardiopulmonary reflex and the resulting response includes tachycardia, a slightly greater increase in forearm resistarlce (Fig. 1) and significant splanchnic vasoconstriction.‘lJ13 The results suggest that in human beings arterial baroreceptors regulate significantly heart rate and splanchnic resistance vessels but not forearm vessels, whereas the cardiopulmonary receptors regulate predominantly resistance of forearm vessels. In order to evaluate more directly the role of carotid baroreceptors in man, a suction device is applied around the neck and the negative pressure increases carotid transmural distending pressure. Reflex bradycardia and hypotension occur but there is no significant
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POOLING
LBNP 40mmHg
LBNP IOmmHg II Central Venous Pressore (mmtig)
OL Systemic Arterial
Pressure (mmliq)
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FIGURE 1. Activation of cardiopulmonary baroreceptor reflex in man. Minimal lower body suction with a lower body negative pressure (LBNP) of - 10 mm Hg causes constriction of vessels of the forearm withput any change in arterial pressure, pulse pressure or first derivative’of pressure (dP/dt); there is no tachycardia. This reflex (left half of figure), which is thought to be mediated through low pressure cardiopulmonary receptors, as indicated by the decrease in central venous pressure, differs from the reflex induced during excessive pooling at LBNP of -40 mm Hg, which causes systemic hypotension and tachycardia but no vasoconstriction (right half of figure).
Venous (LENP
Neck
Poolinp
(NNP
40mmHg)
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FIGURE 2. Comparison of the role of cardiopulmonary baroreceptors and carotid baroreceptors in the regulation of circulation in man. High levels of lower body negative pressure (LBNP) caused the decrease in central venous pressure, hypotension, reflex tachycardia and forearm vasoconstriction. When lower body negative pressure at high levels (LBNP 40 mm Hg) was applied simultaneously with carotid neck suction (NNP 40 mm Hg) (the latter to inhibit the input from the carotid baroreceptor reflex), the interaction resulted in a disappearance of the reflex bradycardia, but the reflex vasoconstrictor response was sustained.
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causing ischemia of the posterior wall of the ventricle,17 or (3) by coronary arteriography.i8 Simultaneously, arterial hypotension reduces the activity of arterial baroreceptors and increases sympathetic drive. The results in these three instances indicate that the net response is inhibition of sympathetic outflow with vasodilatation of the perfused skeletal muscle, decrease in renal nerve activity or bradycardia. Thus, the “cardiac reflex” overrides the effects of arterial hypotension. Figure 3 illustrates the change in renal activity during hypotension induced by transient occlusion of the left anterior descending and circumflex coronary artery sequentially. Occlusion of the left anterior descending coronary artery caused hypotension and an increase in renal nerve activity. In contrast, occlusion of the circumflex coronary artery caused greater hypotension, bradycardia and a reduction in renal nerve activity in more than half of the animals studied despite the hypotension and intact sinoaortic nerves.lg In these animals, the cardiac reflex triggered by circumflex arterial occlusion overrides the effect of inhibition of arterial baroreceptor activity during arterial hypotension. After sinoaortic denervation, the influence of arterial hypotension is minimized and the inhibitory effect of the “cardiac reflex” becomes much more pronounced.lg Although evident with occlusions of both the circumflex and left anterior descending artery, it is more pronounced with circumflex occlusion. The greater inhibitory reflex response during occlusion of the circumflex than during occlusion of the left anterior descending artery reflects a greater density of cardiac sensory receptors with vagal afferents in the posterior wall of the left ventricle. The reflex is mediated through vagal afferents because after bilateral vagotomy there is lesser hypotension and a slight increase in the sympathetic nerve activity during occlusion of both left anterior descending and circumflex arteries.lg
decrease in forearm vascular resistance, thus confirming the belief that carotid baroreceptors do not modulate sympathetic efferents to resistance vessels of the forearm in human beings.zxi4 It is possible, however, that forearm vessels do not dilate during neck suction because sympathetic tone is very low to begin with in these subjects. When sympathetic tone is increased by excessive lower body negative pressure, forearm and splanchnic resistance vessels constrict and heart rate increases. Under these circumstances, simultaneous neck suction suppresses the reflex tachycardia and splanchnic vasoconstriction but the vasoconstriction in the forearm is unalteredl’J” (Fig. 2). These results demonstrate that the two inhibitory reflexes, namely, the carotid and cardiopulmonary reflexes in man, have selective influences on sympathetic efferents to various parts of the circulation. The carotid sinus reflex regulates heart rate and splanchnic resistance and has minimal effect on vessels of the forearm, whereas the cardiopulmonary reflex modulates sympathetic efferents to resistance vessels of the forearm. This situation is different from that in the dog where the same change in muscle resistance is associated with a greater change in renal resistance and heart rate in response to stimulation of cardiac vagal afferents as compared with stimulation of arterial baroreceptor afferents.12 Simultaneous
Activation
of Opposing Reflexes
In pathologic states, several groups of sensory afferents are activated simultaneously and their effects are synergistic. There are instances in which two groups of sensory afferents that cause opposing responses are activated simultaneously. An important question is whether the net effect will be “zero” or whether the effect of one sensory afferent will override the other. Following are three examples of conditions in which opposing reflexes are triggered simultaneously. Cardiac sensory afferents, which reflexly inhibit sympathetic drive, are stimulated (1) by inflation of a balloon in the ascending aorta causing acute left ventricular distension,i6 (2) by occlusion of the circumflex coronary artery
Interaction
The output from neurons in the medullary centers along the sympathetic and parasympathetic efferent
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The American Journal of CARDIOLOGY
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FIGURE 3. Occlusion of the left circumflex (Cx) and left anterior descending (LAD) coronary arteries causes similar increases in mean left atrial pressure (MLAP) but the decrease in mean arterial pressure (MABP) is greater with left circumflex occlusion. Despite the greater decrease in pressure there are several experiments where renal nerve activity (RNA) and heart rate (HR) decrease during left circumflex occlusion. After sinoaortic denervation, occlusions of the left circumflex and left anterior descending coronary arteries both reduce renal nerve activity and mean left atrial pressure but the reductions are much greater with occlusion of the former. P = probability.
INTEGRATION OF CARDIOVASCULAR REFLEXES-ABBOUD
afferents and their neuronal connections. They are also important in pathophysiologic states where the input from arterial or cardiac receptors may be suppressed, as in hyptertension or heart failure. Under those conditions responses to activation of somatic afferents with exercise or activation of chemoreceptors with hypoxia might be drastically modified. Three examples of important interactions are used to illustrate the concept.
pathways is constantly modulated by afferent input from various sensory receptors in the cardiovascular system and other parts of the body. Sensory afferent impulses originate in baroreceptors such as the arterial or cardiopulmonary baroreceptors or in receptors concerned with oxygen conservation and delivery such as the chemoreceptors, the trigeminal sensory afferents that mediate the “diving reflex,” and the somatic receptors activated during exercise. Other receptors in the skin and in the hypothalamic region are sensitive to temperature. The medullary neurons are also under the control of spinal afferents from various viscera and afferents from various regions of the brain such as the hypothalamus, cerebellum, fastigial nuclei and cortex. These reflexes essentially subserve three functions: (1) maintenance of arterial pressure; (2) delivery of oxygen and nutrients to vital organs or to organs with increasing oxygen demand under stress; and (3) regulation of body temperature. The reflex response to activation of one group of sensory afferents may be dependent on the input from other groups of afferents to the medullary neurons. Several questions may be asked in this context: (1) What is the influence of the tonic input from certain sensory receptors on the reflex response observed when the input from one group of sensory afferents is modified? In other words, if the arterial baroreceptor input is increased or decreased, does that modify the response to chemoreceptor stimulation? (2) Can the input from cardiac vagal afferents modify the effects of changes in the activity of arterial baroreceptors or of chemoreceptors on blood pressure, renin release, antidiuretic hormone release and other variables? These questions have physiologic implications concerning the nature of the central projections of these
MUSCLE PP (mmlig)
pressure, the “gains” of the chemoreceptor and somatic reflexes are augmented. 1. Carotid chemoreceptors: Elevation of carotid sinus pressure in the left carotid artery suppresses the chemoreceptor reflex activated by perfusion of the right carotid artery with hypoxic, hypercapnic blood at constant perfusion pressure (Fig. 4). Conversely, a reduction in arterial pressure induced by hemorrhage augments the vasoconstrictor response to stimulation of chemoreceptors.21 A similar interaction occurs with respect to the hyperventilatory response to chemoreceptor stimulation, which is augmented at low carotid sinus pressure.22 2. Carotid somatic receptors: The reflex response to activation of the somatic reflex is also augmented during carotid sinus hypotension. Activation of somatic afferents (by contraction of skeletal muscle or by electric stimulation of the central end of the cut sciatic nerve at high frequency) causes reflex vasoconstriction in the perfused gracilis muscle, an increase in arterial pressure and tachycardia. The magnitude of this reflex response is augmented significantly when the carotid sinuses are perfused at low pressure and inhibited when the carotid sinuses are perfused at high pressure.23 This interaction is not caused by a change in reactivity of blood vessels
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A. Carotid baroreceptors modulate the chemoreceptor and somatic reflexes: At low carotid sinus
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4. The carotid chemoreflex caused by perfusion of one carotid with hypoxic hypercapnic blood at normal pressure is suppressed when
the opposite carotid is perfused at high perfusion pressure (PP) demonstrating a central interaction between the carotid baroreceptors and chemoreceptors. POn = oxygen tension.
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in the gracilis muscle to the released neurotransmitter, norepinephrine. When the somatic reflex is augmented at low carotid sinus pressure, the response to intraarterial norepinephrine injected into the perfused gracilis artery is, if anything, lesser than the control response and, conversely, when the somatic reflex response is inhibited at high carotid sinus pressure, the response to norepinephrine tends to be even greater. The change in gain of the somatic reflex is due to neural interactions rather than to a change in the responsiveness of vascular muscle to the released neurotransmitter. The interaction between carotid baroreceptors and somatic afferents has clinical implications. Activation of somatic afferents in hypertensive states is associated with an increased sympathetic outflow to blood vessels. The augmented neural adrenergic response to exercise in hypertensive states may be related to the fact that carotid baroreceptor activity is suppressed in hypertension. B. Interaction of cardiopulmonary vagal afferents with other reflexes: The cardiopulmonary vagal afferents modulate the arterial baroreceptor reflex with respect to changes in vascular resistance, antidiuretic hormone reIease, and renin release. They can also modulate the chemoreceptor and somatic reflexes. 1. Cardiopulmonary arterial baroreceptors: Carotid hypotension increases arterial pressure and vascular resistance in the gracilis muscle in dogs with cut aortic depressor nerves. Bilateral vagotomy augments this reflex.24 It is postulated that the tonic inhibitory input from cardiopulmonary vagal afferents reduces the gain of the baroreceptor reflex, particularly in the lower range of carotid sinus pressures between 120 and 50 mm Hg. 2. Cardiopulmonary chemoreceptors: Similarly, the response to chemoreceptor stimulation is augmented when the vagal afferent input is absent. The reflex
vasoconstrictor response to injections of nicotine or cyanide into the carotid arteries was significantly greater after than before vagotomy in animals in which the aortic depressor nerves had been cut and carotid sinus pressure was maintained constant.24 3. Cardiopulmonary arterial baroreceptors and ADH: Release of antidiuretic hormones (ADH) is under the control of both the arterial sinoaortic baroreceptors as well as the cardiopulmonary vagal afferents. Thames and Schmidz5 showed that when the aortic nerves and carotid sinus nerves are cut sequentially in the presence of the vagi, there are no changes in ADH concentration but, immediately after vagotomy, there is a significant rise. When the order of these interventions is reversed so that vagotomy is carried out first, followed by section of aortic then carotid sinus nerves, there is a progressive rise in vasopressin concentrations after section of each set of nerves. These results emphasize two points. First, that the order of interventions determines in a significant way the nature of the response, suggesting that there are interneuronal connections that modulate the final pathway for the response in a differential way. The second and more important finding is that the cardiopulmonary vagal input is critical and can suppress the influence of the arterial baroreceptors on ADH release. 4. Cardiopulmonary somatic afferents: The central end of the cut sciatic nerve is stimulated electrically in anesthetized dogs to activate somatic afferents and simulate exercise. The resulting decrease in renal blood flow, increase in arterial pressure and tachycardia are measured as indexes of the magnitude of the somatic reflex. During hypervolemia caused by infusion of dextran, the reflex renal response is reduced whereas, immediately after vagotomy, the response is augmented.26 The magnitude of the renal response in these dogs with cut sinoaortic nerves is inversely related to the
.s F
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FIGURE 5. The increases in renal vascular resistance during activation of somatic afferents (right panel) are reduced by volume loading with intravenous dextran (5, 10 and 15 ml/kg) and augmented by vagotomy (V). A similar trend is seen for the simultaneous increase in arterial pressure and decrease in renal blood flow (left panel). C = control (before dextran); n = number of experiments; P = probability.
INTEGRATION OF CARDIOVASCUCAR
intensity of cardiopulmonary receptor activity (Fig. 5). This interaction is most evident with respect to the changes in renal vascular resistance, but it is less evident with respect to changes in arterial pressure and it is absent with respect to changes in heart rate. In an attempt to determine whether such tin interaction occurs in human beings, somatic afferents are activated by asking normal subjects to perform isometric exercise of the left arm by compressing a dynamometer. Handgrip pressures of 10 and 20 percent of maximal contraction are sustained over a period of 1.5 minutes. The resulting reflex responses are studied by measuring changes in arterial blood pressure and heart rate. This reflex response is examined in a control state and when the input from the cardiopulmonary afferent is reduced by lower body negative pressure at -5 mm Hg. Lower body negative pressure at this minimal level of suction reduces central venous pressure and causes a slight increase in forearm vascular resistance without a change in arterial pressure or heart rate. The reflex response to lower body negative pressure is ascribed to withdrawal or inhibition of cardiopulmonary baroreceptor activity. When isometric exercise is performed during this low level of lower body negative pressure, the reflex vasoconstrictor response is augmented severalfold.” (Fig. 6). These findings indicate that in animals and human beings, the magnitude of reflex neuroadrenergic drive during exercise is modulated by the input from cardiopulmonary vagal afferents. It is tempting to speculate that augmented neuroadrenergic response to exercise in heart failure, which has been documented in patients as well as in animal models, might be related to the decreased afferent input from the heart. Studies by Greenberg et al.*” and by Zucker et a1.2g demonstrated that the activity of left atria1 stretch receptors with vagal afferents is suppressed in animal models of heart failure. If the large number of unmyelinated inhibitory vagal afferents from the left ventricle were hypoactive in heart failure, one might expect the augmented exercise response on the basis of the interaction we demonstrated in normal animals and human beings. C. Interaction of thermal receptors and baroreceptors in the control of cutaneous blood flow: Thermal receptors in the skin mediate responses that modify vascular tone in cutaneous beds to either increase or decrease heat dissipation. We postulated30 that heating of one forearm in human beings could interfere with reflex vasoconstrictor responses in the cutaneous bed (finger or hand) of the opposite arm. Lower body negative pressure at -40 mm Hg increases sympathetic efferent activity; blood flow to the fingers and fore&m decreases. When one forearm is immersed in warm water, the reflex vasoconstrictor response to lower body negative pressure is markedly inhibited in the contralateral fingers but the forearm response is altered only slightly. When the temperature of the water is cooled to loo to 12O C, the reflex response is increased. Thus, the baroreceptor reflex effect on blood flow to the
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fingers is inhibited when the input from thermoreceptors in the contralateral forearm signals an increase in skin temperature. This interaction does not extend as effectively to vessels of the forearm presumably because the forearm is predominantly skeletal muscle. Input from thermal receptors overrides the input from arterial or cardiopulmonary baroreceptors in the control of blood flow to the fingers. of Aff erent Receptors
Sensitization
Stimulation of sensory afferent receptors may be modified by drugs or humoral factors acting on the receptor itself or on the chemical and mechanical characteristics of the tissues surrounding the receptor. Acetylstrophanthidin activates directly cardiac receptors with vagal afferents and arterial baroreceptors, causing reflex bradycardia and inhibition of sympathetic outflow. This effect is transient and lasts several minutes. We recently”’ tested the possibility that acetylstrophanthidin may sensitize cardiac inhibitory receptors and augment responses to expansion of blood volume or to myocardial ischemia. Injection of acetylstrophanthidin (25 pg) into the circumflex coronary artery of dogs with sinoaortic denervation produces an acute and transient bradycardia with decrease in sympathetic nerve activity. Ten to 15 minutes after the injection, when resting values are back to control levels, occlusion of the circumflex coronary artery causes a greater inhibition of sympathetic nerve traffic. Similarly, volume loading with infusion of dextran causes a
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Handgrip
(-5
t_B+NP mmHg)
FffiURE 6. The increases in forearm vascular resistance in 11 subjects during combined lower body negative pressure (LBNP) and handgrip exercise at 10 and 20 percent of maximal voluntary contraction are much greater than those noted with handgrip exercise or lower body negative pressure alone. The bare represent mean changes in vascular resistance in arbitrary units (mm Hg/ml per min per 100 ml f 1 standard error).
22, 1979
The American Journal of CARDIOLOGY
Volume 44
909
INTEGRATION OF CARDIOVASCULAR
REFLEXES-ABBOUD
“Sensitization”
of Cardiac
Acetyl
Reflex
(Sino-Aorfic Before mmHg 4OOT
Systemic
Strophantidin
After
AS
Arterial
Systemic
Pressure
c
25 pg I.C.
Denervated) AS
Arterial
Pressure
:
I
0
0 Integrated
(>
,
Renal
:
:
;
Left Atrlal
12
Nerve
/ iI ,, I) # ,
__h/+_+.,,&--,-_._,*~
Activity
;
Integrated
;’ ’
, i/ ,, I /I ;I ,’ .’ .:, : ,,’ ; i
,
Pressure [email protected]=*w -whr ,*.““-+=,,+P
/
Renal
Nerve
Actlvity
, ,,f t ,i ,,’ !’ ,i /” I , ,’ / ,A’ ,’ ’
Left Atrlal
-2OIk
12
Pressure
~~&_w~_~*~.*~~ 0
0 4OOr
,,’ ,’ ’ -6HZ
I
,i ,; /
Lefl Ventricular
mmGg/sec
Pressure
Leff Ventricular
4OOr
LV dpldt
LV dp/dt
5 ml/kg
10 ml/kg
5 ml/kg
Pressure
I.V. Dextran
Infusion
10 ml/kg
i
FIGURE 7. Rapid intravenous (I.V.) infusion of dextran causes hypervolemia, This reflex is augmented pressure.
significantly
after intracoronary
a rise in left atrial pressure and reflex reduction in renal nerve activity. (l.c.) injection of acetylstrophanthidin (AS). LV dp/dt = first derivative of left ventricular
greater inhibition of renal sympathetic nerve activity after than before acetylstrophanthidin (Fig. 7). These results suggest that one of the mechanisms of action of acetylstrophanthidin in heart failure might be to sensitize cardiac receptors and thereby result in an inhibition of sympathetic activity. In addition to its direct inotropic effect, sensitization of these baroreceptors which are known to be depressed in heart failure may explain the effect of the drug on the peripheral circulation in heart failure. Conclusions An overview of four important concepts related to integration of cardiovascular reflexes is presented: 1. Nonuniformity of sympathetic efferent activity to various organs and of vagal parasympathetic efferent activity to the heart is emphasized. The reflex control of the circulation is selective and optimal for the necessary adjustments under stress. This is evident in the differential effect on the heart and peripheral circulation in diving and during chemoreceptor stimulation. Optimal oxygen conservation and distribution are achieved by a reduction in heart rate and myocardial oxygen demand as well as coronary vasodilatation and intense peripheral vasoconstriction which limits oxygen delivery to organs that are not as dependent on oxygen as the brain and heart.
910
October 22, 1979
The American Journal of CARDIOLOGY
2. Simultaneous activation of two or more sensory afferents is not uncommon in pathologic conditions. One set of reflex responses may override the other. It is difficult to predict which reflex overrides. It appears that cardiac reflexes and reflexes related to oxygen conservation and delivery may override the baroreceptor reflexes when these are activated simultaneously. 3. The input from the cardiopulmonary baroreceptors and the arterial baroreceptors may modify significantly responses to chemoreceptor activation and to activation of somatic afferents. There is a significant augmentation of the somatic reflex at low carotid sinus pressures and when the cardiopulmonary vagal afferents are inhibited. The interaction between somatic and cardiopulmonary vagal afferents can be seen in man and may have implications with respect to the response to exercise in patients with hypertension as well as those with heart failure. 4. Finally, the concept of sensitization of receptors is important. The magnitude of a response to a specific stimulus may be modified several fold in the presence of certain drugs or hormones which alter the sensitivity of the receptors to the stimulus. The cardiopulmonary baroreceptors appear to be sensitized by acetylstrophanthidin. This sensitization may explain in part the action of digitalis on the peripheral circulation in heart failure.
Volume 44
INTEGRATION OF CARDIOVASCULAR
REFLEXES-ABBOUD
References 1. Abboud FM: Control of the various components of the peripheral vasculature. Fed Proc 31:1226-1239, 1972 2. Abboud FM, Heisfad DD, Mark AL, Schmid PG: Reflex control of the peripheral circulation. Prog Cardiovasc Dis 16:371-403, 1976 3. Calvelo MG, Abboud FM, Ballard IN?, Abdel-Sayed WA: Reflex vascular responses to stimulation of chemoreceptors with nicotine and cyanide. Circ Res 27:259-276, 1970 4. Little R, Oberg B: Circulatory responses to stimulation of the carotid body chemoreceptors in the cat. Acta Physiol Stand 93:34-51, 1975 5. Hackett JG, Abboud FM, Mark AL, Schmid PG, Heistad DD: Coronary vascular responses to stimulation of chemoreceptors and baroreceptors: evidence for reflex activation of vagal cholinergic innervation. Circ Res 31:6-17, 1972 6. Heistad DD, Marcus ML. Ehrhatdt JC. Abboud FM: Effect of stimulation of carotid chemoreceptors on total and regional blood flow. Circ Res 36:20-25, 1976 7. Heistad DD, Abboud FM, Eckstein JW: Vasoconstrictor response to simulated diving in man. J Appl Physiol 25:542-549, 1966 6. deBurgh Daly M, Elsner R, Angell-James JE: Cariorespiratory control by carotid chemoreceptors during experimental dives in the seal. Am J Physiol 232:H508-H516, 1977 9. Blix AS, Wennergren G, Folkow B: Cardiac receptors in ducks-A link between vasoconstriction and bradycardia during diving. Acta Physiol Stand 97:13-19, 1976 10. Zoller RP, Mark AL, Abboud FM, Schmid PG, Heistad DD: The role of low pressure baroreceptors in reflex vasoconstrictor responses in man. J Clin Invest 51:2967-2972, 1972 11. Abboud FM, Eckberg DL, Johannsen UJ, Mark AL: Carotid and cardiopulmonary baroreceptor control of splanchnic and forearm vascular resistance during venous pooling in man. J Physiol 286:173-184 1979 12. Kendrick E, Oberg B, Wennergren G: Vasoconstrictor fibre discharge on skeletal muscle, kidney, intestine and skin at varying levels of arterial baroreceptor activity in the cat. Acta Physiol Stand 85~464-476, 1972 13. Johnson JA, Moore WW, Segar WE: Small changes in left atrial pressure and plasma antidiuretic hormone sites in dogs. Am J Physiol 217:210-214, 1969 14. Eckberg DL, Cavanaugh MS, Mark AL, Abboud, FM: A simplified neck suction device for activation of carotid baroreceptors. J Lab Clin Med 85167-173, 1975 15. Abboud FM, Mark AL, Heistad DD, Schmid PG: Selectivity of autonomic control of the peripheral circulation in man. Trans Am Clin Climatol Assoc 87:184-197, 1975 16. Mark AL, Abboud FM, Schmid PG, Heistad DD: Reflex vascular responses to left ventricular outflow obstruction and activation of ventricular baroreceptors in dogs. J Clin Invest 52: 1147-l 153, 1973
17. Thames MD, Klopfenstein HS, Abboud, FM, Mark AL, Walker JL: Preferential distribution of inhibitory cardiac receptors with vagal afferents to the inferoposterior wall of the left ventricle activated during coronary occlusion in the dog. Circ Res 43:512-519, 1976 18. Eckberg DL, White CW, Kioschos JM, Abboud FM: Mechanisms mediating bradycardia during coronary arteriography. J Clin Invest 54~1445-1461, 1974 19. Thames MD, Abboud FM: Reflex inhibition of renal sympathetic nerve activity during myocardial ischemia mediated by left ventricular receptors with vagal afferents in dogs. J Clin Invest 63: 395-402, 1979 20. Walker JL, Thames MD, Abboud FM, Mark AL, Klopenfenstein HS: Preferential distribution of inhibitory cardiac receptors in left ventricle of the dog. Am J Rhysiol 235:H188-H192, 1978 21. Heistad DD, Abboud FM, Mark AL, Schmfd PG: Interaction of baroreceptor and chemoreceptor reflexes: Modulation of the chemoreceptor reflex by changes in baroreceptor activity. J Clin Invest 53:1226-1236, 1974 22. Heistad DD, Abboud FM, Mark AL, Schmid PG: Effect of baroreceptor activity on ventilatory response to chemoreceptor stimulation. J Appl Physiol 39:411-416, 1975 23. Mark AL, Koike H, Abboud FMr Inhibition of the somatic pressor reflex by increases in carotid baroreceptor activity. Clin Res 23: 473A, 1975 24. Koike H, Mark AL, Heistad DD, Schmid PG: Influence of cardiopulmonary vagal afferent activity on carotid chemoreceptor and baroreceptor reflexes in the dog. Circ Res 37:422-429, 1975 25. Thames MD, Schmid PG: Cardiopulmonary receptors with vagal afferents tonically inhibit ADH release in the dog. Am J Physiol, in press 26. Thames MD, Abboud FM: Interaction of somatic and cardiopulmonary receptors in control of renal circulation. Am J Physiol, in press 27. Walker JL, Abboud FM, Mark AL, Thames MD: Interaction of cardiopulmonary receptors with somatic receptors in man. Submitted for publication 28. Greenberg lT, Richmond WH, Stocking RA, Gupta PD, Meehan JP, Henry JP: Impaired atrial receptor responses in dogs with heart failure due to tricuspid insufficiency and pulmonary artery stenosis. Circ Res 32~424-433, 1973 29. Zucker IH, Earle AM, Gilmore JP: The mechanism of adaptation of left atrial stretch receptors in dogs with chronic congestive heart failure. J Clin Invest 60.323-331,-1977 30. Heistad DD. Abboud FM. Mark AL, Schmid PG: Interaction of thermal and baroreceptor reflexes ‘in man. J Appl Physiol 35: 581-587, 1973 3 1. Thames MD, Abboud FM, Richter R: Sensitization of cardiac receptors by acetylstrophantidin. Clin Res 27:503A, 1979
October 22, 1979
The American Journal of CARDIOLOGY
Volume 44
911
