Richard A. Gillis

Role of the Vagus Nerves in the Cardiovascular Changes Induced by Coronary Occlusion

The importance of vagus nerves to the heart rate, contractile force, blood pressure, and incidence of fatal arrhythmias produced by occlusion of the anterior descending branch of the left coronary artery was studied in chloralose-anesthetized cats. Occlusion performed in 20 animals with intact vagus nerves produced significant decreases in heart rate (23 ± 5.3 beats/min), contractile force (23 ± 6.6%), and blood pressure (20 ± 2.7 mm Hg). Time to onset of arrhythmias was 2.6 ± 0.4 minutes and death due to ventricular fibrillation occurred in four of 20 animals. Occlusion performed in 20 animals with bilateral vagotomy and 20 animals with intact vagus nerves but pretreated with atropine did not decrease heart rate and resulted in significantly more deaths. Time to onset of the arrhythmia was significantly less in both cases. Occlusion produced the usual decrease in contractile force and blood pressure. In addition, a delayed (i.e., after sinus rhythm was restored) decrease in blood pressure and contractile force occurred in animals with vagus nerves sectioned. Pacing hearts of animals with intact and functional vagus nerves to rates comparable to those seen in vagotomized and atropinized cats resulted in a mortality rate identical to that seen in controls. On the other hand, time to onset of the arrhythmia was significantly less than controls and equivalent to the onset times of the vagotomized and atropinized groups. These results suggest that 1) efferent vagus nerves mediate sinus bradyeardia that occurs after coronary occlusion, 2) presence of efferent vagus tone per se reduces the incidence of death, 3) rate effect of efferent vagal tone increases the time to onset of arrhythmias, and 4) presence of afferent vagal tone counteracts the late decline in arterial pressure and contractile force.

Medullary ventral surface GABA receptors affect respiratory and cardiovascular function

We previously demonstrated that GABA and muscimol administered either into the cisterna magna or the fourth ventricle to chloralose-anesthetized cats cause respiratory depression, hypotension, and bradycardia. Injection of these substances into the lateral and third ventricles had no effect. In order to localize the site of action, muscimol and GABA were applied by Perspex rings to the ventral surface of the medulla. Application of muscimol (0.25-2.66 micrograms) to Schlaefkes area in 6 cats reduced minute ventilation from 443 +/- 38 to 291 +/- 52 ml/min by reducing tidal volume from 31.8 +/- 2.3 to 17.6 +/- 1.4 ml, without changing respiratory rate and duration of inspiration. Hypotension and bradycardia were also observed. Application of GABA (0.14-4.86 mg) produced similar effects on respiratory activity and arterial blood pressure. No significant effects occurred when high doses of these agents were applied to Loeschckes and Mitchells areas. Application of bicuculline (5-25 micrograms) to Schlaefkes area had the opposite effect of muscimol and GABA on respiratory activity and blood pressure, and reversed the respiratory and cardiovascular depressant effects of both agents. We conclude that GABA receptors are present at Schlaefkes area, and that activation of these receptors results in respiratory depression, hypotension, and bradycardia. Our results suggest that GABA may be an important inhibitory neurotransmitter in the modulation of respiratory and cardiovascular control.

Role of the nervous system in the arrhythmias produced by coronary occlusion in the cat

Abstract The importance of the nervous system in the arrhythmias generated by occlusion of the left coronary artery of the cat was investigated. This was carried out by (1) monitoring the spontaneous electrical activity in sympathetic and parasympathetic cardiac nerves and (2) determining the influence of ablation of the nervous system on time taken for death to occur and on incidence of ventricular fibrillation. It was found that coronary occlusion increased the spontaneous firing in cardiac-bound autonomic fibers and that the enhanced neural activity was correlated in time with electrocardiographic changes consisting of ventricular arrhythmias. Removal of the central nervous system and both vagi conferred protection against arrhythmogenesis. Animals with no neural input to the heart (as indicated by the nerve recordings) survived more than twice as long after coronary occlusion and showed a significant reduction in the incidence of ventricular fibrillation. These results suggest that the nervous system plays an important role in the generation of arrhythmias produced by coronary occlusion in the cat.

Cardiac Sympathetic Nerve Activity: Changes Induced by Ouabain and Propranolol

A study of the effects of ouabain and propranolol on the spontaneous activity in the preganglionic sympathetic nerves to the cat heart showed that ouabain can produce both an inhibition and a stimulation of the spontaneous activity in sympathetic nerves. The inhibition appears to be reflex in nature and is not present when the buffer nerves are sectioned. The stimulation is correlated with the development of cardiac arrhythmias and is antagonized by propranolol.

Projections from the raphe nuclei to the phrenic motor nucleus in the cat

The purpose of this study was to identify the projections from the brain to the phrenic motor nucleus in the cat by employing a retrogradely-transported fluorescent dye. Propidium iodide was iontophoresed into the phrenic motor nucleus which is located in the fourth, fifth and sixth segments of the cervical spinal cord. Retrogradely-labeled cell bodies were found in the brainstem within recognized respiratory areas. In addition, retrogradely-labeled cell bodies were found within the raphe nuclei, nuclear areas not previously associated with respiratory control. The results of this study suggest that the raphe nuclei may play a role in the central regulation of breathing.

Effect of Digitalis on Carotid Sinus Baroreceptor Activity

The effect of intracarotid injections of ouabain (25.0 μg) or acetylstrophanthidin (1.56 μg) on feline carotid sinus baroreceptors was evaluated using an isolated perfused carotid sinus preparation. The effects of the drugs on baroreceptor activity were determined by monitoring carotid sinus nerve activity and systemic arterial blood pressure. Administration of either drug to the isolated carotid sinus region altered the relationship between the change in carotid sinus pressure and the fall in systemic arterial blood pressure. Raising the carotid sinus pressure produced a greater depressor response when digitalis was present (−29.6 ± 3.8 mm Hg) than it did when digitalis was absent (−15.3 ± 2.6 mm Hg). Digitalis administration also resulted in a greater increase in carotid sinus nerve discharge when carotid sinus pressure was increased. At a constant carotid sinus pressure, digitalis increased the spontaneous firing of the carotid sinus nerve; the drug-induced augmentation in nerve firing was identical to that produced by raising carotid sinus pressure. These changes in baroreceptor activity in the presence of digitalis occurred without drug-induced changes in the pressure in the isolated carotid sinus region. The results demonstrate that the digitalis preparations studied can directly alter the sensitivity of baroreceptors and produce significant changes in carotid sinus nerve activity and cardiovascular function.

Parasympathetic neurons in the cranial medial ventricular fat pad on the dog heart selectively decrease ventricular contractility

We hypothesized that selective control of ventricular contractility might be mediated by postganglionic parasympathetic neurons in the cranial medial ventricular (CMV) ganglion plexus located in a fat pad at the base of the aorta. Sinus rate, atrioventricular (AV) conduction (ventricular rate during atrial pacing), and left ventricular contractile force (LV dP/dt during right ventricular pacing) were measured in eight chloralose-anesthetized dogs both before and during bilateral cervical vagus stimulation (20-30 V, 0.5 ms pulses, 15-20 Hz). Seven of these dogs were tested under beta-adrenergic blockade (propranolol, 0.8 mg kg(-1) i.v.). Control responses included sinus node bradycardia or arrest during spontaneous rhythm, high grade AV block or complete heart block, and a 30% decrease in contractility from 2118 +/- 186 to 1526 +/- 187 mm Hg s(-1) (P < 0.05). Next, the ganglionic blocker trimethaphan (0.3-1.0 ml of a 50 microg ml(-1) solution) was injected into the CMV fat pad. Then vagal stimulation was repeated, which now produced a relatively small 5% (N.S., P > 0.05) decrease in contractility but still elicited the same degree of sinus bradycardia and AV block (N = 8, P < 0.05). Five dogs were re-tested 3 h after trimethaphan fat pad injection, at which time blockade of vagally-induced negative inotropy was partially reversed, as vagal stimulation decreased LV dP/dt by 19%. The same dose of trimethaphan given either locally into other fat pads (PVFP or IVC-ILA) or systemically (i.v.) had no effect on vagally-induced negative inotropy. Thus, parasympathetic ganglia located in the CMV fat pad mediated a decrease in ventricular contractility during vagal stimulation. Blockade of the CMV fat pad had no effect on vagally-mediated slowing of sinus rate or AV conduction.

Glucose effects on gastric motility and tone evoked from the rat dorsal vagal complex

1 To examine the effects of glucose on the central components of the vago‐vagal reflex control of gastric function, we performed both in vivo and in vitro experiments on neurones in the medial nucleus of the tractus solitarius (mNTS) and in the dorsal motor nucleus of the vagus (DMV). 2 In the in vivo anaesthetized rat preparation, unilateral microinjection of d‐glucose (10 or 50 mm (60 nl)−1) in mNTS produced inhibition of gastric motility and an increase in intragastric pressure. d‐glucose had no effect in the DMV. 3 In the in vitro rat brainstem slice preparation, whole‐cell recordings of DMV neurones showed that increasing the glucose concentration of the perfusion solution from 5 mm to 15 or 30 mm produced outward currents of 35 ± 5 pA (n= 7) and 51 ± 10 pA (n= 11), respectively. These were blocked by tetrodotoxin and picrotoxin, indicating that glucose was acting indirectly to cause the release of GABA. Decreasing the glucose concentration of the perfusing solution by one‐half produced an inward current of 36 ± 5 pA (n= 7). 4 Stimulation of the NTS evoked inhibitory postsynaptic currents (IPSCs) in DMV neurones. The amplitude of the evoked IPSCs was positively correlated with glucose concentration. Perfusion with the ATP‐sensitive K+ (KATP) channel opener diazoxide mimicked the effect of reduced glucose, while perfusion with the KATP channel blocker glibenclamide mimicked the effects of increased glucose. 5 Our data indicate that glucose had no direct excitatory effect on DMV neurones, but DMV neurones appear to be affected by an action of glucose on cell bodies of mNTS neurones via effects on an ATP‐sensitive potassium channel.

Effect of cocaine on the coronary circulation and systemic hemodynamics in dogs

This study investigated the effect of intravenous cocaine (0.5 to 2 mg/kg body weight) on the coronary circulation and systemic hemodynamics in closed chest sedated dogs. The role of alpha- and beta-adrenoceptor stimulation in mediating these effects was also investigated. Cocaine produced dose-dependent increases in mean arterial pressure and rate-pressure product. Although the lower doses of cocaine had no significant effect on the coronary circulation, the 2 mg/kg dose produced a 55 +/- 14% increase in coronary vascular resistance (p less than 0.05 versus baseline) and a 19 +/- 3% reduction in diameter of the left anterior descending coronary artery (p less than 0.05 versus baseline). Despite these potentially deleterious effects on the coronary circulation (occurring at a time of markedly increased myocardial oxygen demand), the electrocardiogram did not demonstrate ischemic changes and there was no myocardial lactate production. Cocaine-induced coronary vasoconstriction was abolished by pretreatment with the alpha-adrenoceptor antagonist phentolamine, but not by pretreatment with the beta-adrenoceptor antagonist propranolol. The findings that cocaine did not change systemic vascular resistance in dogs without adrenergic blockade, reduced systemic vascular resistance in dogs after alpha-blockade (p less than 0.05) and increased systemic vascular resistance in dogs after beta-blockade (p = 0.06) suggest that epinephrine (rather than norepinephrine) is primarily responsible for the peripheral vascular actions of cocaine. Thus, in this canine preparation with normal coronary arteries, cocaine produced vasoconstriction of both epicardial and coronary resistance vessels that was not associated with evidence of myocardial ischemia. The pharmacologic mechanism for the effect of cocaine on the coronary circulation is alpha-adrenoceptor stimulation, whereas systemic hemodynamic effects are mediated by combined alpha- and beta-adrenoceptor stimulation.

Neural control of left ventricular contractility in the dog heart: synaptic interactions of negative inotropic vagal preganglionic neurons in the nucleus ambiguus with tyrosine hydroxylase immunoreactive terminals

Recent physiological evidence indicates that vagal postganglionic control of left ventricular contractility is mediated by neurons found in a ventricular epicardial fat pad ganglion. In the dog this region has been referred to as the cranial medial ventricular (CMV) ganglion [J.L. Ardell, Structure and function of mammalian intrinsic cardiac neurons, in: J.A. Armour, J.L. Ardell (Eds.). Neurocardiology, Oxford Univ. Press, New York, 1994, pp. 95-114; B.X. Yuan, J.L. Ardell, D.A. Hopkins, A.M. Losier, J.A. Armour, Gross and microscopic anatomy of the canine intrinsic cardiac nervous system, Anat. Rec., 239 (1994) 75-87]. Since activation of the vagal neuronal input to the CMV ganglion reduces left ventricular contractility without influencing cardiac rate or AV conduction, this ganglion contains a functionally selective pool of negative inotropic parasympathetic postganglionic neurons. In the present report we have defined the light microscopic distribution of preganglionic negative inotropic neurons in the CNS which are retrogradely labeled from the CMV ganglion. Some tissues were also processed for the simultaneous immunocytochemical visualization of tyrosine hydroxylase (TH: a marker for catecholaminergic neurons) and examined with both light microscopic and electron microscopic methods. Histochemically visualized neurons were observed in a long slender column in the ventrolateral nucleus ambiguus (NA-VL). The greatest number of retrogradely labeled neurons were observed just rostral to the level of the area postrema. TH perikarya and dendrites were commonly observed interspersed with vagal motoneurons in the NA-VL. TH nerve terminals formed axo-dendritic synapses upon negative inotropic vagal motoneurons, however the origin of these terminals remains to be determined. We conclude that synaptic interactions exist which would permit the parasympathetic preganglionic vagal control of left ventricular contractility to be modulated monosynaptically by catecholaminergic afferents to the NA-VL.