Cardiac Sympathetic Nerve Stimulation Research Articles

Presence of presynaptic inhibitory α1-adrenoceptors in the cardiac sympathetic nerves of the dog: Effects of prazosin and yohimbine on sympathetic neurotransmission to the heart

The effects of prazosin and yohimbine on sympathetic neurotransmission to the heart were investigated in perfused dog hearts in situ in an attempt to determine whether α1-adrenoceptors are located presynaptically in the cardiac sympathetic nerves. Intra-arterial injections of prazosin (1–30 μg) and yohimbine (0.3–10 μg) into the right coronary artery during cardiac sympathetic nerve stimulation further increased the tachycardia resulting from the stimulation. Continuous infusions of methoxamine (20–40 μg/min) and of clonidine (2–4 μg/min) into the right coronary artery during cardiac sympathetic nerve stimulation caused sustained reduction of the tachycardia. Prazosin under methoxamine infusion enhanced the tachycardia to a greater extent than in the absence of methoxamine. Prazozin under clonidine infusion enhanced the tachycardia to the same extent as it did in the absence of clonidine. These results suggest that prazosin antagonizes the effect of methoxamine but does not antagonize that of clonidine. The results obtained with yohimbine were in contrast to the effects of prazosin, showing the antagonism of clonidine by yohimbine. Prazosin and yohimbine both had little effect on the heart rate during either the resting state or the infusion of norepinephrine. These results suggest that the prazosin- and yohimbine-induced enhancement of the tachycardia resulting from cardiac sympathetic nerve stimulation is due to a presynaptic effect. However, the presynaptic effect of prazosin appears to differ from that of yohimbine. The presence of presynaptic α1-adrenoceptors regulating norepinephrine release, as well as of α2-adrenoceptors, is suggested in the cardiac sympathetic nerves of the dog.

The phase-dependency of the cardiac chronotropic responses to vagal stimulation as a factor in sympathetic-vagal interactions.

We determined the effects of the timing of repetitive bursts of vagal stimulation on the positive chronotropic responses of the heart to trains of cardiac sympathetic nerve stimulation in open-chest anesthetized dogs. Trains of sympathetic stimulation alone, at frequencies of 2 and 4 Hz, decreased the cardiac cycle length by 176 +/- 19 msec (mean +/- SE) and 190 +/- 22 msec, respectively. When bursts of vagal stimuli were given once each cardiac cycle and they were placed at their least effective time in the cycle, sympathetic stimulation at frequencies of 2 and 4 Hz decreased cardiac cycle length by only 107 +/- 8 and 120 +/- 8 msec, respectively. However, when the bursts of vagal stimuli were delivered at their most effective time in each cycle, the same levels of sympathetic stimulation elicited much larger reductions in cardiac cycle length (285 +/- 32 and 330 +/- 32 msec, respectively). Therefore, the effects of sympathetic stimulation were significantly attenuated by the vagal stimuli when the vagal bursts were relatively ineffective. Conversely, the chronotropic effects of the sympathetic stimulation were exaggerated substantially when the vagal stimulus bursts were initially positioned at their most effective time in the cardiac cycle. This latter response is contrary to the characteristic "accentuated antagonism," wherein the effect of any given level of sympathetic stimulation is diminished as the level of vagal activity is increased. This vagally mediated enhancement of the positive chronotropic response to sympathetic stimulation occurs because the phase dependency of the response of the automatic cells to the bursts of vagal stimulation is altered by the increased sympathetic activity.

Nifedipine prevents sympathetic vasoconstriction distal to severe coronary stenoses.

Cardiac sympathetic nerve stimulation ( CSNS ) can induce vasoconstriction distal to severe coronary stenoses by activation of vascular alpha 2-adrenoceptors. Whether nifedipine can antagonize this CSNS -induced vasoconstriction was tested in 11 anesthetized, vagotomized dogs. CSNS decreased the end-diastolic resistance of intact coronary arteries from 0.76 +/- 0.07 to 0.56 +/- 0.05 mm Hg x min x 100 g/ml (p less than 0.05). In contrast, the resistance distal to severe stenoses, which were defined by a reduction of the postocclusive reactive hyperemia to almost zero, was increased during CSNS from 0.52 +/- 0.06 to 0.87 +/- 0.14 mm Hg x min x 100 g/ml (p less than 0.05). This increase in resistance was associated with severe ischemia, as indicated by a net lactate production of the circumflex-perfused myocardium and a decrease in systolic segment shortening from 8.4 +/- 0.7 to 7.0 +/- 0.7% (p less than 0.05). Both intracoronary (10 micrograms) and intravenous (10 micrograms/kg) administration of nifedipine did not change the poststenotic resistance at rest, but did prevent the CSNS -induced increase in resistance, the decrease in regional contraction, and the net lactate production. We conclude that nifedipine can prevent the deleterious role of alpha-adrenoceptor-mediated vasoconstriction in the genesis of myocardial ischemia.

No evidence for the involvement of histamine (H 1 or H 2) receptors in the hypotension and presynaptic inhibition of sympathetic nerve function caused by LY-141865 in dogs

LY-141865, a partial ergoline, caused hypotension, bradycardia and significant impairment of cardioacceleration elicited during stimulation of cardiac sympathetic nerves. These cardiovascular actions of LY-141865 were not affected either by the H 1-receptor antagonist mepyramine or the H 2-receptor antagonist cimetidine. The dopamine receptor antagonist sulpiride significantly reduced the hypotensive, bradycardic and presynaptic inhibitory actions of LY-141865. These results show that while dopamine receptor activation is responsible for the hypotension and presynaptic inhibition of sympathetic nerve function caused by LY-141865, histamine (H 1- or H 2-) receptors do not play any role in these actions of the compound.

Neurohumorally induced cardiac dysrhythmias during nitrous oxide-oxygen-thiopental anesthesia

Barbiturate, nitrous oxide, and oxygen are commonly used by the oral and maxillofacial surgeon to anesthetize the ambulatory oral surgery patient. The authors report three cases of ventricular dysrhythmia occurring from surgical stimulation during nitrous oxide-oxygen-thiopental anesthesia. These dysrhythmias were most likely mediated via direct neural stimulation of cardiac sympathetic nerves. Concomitant with adrenergic stimulation, a rise in the arterial plasma norepinephrine level was documented, along with an increase in the rate-pressure product. Immediate recognition and treatment of ventricular dysrhythmia is mandatory to preclude further serious cardiovascular complications or death.

Multisegmental spinal sympathetic reflexes originating from the heart.

Activation of cardiac sympathetic afferent nerves can initiate excitatory cardiocardiac reflexes through pathways that are exclusively spinal. In addition, stimulation of the same nerves also causes lower thoracic and lumbar sympathetic excitation, but the contribution of spinal pathways to these reflexes is unknown. Therefore experiments were performed to compare cardiac, splenic, and renal sympathetic responses to cardiac sympathetic afferent stimulation before and after cervical spinal cord transection in anesthetized, vagotomized, sinoaortic-denervated cats. Electrical stimulation of afferent cardiac sympathetic nerves produced excitatory responses in cardiac and renal nerves before transection but only cardiac nerve responses after transection. In contrast, afferent stimulation by epicardially applied bradykinin excited cardiac, renal, and splenic nerves before and after cord transection. Splenic nerve responses were greater than renal nerve responses in intact and spinal cats. These results demonstrate that spinal reflexes initiated by activation of cardiac sympathetic afferent nerves are not limited to cardiocardiac pathways. The similarity of patterns of responses in intact and spinal cats suggests that spinal pathways contribute significantly to the reflex excitation observed in intact animals.

The effects of cardiac sympathetic nerve stimulation on perfusion of stenotic coronary arteries in the dog.

The effects of cardiac sympathetic nerve stimulation on perfusion of stenotic coronary arteries in the dog.

Effects of cocaine and desipramine on the neurally evoked overflow of endogenous noradrenaline from the rat heart

1 Stimulation of postganglionic cardiac sympathetic nerves produced a stimulation frequency-dependent overflow of endogenous noradrenaline from the otherwise isolated rat heart. 2 Such nerve stimulation also produced increases in heart rate. There was significant correlation between heart rate increases and corresponding noradrenaline concentrations in the coronary venous effluent. 3 Cocaine (3 X 10(-5)M) caused a significant reduction in both the noradrenaline overflow and the heart rate increase, produced by nerve stimulation for 1 min at 4 Hz. 4 Desipramine (10(-6)M) caused a significant increase in the noradrenaline overflow produced by stimulation for 1 min (4 Hz) with a mean increase of approximately 60%. There was no significant effect on the heart rate increase produced by such stimulation. 5 The opposite effects of cocaine (3 X 10(-5)M) and desipramine (10(-6)M) on noradrenaline overflow are attributed to differences in the local anaesthetic properties of these agents.

Inhibition of cardiac sympathetic neurotransmission by histamine in the dog is mediated by H1-receptors.

1 The role of histamine H1- and H2-receptors in mediating prejunctional inhibition of cardiac sympathetic neurotransmission and histamine-induced coronary vasodilatation were investigated in perfused dog hearts in situ. 2 Intra-arterial injections of histamine into the right coronary artery during the resting state caused slightly positive chronotropic responses in doses larger than 1 microgram. 3 Histamine in doses of 0.1 to 10 micrograms into the right coronary artery reduced the tachycardia resulting from electrical stimulation of the cardiac sympathetic nerves. 4 Intra-coronary infusions of chlorpheniramine (300 micrograms/min) significantly reduced the histamine-induced depression of cardiac nerve stimulation. The effects of cimetidine (300 micrograms/min) and metiamide (300 micrograms/min) were less pronounced. 5 Histamine (1 to 10 micrograms) further increased heart rate resulting from the continuous intra-coronary infusion of noradrenaline (1 or 3 micrograms/min). 6 Intra-arterial injections of histamine (0.1 to 10 micrograms) caused an increase in coronary blood flow in a dose-dependent manner. This was partially inhibited by intra-coronary infusion of chlorpheniramine (10 to 300 micrograms/min) and by cimetidine (10 to 300 micrograms/min). The combination of both drugs (10 to 100 micrograms/min of each) caused a larger inhibition. 7 The present results suggest that the histamine-induced depression of heart rate during cardiac sympathetic nerve stimulation is due to a prejunctional effect mediated mainly by H1-receptors. Histamine-induced coronary vasodilatation in the dog is mediated both by H1- and H2-receptors.

Presynaptic inhibition by histamine of cardiac sympathetic neurotransmission in dogs.

The role of histamine H1 and H2-receptors in mediating presynaptic inhibition of cardiac sympathetic neurotransmission and histamine-induced coronary vasodilatation were studied in perfused dog hearts in situ. Histamine (0.1 to 10 μg) into the right coronary artery reduced tachycardia resulting from electrical stimulation of the cardiac sympathetic nerves. Intra-coronary infusions of chlorpheniramine (300 μg/min) reduced the histamine-induced depression of cardiac sympathetic nerve stimulation. The effects of Cimetidine (300 μg/min) and metiamide (300 yg/min) were less pronounced. Histamine (1 to 10 μg) caused slightly positive chronotropic responses during resting state and further increased heart rate resulting from the continuous intra-coronary infusion of norepinephrine (1 or 3 μg/min). Intra-arterial injections of histamine (0.1 to 10 μg) caused increase in coronary blood flow. This was partially inhibited by intra-coronary infusion of chlorpheniramine (10 to 300 μg/min) and by Cimetidine (10 to 300 μg/min). The combination of both drugs caused a larger inhibition. The present results suggest that the histamine-induced depression of heart rate during cardiac sympathetic nerve stimulation is due to a presynaptic effect mediated mainly by H1-receptors. Histamine-induced coronary vasodilatation is mediated both by H1- and H2-receptors.

Effect of stimulation of ansa subclavia on regional myocardial O2 supply and O2 consumption.

Cardiac sympathetic nerve stimulation produces increases in various indices of cardiac work and metabolism. To determine how these increased O2 demands are met, the effects of stimulation of the ansa subclavia on regional arterial and venous O2 saturation, O2 extraction, blood flow, and O2 consumption were determined in the hearts of 16 pentobarbital-anesthetized open-chest dogs. Microspectrophotometric observations of small regional arteries and veins in quick-frozen hearts to determine regional O2 extraction were combined with regional blood flow measurements with radioactive microspheres to determine regional myocardial O2 consumption by the Fick principle. Ansa subclavia stimulation produced significant increases in maximum rate of pressure development, heart rate, and blood pressure. Under control conditions, venous O2 saturation was lower and O2 extraction higher in the subendocardial compared with the subepicardial region of the left ventricle. While sympathetic stimulation did not alter the mean O2 extraction or venous O2 saturation values, there were no longer significant subepicardial vs. subendocardial differences in these parameters. Flow and O2 consumption in these regions increased proportionally during stimulation. The ratio of O2 supply to O2 consumption was not significantly altered by ansa subclavia stimulation, indicating that sympathetic stimulation produced no adverse effect in either region.

Alpha-Adrenoceptor blocking properties of raubasine in pithed rats.

1 Raubasine was compared with yohimbine and corynanthine in pithed rats. Antagonist activity at alpha 1-adrenoceptors was evaluated on the pressor response to electrical stimulation of the spinal sympathetic outflow and to phenylephrine administration, both being reduced by raubasine in the dose range 1 to 4 mg/kg. Corynanthine was quantitatively similar, but yohimbine was not only less potent but also in doses of 0.125 to 0.5 mg/kg enhanced the effects of electrical stimulation. 2 Antagonist activity at alpha 2-adrenoceptors was determined against the inhibitory effects of clonidine on tachycardia induced by electrical stimulation of cardiac sympathetic nerves and against the pressor responses to B-HT-933 injection. Raubasine up to 4 mg/kg, like corynanthine, did not affect the pressor responses to B-HT-933 nor did it reduce the inhibitory effect of clonidine. By contrast yohimbine reduced the response to BHT-933 and antagonized clonidine as well as enhancing the tachycardia caused by electrical stimulation. 3 The results indicate that, in vivo, raubasine, like corynanthine, is a selective antagonist at alpha 1-adrenoceptors and that yohimbine is more potent in blocking alpha 2-than alpha 1-adrenoceptors.

Responsiveness to cardiac sympathetic nerve stimulation during maximal coronary dilation produced by adenosine.

Responsiveness to cardiac sympathetic nerve stimulation during maximal coronary dilation produced by adenosine.

Analysis of phasic coronary resistances during cardiac sympathetic nerve stimulation (CSNS)

Analysis of phasic coronary resistances during cardiac sympathetic nerve stimulation (CSNS)

Studies on the autonomic nervous system with SK&F 92657, a new antihypertensive agent causing direct arterial vasodilatation and beta-adrenoceptor blockade.

The beta-adrenoceptor-blocking properties of SK&F 92657, D,L-3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine, were studied in both in vivo and in vitro. The pA2 against isoprenaline tachycardia (beta 1 effect) in isolated guinea pig right atria was 7.16 (6.14-7.87). In contrast, histamine-induced tachycardia was unaffected by SK&F 92657. The pA2 against isoprenaline relaxation of guinea pig tracheal muscle (beta 2 effect) was 7.03 (6.28-7.61). In vivo ED50's against isoprenaline tachycardia (beta 1) and vasodilation (beta 2) in anesthetized cats were 5.7 x 10(-8) and 6.2 x 10(-8) mol/kg, i.v., respectively. Increases in heart rate caused either by activation of autonomic reflexes or by stimulation of efferent cardiac sympathetic nerves were also antagonized by SK&F 92657. The beta-adrenoceptor blockade caused by SK&F 92657 was shown to be competitive both in vivo an vitro and to be equally effective on beta 1- and beta 2-receptor populations. SK&F 92657 was a weak partial agonist in vivo and had only minimal local anesthetic activity. The compound had no direct effect on the functioning of the autonomic nervous system, apart from beta-blockade, but reflexes maintaining homeostasis were reduced because (1) SK&F 92657 is a beta-adrenoceptor antagonist preventing reflex increases in heart rate and cardiac output, and (2) it is a potent vasodilator counteracting reflex vasoconstriction. Postural reflexes were unaffected because SK&F 92657 selectively dilates arterial blood vessels.

Presynaptic modulation of heart rate responses to cardiac nerve stimulation in pithed rats.

The effects of presynaptic alpha-adrenoceptor blockade with phentolamine, before and after inhibition of uptake-1 with cocaine, on the positive chronotropic response to cardiac sympathetic nerve stimulation in pithed rats was investigated. Phentolamine or cocaine each enhanced the cardiac responses to stimulation at 1 Hz for 15 sec by 10-25%; the combination of the drugs caused no greater enhancement than did either drug alone. Cocaine considerably potentiated the tachycardia produced during prolonged stimulation at 0.1 but not at 0.2-1 Hz. Phentolamine potentiated the responses to stimulation at 0.2 and 0.5 Hz by 21 and 12%, respectively, but not those at 0.1 or 1 Hz. After cocaine, phentolamine caused a further small increase in the response at 0.1 Hz but not other frequency. It is concluded that presynaptic alpha-adrenoceptors exert only modest control over the responses of the rat heart to cardiac nerve stimulation and that this modulation is little influenced by uptake-1.

心臓交感神経刺激による心電図変化(実験的検討)

心臓交感神経刺激による心電図変化(実験的検討)

Inhibition of cardiac sympathetic neurotransmission by adenosine

Experiments were performed to study the effect of adenosine on sympathetic neurotransmission to the myocardium. Adenosine administration to pentobartial-anesthetized dogs resulted in decrerease in blood pressure and significant impairment of cardioacceleration produced of stimulation of cardiac sympathetic nerves. The positive chronotropic effect of intravenous norepinephrine was not affected by adenosine. The blood pressure lowering as well as the inhibitory effect of adenosine on cardiac sympathetic nerve function could be significantly antagonized by theophylline. These results provide in vivo evidence in support of the hypothesis that adenosine caused inhibition of sympathetic neurotransmission via an action on purinergic receptors located on sympathetic nerve terminals.

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.

The effects of cocaine and metanephrine on the cardiac responses to sympathetic nerve stimulation in dogs.

The effects of infusions of cocaine (COC) and metanephrine (MET) on the inotropic and chronotropic responses to cardiac sympathetic nerve stimulation were studied in open-chest, anesthetized dogs. COC blocks the neuronal uptake of norepinephrine (NE), whereas MET blocks the extraneuronal uptake. Both blocking agents slightly enhanced the inotropic but not the chronotropic responses. COC prolonged the cardiac responses significantly, particularly the chronotropic responses, whereas MET had no appreciable effect on the durations of these responses. Hence, it appears that the neuronal uptake mechanism plays a major role in the dissipation of neurally released NE in the heart, but that the extra-neuronal uptake mechanism plays only a minor role in its dissipation. In contrast to the results in certain other tissues, the combined effects of COC and MET on the cardiac responses were no greater or more prolonged than the sum of the effects produced by each agent acting alone.