Reflex Inhibition of Sympathetic Nerve Activity by Phenoxybenzamine

The effects on baroreceptor and sympathetic nerve activity of the a-adrenergic blocking agent phenoxybemamirie have been investigated in 13 anesthetized rabbits. Nerve activities were recorded at various blood pressure levels, obtained by stepwise changes of blood volume. With phenoxybenzamine, aortic nerve activity at 80 and 90 mm Hg exceeded control values by 66 and 62 %. At the same pressures, renal nerve activity was reduced by 30 and 55 %. Although blood pressure started to fall shortly after injecting the drug, about 20 min elapsed before development of maximum effects on the nerves. When studied during stepwise changes of blood pressure after a similar period of hypotension—but without the drug-sympathetic nerve activity had increased. Phenoxybenzamine had accordingly effected a suppression of sympathetic activity, suggesting that the hypotensive response to phenoxybenzamine is aided by increased reflex inhibition of sympathetic nerve activity.     

Neural control of sympathetic nerve response to cardiogenic hypotension in anesthetized cat

The present study was designed to determine effect of the preganglionic splanchnic nerve activity (SNA) on the brief hypotension accompanied with the occlusion of left circumflex coronary artery (CxCAO) in chloralose anesthetized cats. Following CxCAO in animals with neuraxis intact, no significant alterations of SNA occurred despite the significant fall in mean blood pressure (MBP). A significant fall in MBP also occurred in vagotomized animals with arterial baroreceptors intact, but SNA was significantly augmented from 12.9 +/- 2.7 impulses/sec before CxCAO to 24.4 +/- 4.3 impulses/sec 60 sec after the occlusion. In vagotomized animals, in which their carotid sinuses were isolated and perfused with the constant pressure at a level equal to systemic blood pressure (112 +/- 6 mmHg) and with higher pressure (167 +/- 7 mmHg), SNA was not altered significantly during the hypotension due to CxCAO. When the carotid sinuses were perfused with lower pressure (53 +/- 8 mmHg), a significant increase in SNA occurred simultaneously with the decrease in MBP after CxCAO. The peak decreases in blood pressure during the coronary occlusion were significantly greater in the vagotomized group (-46 +/- 5 mmHg) and in the Low-CSP group (-50 +/- 5 mmHg) than in other groups. Onset of this excitatory efferent sympathetic response to the hypotension due to the coronary occlusion in the vagotomized and Low-CSP groups was delayed significantly despite a significant fall in arterial blood pressure. These results show that vagal afferents from the heart may play a role of inhibiting the sympathetic augmentation mediated by arterial baroreceptors during cardiogenic hypotension. An excessive activation of cardiac receptors with sympathetic afferents may be induced by the profound fall in blood pressure, resulting in further impairment of cardiac function due to progressive myocardial ischemia under the condition of high sympathetic tone activated by baroreceptor reflex.     

Baroreflex “resetting” by arterial hypoxia in the renal and cardiac sympathetic nerves of the rabbit

1. Renal and cardiac sympathetic baroreflex functions were studied in sodium pentobarbitone anaesthetized rabbits given succinylcholine, during constant artificial ventilation with air and with hypoxic gas mixtures. Mean arterial pressure (MAP) was raised and lowered between values of 40 and 140 mm Hg by means of aortic and vena caval periovascular balloons and integrated sympathetic nerve activity (SNA) was recordered. 2. The relationship between MAP and SNA was sigmoid, with upper and lower plateau levels. The curves were defined by calculating median blood pressure, SNA Range and reflex gain. In both renal and cardiac sympathetics section of the carotid sinus and aortic nerves completely abolished the MAP-related changes in SNA. 3. The renal baroreflex curves were reset from control levels during hypoxia. Median blood pressure increased, as did SNA Range and gain. These effects were due to central interactions between arterial baroreceptor, arterial chemoreceptor and vagal afferent activity. 4. The cardiac sympathetic baroreflex curves were shifted in the opposite direction from control with reduction in median blood pressure, SNA Range and reflex gain. These changes were due to chemoreceptor-arterial baroreceptor interactions. 5. Arterial hypoxia thus evokes a differentiated pattern of baroreflex resetting in the renal and cardiac sympathetic montoneuron pools with differing changes in neural response range and sensitivity to arterial pressure changes.     

Effects of sympathetic nerves on cerebral blood flow in awake dogs.

Although cerebral blood vessels are densely innervated by sympathetic nerve fibers, the functional significance of the nerves is controversial. Because previous studies have been primarily performed in anesthetized animals, it is possible that failure to observe prominent neural control of the cerebral circulation was secondary to anesthetic-induced depression of the sympathetic nervous system. Therefore, we studied sympathetic control of the cerebral circulation in 11 awake chronically instrumented dogs. Total and regional cerebral blood flow was measured with 15-micrometer microspheres at control blood pressure and during three levels of progressive hemorrhagic hypotension. Sympathetic nerves had only a small effect (11% decrease; P less than 0.05) on flow to the cerebrum during moderate hypotension (mean arterial pressure 49 +/- 2 mmHg). Also, during severe hypotension, there was a bilateral redistribution of brain blood flow that tended to preserve flow to the medulla. Although these studies suggest that sympathetic nerves have a definite constrictor effect on cerebral vessels, the data support the concept that the functional importance of sympathetic nerves to cerebral vessels is limited.     

Circulatory control in hypoxia by the sympathetic nerves and adrenal medulla

1. The effects of severe arterial and primary tissue (carbon monoxide) hypoxia on cardiac output, arterial and right atrial pressures, heart rate and ventilation, have been studied in unanaesthetized normal rabbits, and in animals subjected to adrenalectomy, ;sympathectomy' (guanethidine), adrenalectomy + ;sympathectomy', and section of the carotid sinus and aortic nerves.2. In both arterial and primary tissue hypoxia the sympathetic nerves play a more important part in the normal circulatory response than the adrenal medullary hormones.3. Provided one adrenergic effector pathway remains intact, animals with intact chemoreceptors and baroreceptors tolerate both types of hypoxia well. Circulatory control during both types of hypoxia by means of sympathetic nerves alone produces relatively more peripheral vasoconstriction than is observed during reflex control through increased adrenal catecholamine secretion.4. The occurrence of tonic sympathetic activity in animals with section of carotid sinus and aortic nerves permits maintenance of a high cardiac output during hypoxia but the arterial pressure is low and there is probably less selective distribution of blood flow to the periphery than in animals with normal reflex control.5. Absence of any adrenergic activity in adrenalectomized and ;sympathectomized' animals results in a gradual fall in cardiac output during prolonged hypoxia, after an initial small rise.6. The results in guanethidine-treated animals suggest that the sympathetic discharge to the arterial chemoreceptors is a factor sustaining chemoreceptor discharge during prolonged arterial hypoxia.     

Pressure-Independent Inhibition of Sympathetic Activity by Noradrenaline: Role of Baroreceptor C Fibres*

The effect of i.v. infusion of noradrenaline on activity in the renal sympathetic nerve was studied in rabbits anesthetized with chloralose and urethane. Noradrenaline (3–8 μg/kg·min) initially increased mean arterial pressure 20–40 mmHg and consequently reduced renal nerve activity. However, studies over a wide range of pressures—obtained by changing the blood volume, revealed that noradrenaline after a few minutes had induced a pressure-independent reduction of sympathetic discharge. The effect disappeared with baroreceptor denervation. An unchanged relationship between arterial pressure and integrated activity in the whole left aortic nerve (which is largely a measure of activity in A fibres) suggested that the sympathetic depression was due to excitation of aortic nerve C fibres. This conclusion was supported by studies of sympathetic responses to selective stimulation of aortic nerve A and C fibres at equal pressures before and during infusion of noradrenaline. Compared to the reflex activity from A fibres, C fibre stimulation was invariably less effective in suppressing renal nerve activity during the infusion. Our studies indicate that noradrenaline may effect a negative feedback control of sympathetic discharge through activation of baroreceptor C fibres.     

Reflex inhibition of sympathetic activity during volume load in awake normotensive and spontaneously hypertensive rats

The reflex inhibition of the sympathetic activity in the splanchnic nerves was recorded upon volume expansion with blood in awake spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto rats (WKR) at an age of 16–20 weeks. At 10% blood volume expansion SHR showed a significantly greater nerve inhibition (43 %) in comparison with WKR (33 %). This augmented reflex response was not caused by the arterial baroreceptors, because the sensitivity of the arterial baroreceptor reflex arch, if anything, tended to be lower in SHR and the increase in arterial blood pressure upon volume load was also lower in SHR. It is suggested that the reason for this increased reflex inhibition in SHR is an augmented low pressure receptor response. The mechanism behind this is discussed. The most likely explanation is a decreased distensibility of the venous system, the systemic andlor the pulmonary veins.     

Influences on colonic and small intestinal motility by the cerebellar fastigial nucleus.

The fastigial influence on intestinal motility was investigated in acute experiments on chloralosed cats. Motility was recorded both from the small and large intestine. Electrical stimulation of the rostral fastigial pole produced, in combination with a blood pressure rise, increased motor activity in ileum and colon while jejunum could respond with either increased on decreased motility. The intestinal responses were neither secondary to changes in intestinal blood flow, nor to baroreceptor reflexes induced by the increased blood pressure. The excitatory responses were not due to increased parasympathetic activity since sectioning of such pathways failed to abolish the responses. Instead, interruption of adrenergic sympathetic discharge, accomplished either by guanethidine or by sectioning of relevant nerves, aid eliminate the responses, indicating that the fastigial effects were mediated by suppression of prevailing adrenergic tone. Noxious stimuli to the abdomen, including laparotomy, inhibit intestinal motility by a reflex increase in adrenergic discharge. It is suggested that fastigial influence on intestinal motility is mainly due to suppression of this reflex.     

Influences on Colonic and Small Intestinal Motility by the Cerebellar Fastigial Nucleus

The fastigial influence on intestinal motility was investigated in acute experiments on chloralosed casts. Motility was recorded both from the small and large intestine. Electrical stimulation of the rostral fastigial pole produced, in combination with a blood pressure rise, increased motor activity in ileum and colon while jejunum could respond with either increased or decreased mobility. The intestinal responses were neither secondary to changes in intestinal blood flow, nor to baroreceptor reflexes induced by the increased blood pressure. The excitatory responses were not due to increased parasympathetic activity since sectioning of such pathways failed to abolish the responses. Insted, interruption of adrenergic sympathetic discharge, accomplished either by guanethidine or by sectioning of relevant nerves, did eliminate the responses, indicating that the fastigial effects were mediated by suppression of prevailing adrenergic tone. Noxious stimuli to the abdomen, including laparotomy, inhibit intestinal motility by a reflex increase in adrenergic discharge. It is suggested that fastigial influence on intestinal motility is mainly due to suppression of this reflex.     

Cardiopulmonary sympathetic afferent influences on renal nerve activity.

Cardiopulmonary sympathetic afferent nerves may affect renal control of intravascular volume by influencing renal sympathetic nerve activity. This influence was evaluated in alpha-chloralose anesthetized, vagotomized, sino-aortic denervated cats. When the afferent nerves were activated with a single electrical stimulus, the renal nerve responded with an excitatory burst of activity followed by a long period of inhibition. This response had characteristics of a supraspinal reflex. Repetitive stimulation of the sympathetic afferent nerve either inhibited or excited renal nerves and increased or decreased systemic blood pressure. The direction of these changes depended on stimulus parameters. No obligatory correlation in the direction of change of nerve activity and blood pressure was observed. Activation of cardiopulmonary sympathetic afferent nerves by intravascular volume expansion inhibited renal nerve discharge. Inhibition was elminated by sectioning the sympathetic afferent nerves. Volume expansion had no effect on lumbar sympathetic discharge monitored simultaneously with renal nerve activity. This observation suggests specificity of reflex influences of these afferent nerves on the kidney. In conclusion, cardiopulmonary sympathetic afferent nerves can reflexly alter renal nerve activity, and therefore may affect renal control of intravascular volume.     

The cause of the difference between the arterial baroreceptor reflex under natural pulsatile circulation and under nonpulsatile systemic circulation

In a previous study we investigated the relation between afferent and efferent activity of the arterial baroreceptor reflex under nonpulsatile systemic circulation using total left heart bypass. The results indicated that the regulation of the arterial baroreceptor reflex was converted under nonpulsatile systemic circulation, and we inferred that a possible reason for this conversion was the transformation in discharge of the afferent activity of the arterial baroreceptor reflex that took place under nonpulsatile systemic circulation. In the present study we tested this hypothesis by sectioning carotid sinus and aortic depressor nerves and electrically stimulating bilateral aortic depressor nerves under anesthesia in five rabbits (400 spikes for 20s, with 0.02ms pulse width and 8 V amplitude), while recording changes in aortic pressure, mean aortic pressure, and heart rate. Continuous stimulation was taken as discharge of the afferent activity of the arterial baroreceptor reflex under nonpulsatile systemic circulation, and periodic stimulation was taken as discharge under natural pulsatile circulation. Aortic pressure, mean aortic pressure, and heart rate decreased under both continous and periodic stimulation. The decreases in mean aortic pressure and heart rate during continuous stimulation were significantly lower than those during periodic stimulation. Our results suggest that the transformation in discharge of the afferent activity of the arterial baroreceptor reflex under nonpulsatile systemic circulation may have played an important causative role in the conversion of the regulation of the arterial baroreceptor reflex under nonpulsatile systemic circulation.     

Carviobascular alterations associated with bursts of panting in the exercising dog

1. In conscious dogs exercising on a treadmill variations in arterial blood pressure and heart rate which were correlated with bursts of panting were observed. The blood pressure variations reflected similar variations in the total peripheral vascular resistance.2. During exercise a change in respiration from slow breathing to panting was followed by a systemic vasodilatation and fall in blood pressure, but a rise in heart rate. Analysis of the time course of these effects demonstrated that the heart rate increase occurred later than the blood pressure fall.3. The correlation between panting and blood pressure changes was not abolished by either of the receptor-blocking drugs atropine sulphate or propranolol, nor by either of the following surgical procedures: acute bilateral cervical vagotomy, and denervation of the carotid sinus baroreceptors and carotid body chemoreceptors.4. The vasodilatation which followed a burst of panting appeared to be due to a decrease in adrenergic vasoconstrictor sympathetic nerve activity, and not to a change in the chemical composition of the arterial blood.5. It is concluded that the vascular changes are not reflex responses to stimulation of peripheral receptors by the bursts of panting. Instead, it is suggested that both the bursts of panting and associated falls in blood pressure are parallel effects resulting from activation at a suprabulbar level of the central nervous system. It is also concluded that the variations in heart rate are mediated by the baroreceptor reflex mechanism, activated by the changes in mean blood pressure.     

The effects of haemorrhage in the unanaesthetized rabbit

1. The circulatory response following acute loss of 26% of the blood volume was examined in unanaesthetized rabbits. The groups of animals studied were normal rabbits; adrenalectomized rabbits; animals subjected to prolonged treatment with guanethidine in which peripheral adrenergic nerve transmission is blocked, but which can reflexly liberate adrenal medullary hormones; animals subjected to combined adrenalectomy and guanethidine treatment with no functional adrenergic effectors; in each case with or without administration of atropine. The responses of animals with section of the carotid sinus and aortic nerves were also examined.

2. The spontaneous rate of replacement of the blood volume after haemorrhage by reabsorption of extravascular fluid was the same in all the above preparations, the blood volume returning to normal 3-4 hr after bleeding.

3. The `passive' effects of haemorrhage were examined in animals without functioning autonomic effectors and include a large fall in right atrial pressure and cardiac output, arterial hypotension, no significant change in total peripheral resistance, and a bradycardia of gradual onset. Reflex autonomic effector activity in normal animals minimizes the fall in atrial pressure, cardiac output and arterial blood pressure, and produces a significant increase in total peripheral resistance and tachycardia. Increased sympathetic nerve activity and secretion of adrenal medullary hormones each play an important and complementary part in the normal circulatory response to haemorrhage of the rabbit. There is also reflex reduction in vagal efferent activity.

4. Reflexes from the carotid sinus and aortic arch limit the fall in arterial pressure for the first 4 hr after haemorrhage. These reflexes also account for the tachycardia normally observed after haemorrhage. The baroreceptor reflexes rather than the chemoreceptors appear to be dominant in these responses.

5. Twenty-four hours after haemorrhage the haemodynamic pattern is similar in all preparations irrespective of their autonomic effector status: blood volume, right atrial pressures and cardiac outputs are all elevated, and the arterial pressure has virtually recovered, consistent with the development of hypervolaemic anaemia at this time.

     

Neurogenic modification of the vulnerability of the blood-brain barrier during acute hypertension in conscious rats

To study the possible influence of sympathetic adrenergic tone on the blood-brain barrier function during acute hypertension in conscious unrestrained rats with indwelling catheters in the aorta and a jugular vein the blood pressure was increased by noradrenaline, 6-hydroxydopamine (6-OHDA) or baclofen. One or 60 min later the rats were sacrificed and the extravasation of ¹²⁵I labelled albumin determined in the brain. After i. v. injection of noradrenaline the baroreceptor reflex will decrease the sympathetic tone whereas the blood pressure increase induced by the other two drugs is accompanied by an increased sympathetic activity. One minute after a corresponding rise in blood pressure the albumin content in the brain was considerably lower in rats given 6-OHDA than in those given noradrenaline. 60 min after the injection of 6-OHDA or baclofen the extravasation in the brain did not differ despite a considerably more rapid increase in pressure after 6-OHDA. Pretreatment with clonidine increased the blood-brain barrier dysfunction in rats given 6-OHDA but not in those given baclofen, probably because the slower rise in pressure facilitates myogenic autoregulation. It is concluded that neurogenic influences on vessel tone can modify the response of the blood-brain barrier during acute hypertension in conscious rats.     

The role of cardiac sympathetic discharges during the pulmonary depressor reflex.

The role played by the cardiac sympathetic fibers in the pulmonary depressor reflex was analyzed in twenty dogs. The selective perfusion with homologous blood of the inferior lobar vessels of the left lung with pressures of 40 to 60 mmHg decreased the spontaneous background discharges recorded from the left superior or inferior cardiac sympathetic nerves. This decrease was maximal at perfusion pressure of 80-100 mmHg. Following the decrease in the sympathetic discharges, the systolic and diastolic systemic arterial blood pressure decrease about 10 per cent. The changes were reversible when the perfusion pressure was returned to the control. The intravenous injection of atropine sulphate did not change either the systemic hypotension or the responses of the sympathetic efferent discharges induced by elevation of the pressure in the vascular bed of the lung lobe. Thus, it is believed that the systemic arterial blood pressure during this reflex may have fallen due to a diminution of the vascular tone caused by a decrease in the sympathetic efferent discharges. After transection of the vagus nerve ipsilateral to the tested lobe, the reduction of the sympathetic discharges as well as the decrease of the systemic arterial blood pressure were no longer observed. Our results further substantiate the concept that the vagus nerve is the afferent pathway for the pulmonary depressor reflex, and it may be concluded that during this reflex the sympathetic efferent activities are inhibited.     

Contrasting reflex influences of cardiac afferent nerves during coronary occlusion

Afferent neurons contained within cardiac sympathetic nerves may have important influences on the circulation when activated during myocardial ischemia. Although such activation is known to reflexly excite upper thoracic sympathetic efferent neurons, effects on other components of sympathetic outflow are unknown. Therefore, cardiac sympathetic afferent nerves were stimulated by occlusion of coronary arteries to investigate their reflex influences on renal sympathetic nerve activity and systemic arterial blood pressure. Responses were observed in anesthetized cats in which sympathetic and/or vagal cardiac afferent nerves remained intact and arterial baroreceptors remained intact or had been denervated. Stimulating sympathetic afferent neurons caused excitation of renal nerve activity, which was accompanied by variable changes in arterial pressure. Stimulation of vagal afferents by coronary occlusion consistently produced inhibition of renal nerve activity and marked depressor responses. When both components of cardiac innervation remained intact, increases or decreases in renal nerve activity and blood pressure were elicited by coronary artery occlusion in the presence or absence of arterial baroreceptors. These results illustrate that cardiac sympathetic afferent nerves can contribute significantly to cardiovascular control during myocardial ischemia.     

Role of the Symphato-Adrenal System in Hemorrhagic Hyperglycemia

Arterial and venous plasma glucose concentration was determined at intervals in cats subjected to hemorrhagic hypotension at 50 mm Hg. The rapid rise of arterial plasma glucose after hemorrhage could be. attributed to an increased release of glucose from the liver. This hyperglycemia could not be eliminated by bilateral adrenalectomy or by sectioning of the hepatic sympathetic nerves, although the response was somewhat depressed by the latter procedure. On the other hand the hyperglycemia was virtually abolished after adrenalectomy when combined with bilateral sectioning of the major and minor splanchnic nerves. The level of plasma glucagon during hemorrhage increased in cats with an intact sympatho-adrenal system, but was unchanged in animals with combined splanchnic sympathectomy and adrenalectomy. It is concluded that, during hemorrhage, the sympatho-adrenal system influences the glucose output from the liver by three different reflex mechanisms: (a) release of catecholamines from the adrenal glands; (b) direct sympathetic nerve influence on the liver; and (c) release of glucagon from the pancreas.     

Vestibular activation of sympathetic nerve activity

AIM: The vestibulosympathetic reflex refers to sympathetic nerve activation by the vestibular system. Animal studies indicate that the vestibular system assists in blood pressure regulation during orthostasis. Although human studies clearly demonstrate activation of muscle sympathetic nerve activity (MSNA) during engagement of the otolith organs, the role of the vestibulosympathetic reflex in maintaining blood pressure during orthostasis is not well-established. Examination of the vestibulosympathetic reflex with other cardiovascular reflexes indicates that it is a powerful and independent reflex. Ageing, which is associated with an increased risk for orthostatic hypotension, attenuates the vestibulosympathetic reflex. The attenuated reflex is associated with a reduction in arterial pressure. CONCLUSION: These findings suggest that the vestibulosympathetic reflex assists in blood pressure regulation in humans, but future studies examining this reflex in other orthostatically intolerant populations are necessary to address this hypothesis.     

Role of the symphato-adrenal system in hemorrhagic hyperglycemia.

Arterial and venous plasma glucose concentration was determined at intervals in cats subjected to hemorrhagic hypotension at 50 mm Hg. The rapid rise of arterial plasma glucose after hemorrhage could be attributed to an increase release of glucose from the liver. This hyperglycemia could not be eliminated by bilateral adrenalectomy or by sectioning of the hepatic sympathetic nerves, although the response was somewhat depressed by the latter procedure. On the other hand the hyperglycemia was virtully abolished after adrenalectomy when combined with bilateral sectioning of the major and minor splanchnic nerves. The level of plasma glucagon during hemorrgage increased in cats with an intact sympatho-adrenal system, but was unchanged in animals with combined splanchnic sympathectomy and adrenalectomy. It is concluded that, during hemorrhage, the sumpatho-adrenal system influences the glucose output from the liver by three different reflex mechanisms: (a) release of catecholamines from the adrenal glands; (b) direct sympathetic nerve influence on the liver; and (c) release of glucagon from the pancreas.     

Spinal sympathetic reflexes initiated by coronary receptors

1. The main left coronary artery of vagotomized spinal cats was perfused at different flows and pressures. The changes in pressure were limited to the coronary bed.2. Increased coronary flow which increased coronary arterial pressure provoked a reflex increase in sympathetic discharge in the white ramus of the third thoracic spinal nerve and the inferior cardiac nerve. Reflex reductions in activity were not observed.3. Occlusion of the coronary sinus and myocardial ischaemia, due to cessation of pump inflow, evoked similar reflex increases of sympathetic activity. The effect of myocardial ischaemia was apparent before systemic arterial blood pressure fell or left ventricular end-diastolic pressure rose.4. Increased coronary arterial pressure, myocardial ischaemia and coronary sinus occlusion could activate the same preganglionic neurone.5. The afferent limb of the excitatory coronary-sympathetic reflex was in the cardiac sympathetic nerves, mainly on the left. Afferent nerve fibres running in these nerves and in the third left thoracic sympathetic ramus communicans were excited by increased coronary arterial pressure, myocardial ischaemia, and occlusion of the coronary sinus. Inhibition was not observed. Many of the receptors were further localized by direct probing over the coronary vessels and adjacent myocardium.6. Some receptors were excited by increased coronary arterial pressure alone, others by coronary sinus occlusion, and still others by myocardial ischaemia. In addition, some receptors were excited by all three stimuli.