Phillip G. Schmid

The Role of Low Pressure Baroreceptors in Reflex Vasoconstrictor Responses in Man

Studies were performed on 11 healthy men to evaluate the role of low pressure baroreceptors in the reflex forearm vasoconstrictor responses (plethysmography) to venous pooling produced by lower body negative pressure. Lower body negative pressure (LBNP) at - 5, - 10, - 20, and - 40 mm Hg lowered central venous pressure by 42, 59, 74, and 93%, respectively, and decreased forearm vascular conductance by 24, 29, 34, and 40%, respectively. The decreases in forearm blood flow and conductance during the low levels of venous pooling (LBNP - 5 and - 10 mm Hg) occurred without significant changes in arterial pressure, arterial dP/dt. and heart rate. These results with the low levels indicate that maneuvers which decrease venous return and central venous pressure in man can influence forearm vascular tone without significant changes in the determinants of carotid and aortic baroreceptor activity. During high levels of venous pooling (LBNP - 20 and - 40 mm Hg), significant decreases in arterial pressure and dP/dt and significant increases in heart rate accompanied the further reductions in central venous pressure, forearm blood flow, and forearm vascular conductance. About 73% of the decrease in conductance during venous pooling at LBNP - 40 mm Hg, which was sufficient to decrease arterial pressure and activate high pressure baroreceptor reflexes, occurred during low levels of venous pooling at LBNP - 10 mm Hg without changes in arterial pressure. This suggests that much of the forearm vasoconstriction with the high levels of venous pooling, which were sufficient to decrease arterial pressure, may be accounted for by reflexes originating in areas other than high pressure baroreceptors. The results of these studies suggest that low pressure baroreceptors exert an important influence on forearm vascular tone during decreases in venous return and central venous pressure in man.

Blood pressure and heart rate responses to microinjection of vasopressin into the nucleus tractus solitarius region of the rat

The nucleus tractus solitarius (NTS) region in the rat has been shown to receive arginine vasopressin (AVP) and oxytocin (OT) neurophysin-containing neuronal projections from the suprachiasmatic (SNC) and paraventricular nucleus (PVN). Thus, vasopressin and oxytocin might have central influences on the circulation. This as investigated by measuring arterial blood pressure and heart rate (HR) responses following microinjection of vasopressin and oxytocin (0.1, 1.0 and 10.0 ng) into the right nucleus tractus solitarius region of rats anesthetized with urethane. Injections of vasopressin into nucleus tractus solitarius produced dose-related increases in blood pressure and heart rate. The effect of oxytocin on the blood pressure and heart rate was of a lesser magnitude without showing a dose-response relationship. Equivolumetric injections of vehicle and luteinizing hormone-releasing hormone (LH-RH) peptide had no detectable effect on blood pressure and minimal effect on heart rate. Injections of vasopressin into three different sites in the brain stem (1 mm anterior, posterior, and lateral to the tractus solitarius) did not produce significant hemodynamic changes. Intravenously injected vasopressin produced increments in blood pressure only at the highest dose level (10.0 ng) and a decrease rather than an increase in heart rate. Ganglionic blockade significantly reduced pressor responses to vasopressin injected into the nucleus tractus solitarius region and completely eliminated HR responses. Pretreatment of the nucleus tractus solitarius with a vasopressin antagonist abolished the blood pressure and heart rate responses produced by injection of vasopressin. These results suggest that vasopressin acts in the region of the nucleus tractus solitarius to exert a central action on the circulation.

Effects of adrenergic stimulation on ventilation in man

The mechanism by which catecholamines affect ventilation in man is not known. Ventilatory responses to catecholamines were observed in normal subjects before and after adrenergic receptor blockade. Intravenous infusions of norepinephrine and isoproterenol caused significant increases in minute volume and decreases in end-tidal P(Co2) which were blocked by the administration of propranolol, a beta adrenergic receptor blocker. The hyperventilatory response to hypoxia was not altered by propranolol. Intravenous infusion of phenylephrine caused a small but significant decrease in minute volume which was antagonized by phentolamine, an alpha adrenergic receptor blocker. Angiotensin, a nonadrenergic pressor agent, also decreased minute volume significantly.100% oxygen was administered to suppress arterial chemoreceptors. Increases in minute volume and decreases in arterial P(Co2) in response to norepinephrine and isoproterenol were blocked by breathing 100% oxygen. The decrease in minute volume during phenylephrine was not altered by 100% oxygen. THE RESULTS INDICATE THAT: (a) beta adrenergic receptors mediate the hyperventilatory response to norepinephrine and isoproterenol but not to hypoxia. (b) the pressor agents phenylephrine and angiotensin decrease ventilation, and (c) suppression of chemoreceptors blocks the ventilatory response to norepinephrine and isoproterenol but not to phenylephrine. Implications concerning the interaction of adrenergic receptors and chemoreceptors with respect to the hyperventilatory response to catecholamines are discussed.

Reflex control of the peripheral circulation.

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

Interaction of Baroreceptor and Chemoreceptor Reflexes MODULATION OF THE CHEMORECEPTOR REFLEX BY CHANGES IN BARORECEPTOR ACTIVITY

The purpose of this study was to determine whether the level of arterial pressure and degree of baroreceptor activation affect responses to stimulation of chemoreceptors. Chemoreceptors were stimulated by injecting nicotine into the common carotid artery of anesthetized and paralyzed dogs. Responses were observed in the innervated gracilis muscle, perfused at constant flow while perfusion pressure was measured. Arterial pressure was lowered by bleeding the animals and raised by transient occlusion of the descending aorta. Vasoconstrictor responses to stimulation of chemoreceptors were enhanced by hypotension and inhibited by elevation of arterial pressure. Potentiation of the chemoreceptor reflex by hemorrhagic hypotension was not the result of altered vascular resistance in the gracilis muscle, sensitization of chemoreceptors by catecholamines or acidosis, or changes in cerebral perfusion pressure. Additional studies were done in which we excluded the possibility that the changes resulted from direct effects of changes in arterial pressure on chemoreceptors. Both carotid bifurcations were isolated and perfused. On one side, pressure was raised to stimulate the carotid sinus baroreceptors. On the other side, the carotid body chemoreceptors were stimulated by nicotine or by hypoxic and hypercapnic blood. Activation of baroreceptors on one side attenuated the vasoconstrictor response to chemoreceptor stimulation on the other side. This excludes a direct effect of changes in arterial pressure on the chemoreceptors and suggests a central interaction of these reflexes. We conclude that vasoconstrictor responses to stimulation of chemoreceptors are potentiated by hypotension and inhibited by transient hypertension. These effects appear to result at least in part from a central interaction of chemoreceptor and baroreceptor reflexes.

Antidiuretic hormone release and the pressor response to central angiotensin II and cholinergic stimulation

Abstract Intraventricular (IVT) injections of angiotensin II (AII) have been shown to produce a short latency blood pressure increase and antidiuretic hormone (ADH) release in several species of mammals. In addition, IVT injections produce these same responses in the rat. Unanaesthetized hydrated rats have been used as their own bioassay to study if the pressor effect produced by IVT AII is caused by the vasopressin release. The results indicate that intraventricular injections of AII in a dose range of 0.5–500 ng result in dose dependent ADH release of from 0.04 to 3.32 mU, and carbachol in doses from 0.025 ng to 250 ng produces ADH release from 0.29 to 4.01 mU. Intravenous AII or carbachol in the same dose range did not release ADH in detectable amounts. The time course and magnitude of ADH release produced by intraventricular AII or carbachol injections and data from hypophysectomized rats indicates that vasopressin is partially but not totally responsible for the centrally-induced blood pressure increase. The data suggest that central activation of the sympathetic nervous system is also involved in the response. To test this, 11 rats received peripheral sympathectomy with 6-hydroxydopamine. The amount of ADH released to a central All challenge in these animals was not changed. Following sympathectomy, there was an increased sensitivity to vasopressin which could completely account for the pressor responses observed.

Organization of the sympathetic postganglionic innervation of the rat heart

The origins and organization of cardiac sympathetic postganglionic nerves in the rat were identified in the present investigation. The retrograde tracer, Diamidino Yellow, was injected into the right or left ventricles to label somata in the sympathetic chain. Analysis of all sympathetic ganglia from superior cervical ganglion through the 10th thoracic ganglion indicated that the postganglionic innervation of the rat cardiac ventricles originates bilaterally. The majority of these somata were located in the middle and inferior cervical ganglia (middle cervical-stellate ganglion complex) (approximately 92% of all labelled cells), with lesser contributions from the superior cervical and 4th through 6th thoracic ganglia. To confirm and further quantitate these findings, the middle cervical-stellate ganglion complex was removed (MC-S ganglionectomy) bilaterally or ipsilaterally from the left or right sides, and regional cardiac norepinephrine concentration (left and right atrial appendages and left and right ventricles) was analysed 7 or 28 days later. At both times after bilateral MC-S ganglionectomy, regional cardiac norepinephrine was reduced by 89% to 100%, indicating the removal of almost all cardiac noradrenergic cells of origin and possibly fibers of passage. The results of unilateral MC-S ganglionectomy experiments indicated that the atrial appendages and the left ventricle receive bilateral innervation from the middle cervical-stellate ganglion complex. However, the left middle cervical-stellate ganglion complex appears to contribute a majority of the norepinephrine to the right ventricle. Furthermore, between 7 and 28 days after contralateral MC-S ganglionectomy, atrial appendages, but not ventricles, display significant recovery of norepinephrine content. The present data demonstrate: (1) a bilateral locus of origin of cardiac sympathetic postganglionic neurons, limited longitudinally to cervical through mid-thoracic ganglia, and (2) the ability of the cardiac postganglionic innervation to regenerate after partial denervation. These results demonstrate anatomical evidence for significant bilateral integration of cardiac sympathetic activity at the level of the sympathetic ganglion in the rat.

Abnormal Vascular Responses to Exercise in Patients with Aortic Stenosis

We tested the hypothesis that the normal forearm vasoconstrictor response to leg exercise is inhibited or reversed in patients with aortic stenosis, possibly because of activation of left ventricular baroreceptors. Forearm vascular responses to supine leg exercise were measured in 10 patients with aortic stenosis and in 2 control groups of 6 patients with mitral stenosis and 5 patients without valvular heart disease.Forearm vasoconstriction occurred during exercise in the control groups. In contrast, forearm blood flow increased and forearm vascular resistance did not change in patients with aortic stenosis. In six patients with aortic stenosis and a history of exertional syncope, forearm vasodilatation occurred during the second minute of leg exercise. Inhibition or reversal of forearm vasoconstrictor responses in aortic stenosis was asscociated with significant increases in left ventricular pressure. In three patients with aortic stenosis and exertional syncope, forearm vasodilator responses to exercise changed to vasoconstrictor responses after aortic valve replacement. The results indicate that forearm vasoconstrictor responses to leg exercise are inhibited or reversed in patients with aortic stenosis, possibly because of activation of left ventricular baroreceptors. The observations suggest that reflex vasodilatation resulting from activation of left ventricular baroreceptors may contribute to exertional syncope in patients with aortic stenosis.

Differences in Direct Effects of Adrenergic Stimuli on Coronary, Cutaneous, and Muscular Vessels

Direct effects of adrenergic stimuli on coronary vessels in dogs were compared with effects on vessels to skin (hind paw) and skeletal muscle (gracilis muscle) after intravenous administration of practolol (2 mg/kg), a selective myocardial beta receptor blocker which minimized indirect effects of myocardial stimulation on coronary vascular resistance. The left circumflex coronary, cranial tibial, and gracilis arteries were perfused separately but simultaneously at constant flow. Perfusion pressures, left ventricular pressure and dP/dt. and heart rate were recorded. Changes in perfusion pressure to each bed reflected changes in vascular resistance. The direct constrictor effects of sympathetic nerve stimulation, norepinephrine and phenylephrine on coronary vessels were minimal compared with effects on cutaneous and muscular vessels. Subsequent blockade of vascular beta receptors did not augment the constrictor responses. Angiotensin, a nonadrenergic stimulus, produced striking coronary vasoconstriction which exceeded that in skin and approximated that in muscle. These results suggests that there is a paucity of alpha adrenergic receptors in coronary vessels compared to cutaneous and muscular vessels. Direct dilator responses to isoproterenol were similar in coronary and cutaneous vessels, but were greater in muscular vessels. Responses to glyceryl trinitrate, a nonadrenergic dilator, also were greater in skeletal muscle. Therefore, differences in effects of isoproterenol on the three beds may reflect differences in reactivity to dilator stimuli rather than differences in the density of beta receptors. In contrast to norepinephrine, the predominant direct effect of epinephrine on coronary vessels was dilatation mediated through activation of vascular beta receptors. A constrictor effect caused by stimulation of alpha receptors was unmasked by propranolol.Finally, the order of potency of agonists in stimulating coronary vascular beta receptors and the demonstration of selective beta receptor blockade with practolol suggest that beta receptors in coronary vessels resemble those in peripheral vessels more than those in myocardium.

Location, distribution and projections of intracardiac ganglion cells in the rat

Physiological studies indicate that cardiac parasympathetic nerves may act selectively at discrete cardiac sites. To determine anatomical sites at which selective integration of cardiac nerve activity may occur, the present study identified and described the location, distribution, and projections of intracardiac ganglion cells in the rat. The estimated 3992 ganglion cells per rat heart were located in 4 distinct groups, all above the atrioventricular groove: (1) between the superior vena cava and aorta (2.5% of total), (2) in the region of the superior interatrial septum (49.9%), (3) posterior to the left atrium (24.0%), and (4) posterior to the inferior interatrial septum and right atrium (23.5%). Only a few ganglion cells were located subepicardially within the infolding of the dorsal interatrial septum. Retrogradely transported fluorescent tracers injected into the left or right ventricles demonstrated that different groups of ganglion cells projected to discrete or selective regions of the heart. Projections to the left ventricle originate only from ganglion cells located posterior to the interatrial septum and the left atrium. In the rat, intracardiac ganglion cells, confined to 4 atrial regions, appear to have discrete sites of termination within the heart. It is proposed that selective activation of different intracardiac ganglion cell groups may elicit specific regional changes in cardiac parasympathetic nerve activity.