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.     

Renal and cardiovascular afferent inputs to hypothalamic paraventriculo-spinal neurons

Experiments were done in chloralose-anesthetized cats to identify single units in the paraventricular nucleus of the hypothalamus (PVH) that responded to stimulation of afferent renal nerves (ARN) and the buffer nerves (carotid sinus (CSN) and aortic depressor (ADN) nerves), and whose axons projected directly to thoracic spinal sympathetic areas. Of 426 single units tested in the PVH region, 20 were antidromically activated by stimulation of the spinal cord. Sixteen of these antidromic units (80%) responded orthodromically to stimulation of ARN and/or the buffer nerves; 6 units (30%) were excited by ARN stimulation only, 2 units (10%) were excited by both ARN and buffer nerve stimulation, and 6 units were excited and 2 inhibited by buffer nerve stimulation only. These data demonstrate that sensory information originating in renal and cardiovascular receptors alters the firing rate of PVH-spinal projecting neurons and suggest that this long renal-PVH reflex loop may contribute to the elevation of arterial pressure (AP) during conditions when ARN are activated.     

Motor innervation of the coronary arteries of the cat

1. The effect on coronary vascular resistance of selective stimulation of the Adelta, B and sC fibre groups of the post-ganglionic cardiac sympathetic nerves was studied. The main left coronary artery was perfused at constant flow. The oxygen saturation of coronary sinus blood was measured continuously.2. Stimulation of the peripheral ends of the cut Adelta afferent fibres, normally excited by myocardial ischaemia, had no effect on coronary vascular resistance; these fibres do not evoke an axon reflex in the heart.3. Stimulation of the preganglionic B fibres that run without synapse through the stellate ganglion also had no measurable effect on coronary resistance.4. Stimulation of the post-ganglionic sC fibres of the cardiac sympathetic nerves caused coronary vasodilatation which occurred earlier than, and was initially independent of the decrease in coronary sinus oxygen saturation.5. The injection of noradrenaline into the perfusion system had the same effect as stimulation of the sC fibres. In the K(+)-arrested heart, both noradrenaline and stimulation of the post-ganglionic nerves elicited coronary vasodilatation without changing the oxygen saturation of coronary sinus blood.6. The intracoronary injection of acetylcholine caused coronary vasodilatation followed by an increase of coronary sinus oxygen saturation.7. Vagal stimulation caused brady cardia and a fall in coronary resistance.8. Propranolol blocked coronary vasodilatation elicited by sympathetic stimulation or noradrenaline without affecting the vasodilatation due to myocardial ischaemia or acetylcholine. Atropine blocked coronary vasodilatation evoked by acetylcholine without affecting that due to ischaemia or noradrenaline. Therefore smooth muscle of the coronary arteries has at least three different receptor sites from which vasodilatation can be elicited.9. Hypertensin caused coronary vasoconstriction.10. The presence of sympathetic cholinergic vasodilator fibres innervating the coronary arteries could not be demonstrated.     

Inferior cardiac nerve activity in the cat during occlusion of the mesenteric artery.

A number of studies in this and other laboratories using hemodynamic and pharmacologic evidence have suggested that occlusion of the mesenteric artery evokes a pressor reflex initiated by mesenteric baroreceptors. To provide additional evidence in support of this hypothesis, neurophysiological recordings were made of inferior cardiac nerve activity during mesenteric artery occlusion (MAO). The results indicate that MAO enhances inferior cardiac nerve activity in the cat, providing that the carotid sinus nerves have been cut. Cutting of the mesenteric nerves further facilitates cardiac nerve activity and abolishes the response to mesenteric artery occlusion. The evidence suggests that MAO evokes a reflex sympathetic discharge which is subject to override by the carotid sinus depressor reflex. The afferent limb of the reflex is characterized by a tonic depressor outflow from the mesenteric pressure receptors.     

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.     

Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats

Myocardial ischaemia causes the release of metabolites such as bradykinin, which stimulates cardiac sensory receptors to evoke a sympathoexcitatory reflex. However, the molecular identity of the afferent neurons and fibres mediating this reflex response is not clear. In this study, we tested the hypothesis that the cardiogenic sympathoexcitatory reflex is mediated by capsaicin-sensitive afferent fibres. Enhanced immunofluorescence labelling revealed that vanilloid receptor 1 (VR1)-containing afferent nerve fibres were present on the epicardial surface of the rat heart. Resiniferatoxin (RTX), a potent analogue of capsaicin, was used to deplete capsaicin-sensitive afferent fibres in rats. Depletion of these fibres was confirmed by a substantial reduction of VR1 immunoreactivity in the epicardium and dorsal root ganglia. The thermal sensitivity was also diminished in RTX-treated rats. Renal sympathetic nerve activity (RSNA) and blood pressure were recorded in anaesthetized rats during epicardial application of bradykinin or capsaicin. In vehicle-treated rats, epicardial bradykinin (10 μg ml⁻¹) or capsaicin (10 μg ml⁻¹) application produced a significant increase in RSNA and arterial blood pressure. The RSNA and blood pressure responses caused by bradykinin and capsaicin were completely abolished in RTX-treated rats. Furthermore, epicardial application of iodo-RTX, a highly specific antagonist of VR1 receptors, blocked capsaicin- but not bradykinin-induced sympathoexcitatory responses. Thus, these data provide important histological and functional evidence that the heart is innervated by VR1-expressing afferent nerves and these afferent nerves are essential for the cardiogenic sympathoexcitatory reflex during myocardial ischaemia.     

Excitation of afferent cardiac sympathetic nerve fibres during myocardial ischaemia

1. Occlusion of the main left coronary artery of lightly anaesthetized cats provoked a pseudaffective reaction. The afferent pathway was in the cardiac sympathetic nerves.2. The compound action potential evoked in the inferior or middle cardiac nerves by stimulation of the thoracic sympathetic trunk contained two elevations, a small Adelta wave and a much larger sC wave. Occasionally a B wave was present.3. During coronary occlusion, the Adelta elevation was reduced by 35-55%, indicating afferent activity in these fibres. Multifibre preparations also showed increased afferent discharge during occlusion.4. It seems probable that the afferent activity in these fibres was mainly responsible for signalling the pseudaffective response elicited by coronary occlusion.5. Myocardial ischaemia produced by coronary occlusion was probably the stimulus for the increased activity.     

The depressor reflex arising from the left coronary artery of the cat

1. The main left coronary artery of the cat was perfused through its own common carotid artery. Changes in perfusion pressure were produced from a pressurized reservoir.

2. In cats anaesthetized with pentobarbital, increased coronary artery pressure always caused a reflex reduction of the discharge in sympathetic nerves. A reflex fall in blood pressure occurred less frequently. In cats anaesthetized with chloralose, increased coronary artery pressure caused a reflex bradycardia without any primary change in sympathetic activity.

3. The afferent fibres of the coronary depressor reflex are in the vagus nerves. The efferent fibres were both sympathetic and vagal.

4. It seems likely that the coronary depressor reflex is initiated by excitation of the coronary mechanoreceptors. It also seems likely that the reflex response to the intracoronary injection of 1 μg veratridine (Bezold—Jarisch effect) was initiated at least in part by excitation of these same receptors.

     

Tachypnea after stimulation of afferent cardiac sympathetic nerve fibers.

The role of afferent cardiac sympathetic nerve fibers in the regulation of respiration has been examined. Application of potassium chloride or lactic acid solutions to the left ventricular surface of anesthetized vagotomized dogs resulted in a decrease in the manimum firing rate and shortening in period duration of firing of phrenic nerves. Also, application of the agents caused a decrease in amplitude and an increase in rate of respiratory thoracic movements. The same changes in phrenic nerve activity and respiratory movements were produced by coronary artery occlusion and centrifugal electrical stimulation of the left inferior cardiac nerves. The results indicate tachypnea that can be produced by excitation of afferent cardiac sympathetic nerve fibers.     

The role of left atrial receptors in the regulation of renin release in anesthetized dogs

Experiments were performed on anesthetized dogs to further define the role of left atrial cardiopulmonary receptors in the reflex neural control of renin release. Non-hypotensive arterial hemorrhage produced reversible decreases in left atrial pressure and increases in renin release without significant changes in mean arterial pressure or renal blood flow. When non-hypotensive arterial hemorrhage was performed, while keeping left atrial pressure constant via left atrial balloon inflation, no increase in renin release was observed. These experiments indicate that changes in blood volume unaccompanied by changes in arterial pressure are sensed by left atrial cardiopulmonary receptors, which results in renin release mediated by a neural reflex arc involving in the vagus as the afferent pathway and the renal sympathetic nerves as the efferent pathway.     

Cutaneous Mechanical Stimulation Regulates Ovarian Blood Flow via Activation of Spinal and Supraspinal Reflex Pathways in Anesthetized Rats

The reflex effects of noxious mechanical stimulation of a hindpaw or abdominal skin on ovarian blood flow, and the reflex pathways involved in those responses were examined in anesthetized rats. Blood flow in the left ovary was measured using a laser Doppler flowmeter, and the activity of the left ovarian sympathetic nerve and mean arterial pressure (MAP) of the common carotid artery were recorded. Stimulation of the left or right hindpaw for 30 s produced marked increases in ovarian sympathetic nerve activity and MAP. Ovarian blood flow slightly decreased during the stimulation and then slightly increased after the stimulation. After the left ovarian sympathetic nerves were severed, the same stimulus produced a remarkable monophasic increase in ovarian blood flow that was explained by passive vasodilation due to a marked increase in MAP. After spinal transection at the third thoracic (T3) level, the responses of MAP, ovarian sympathetic nerve activity, and ovarian blood flow to hindpaw stimulation were nearly abolished. Stimulation of the abdomen at the right or left side for 30 s produced slight increases in ovarian sympathetic nerve activity and MAP. Ovarian blood flow slightly decreased during the stimulation and then slightly increased after the stimulation. After the ovarian sympathetic nerves were severed, the response of the ovarian blood flow changed to a monophasic increase due to an increase in MAP. After spinal transection, stimulation of the left abdomen produced a moderate increase in MAP, a remarkable increase in ovarian sympathetic nerve activity and a slight decrease in ovarian blood flow during the stimulation. In contrast, stimulation of the right abdomen produced a smaller response in ovarian sympathetic nerve activity during the stimulation while it increased the MAP to a similar degree. Ovarian blood flow slightly increased after the end of stimulation, which was explained as passive vasodilation due to the increase in MAP. In conclusion, stimulation of somatic afferents affects ovarian blood flow by inducing changes in ovarian sympathetic nerve activities and blood pressure. When stimulation was applied to a hindpaw whose segment of afferent input is far from the segment of the ovarian sympathetic nerves, it took a supraspinal reflex pathway. However, when stimulation was applied to the abdomen whose spinal segment of the afferent is close to the segment of the ovarian sympathetic nerve output, there are spinal segmental reflex pathways. The present results demonstrate that spinal reflexes depend on the laterality of the stimulus, while supraspinal reflexes do not depend on the laterality of the stimulus.     

Action potentials from ventricular mechanoreceptors stimulated by occlusion of the coronary sinus in the dog

1. In experiments to determine the type of intra-cardiac receptors which cause the coronary sinus occlusion reflex, recordings were made from sixty-nine single and small multi-fibre preparations of cardiac vagal afferents in open-chest anaesthetized dogs.2. Thirty-two fibres were stimulated by occlusion of the coronary sinus outflow through an indwelling Morawitz cannula. No receptors were stimulated during occlusions at peak systolic coronary venous pressures below the threshold for reflex cardiovascular depression. At higher pressures, fibre recruitment and further increases in stimulated discharge were demonstrated.3. The afferent endings of twenty-nine of these fibres were mechanically localized to the epicardium and myocardium of the left ventricle. Three were in the right ventricle. Seventeen single fibres discharged spontaneously at an average of 0.9 impulses/sec. There was cardiac modulation of both resting and stimulated discharge, with most action potentials in systole. Seven of eight fibres conducted at less than 1.0 m/sec.4. These ventricular receptors and a further twenty-two otherwise like them but not stimulated by occlusions were designated epi-myocardial receptors.5. 73% of receptors were stimulated by intrapericardial nicotine (50-100 mug). Presumptively superficial receptors were more sensitive to this stimulus.6. Epi-myocardial receptors were stimulated by intravenous or intracoronary catecholamines, by electrical stimulation of cardiac sympathetic nerves, and by eliciting the carotid sinus occlusion reflex. Aortic occlusion stimulated 66% of fibres tested, but was a less effective stimulus. After all these stimuli, there was a systolic modulation of discharge in more than 70% of fibres.7. It was concluded that the epi-myocardial receptors are similar to those previously shown to cause the epicardial chemoreflex, and to participate in the coronary chemoreflex. It is suggested that they are responsive to systolic mechanical changes which are accentuated by catecholamines. Their possible effectiveness in other cardiac reflexes and in initiating circulatory changes at the beginning of exercise and the vasovagal syndrome is discussed.     

The reflex cardiovascular depression caused by occlusion of the coronary sinus in the dog

1. Brief occlusions of the outflow from the cannulated coronary sinus in the open chest anaesthetized dog caused a rise in coronary venous pressure, bradycardia, and systemic hypotension.2. The bradycardia and hypotension were directly proportional to the peak systolic coronary venous pressures above a threshold value of about 50 mm Hg.3. The bradycardia, but not the systemic hypotension, was abolished by intravenous atropine. Both responses were abolished by cutting the cervical vagi, and reversibly abolished by cooling them to less than 7 degrees C.4. During occlusions, there was inhibition of activity in single and small multi-fibre preparations of sympathetic efferent nerves in the ansae subclaviae and the cervical sympathetic.5. On the right side, nearly all afferent fibres ran in the recurrent cardiac nerve. There was no concentration of afferents in one cardiac nerve on the left side.6. It was concluded that the cardiovascular depression was reflex, and was caused by the stimulation of nerves or nerve endings in the ventricles of the heart.     

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.     

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.     

Role of cardiac sympathetics in the tonic circulatory restraint by vagal afferents.

In anesthetized cats with aortic nerves sectioned and carotid arteries occluded, we determined the role of cardiac sympathetic nerves on the tonic inhibitory restraint by cardiac vagal afferents on the cardiovascular system. The effect of afferent vagal blockade on mean arterial pressure and cardiac contractility was determined when sympathetic tone to the heart was altered. Bilateral cardiac sympathectomy produced a significant decrease in left ventricular dP/dt and attenuated the arterial pressure response to afferent vagal cold block to less than 40% of the control. The increase in dP/dt normally observed with vagal blockade was also reduced significantly. Increasing dP/dt by efferent stimulation of cardiac sympathetic nerves restored the arterial pressure response to vagal blockade to near control levels. While the vagal inhibitory activity appeared to be dependent on the resting dP/dt, left ventricular peak pressure did not seem to be contributing to the reflex. Thus, the inhibitory effects of vagally mediated reflexes from the heart which contribute to arterial pressure regulation appear to be influenced by changes in cardiac contractility induced by cardiac sympathetic nerve stimulation.     

A comparative morphologic study of the cardiac innervation in domestic animals II. The feline

Detailed morphological studies of the cardiac innervation of the cat were reported. Sympathetic cardiac nerves arose from the thoracic, cervicothoracic, vertebral, and intermediate ganglia. Parasympathetic cardiac nerves arose from the vagi, both cranial and caudal to the origin of the recurrent laryngeal nerves, and from the right recurrent laryngeal nerve. Left cardiac nerves passed primarily to the caudal and right surfaces of the left chambers while right ones ramified on the right chambers and left portion of the left chambers. Left cardiac nerves are more prominent around the coronary sinus and atrioventricular node, while right ones contribute more to the area of the sinoatrial node. Both sympathetic and parasympathetic nerves were followed to each chamber. Interconnections through the cardiac plexus facilitated overlapping of nerve distributions.     

Afferent fibres from pulmonary arterial baroreceptors in the left cardiac sympathetic nerve of the cat

1. Afferent discharges were recorded from the left cardiac sympathetic nerve or the third sympathetic ramus communicans of anaesthetized cats. Twenty-one single units with baroreceptor activity were obtained.2. The receptors of each unit were localized to the extrapulmonary part of the pulmonary artery, determined by direct mechanical probing of the wall of the pulmonary artery after death of the animals. Conduction velocity of the fibres ranged from 2.5 to 15.7 m/sec.3. Afferent discharges occurred irregularly under artificial ventilation. The impulse activity was increased when pulmonary arterial pressure was raised by an intravenous infusion of Locke solution, or by occlusion of lung roots, and decreased by bleeding the animal from the femoral artery.4. Above a threshold pressure, discharges occurred synchronously with the systolic pressure pulse in the pulmonary artery. A progressive further rise in pressure did not produce an increase in the number of impulses per heart beat. Occlusion of lung roots initially elicited a burst of discharges but the number of impulses for each cardiac cycle gradually decreased.5. The receptors responded to repetitive mechanical stimuli up to a frequency of 10/sec, but failed to respond to stimuli delivered at 20/sec.6. The results provide further evidence for the presence of afferent fibres in the cardiac sympathetic nerve. These afferent fibres are likely to provide the spinal cord with specific information only on transient changes in pulmonary arterial pressure.     

The effect of baroreceptors on the latency of evoked responses in sympathetic nerves during the cardiac cycle

1. A rapid increase in pressure in a vascularly isolated perfused carotid sinus has been shown to inhibit a reflex response in efferent sympathetic nerves of the dog evoked by electrical stimulation of the radial nerve.2. In intact preparations with the carotid baroreceptors innervated, the mean latency and the variance of the latency of reflex sympathetic nerve responses was reduced when the stimuli evoking the responses were applied at one point of both cardiac and respiratory cycles. When the baroreceptors were denervated there were no significant differences in the responses to random and synchronized stimuli.3. In intact preparations the latency of evoked responses in sympathetic nerves was found to vary progressively during a cardiac cycle; the maximum increase in latency was observed with the responses that occurred at that phase of the cardiac cycle when the baroreceptors exert maximal inhibition on spontaneous sympathetic activity. After denervation of the carotid sinuses a much smaller change during the cardiac cycle was still present, possibly due to effects produced by baroreceptors of the aortic arch and elsewhere.4. It was concluded that changes in baroreceptor activity, due to beat to beat fluctuations of the systemic arterial pressure are a major factor causing variations in the latency of responses in sympathetic nerves evoked by stimuli applied to a cutaneous nerve.