Cholinergic Innervation of the Canine and Human Ventricular Conducting System

Abstract

SUMMARYAugmentation of vagal tone increases ventricular fibrillation threshold (VFT) under nonischemic and ischemic conditions and protects against spontaneous ventricular fibrillation during experimental myocardial infarction. The purpose of this study was to identify the anatomic pathways responsible for this cholinergically-mediated enhanced electrical stability and to determine whether or not these pathways are present in human hearts. Rich cholinergic innervation of the sinoatrial node, atrioventricular node, and atrial myocardium was confirmed in both canine and human hearts. Although sparse cholinergic innervation was present in ventricular myocardium, numerous cholinergic nerve fibers were present in ventricular conduction tissue of both canine and human hearts. To determine whether these cholinergic fibers mediate the protective effects of vagal stimulation, cholinergic fibers to the ventricular conducting system were ablated in dogs. The ablation procedures used resulted in histologic absence of cholinergic nerves in the ventricular conducting system; innervation of the atrium, however, was histologically intact. In these animals vagal stimulation no longer increased VFT but still caused slowing of the sinus rate. The effect of vagal stimulation on VFT was shown to be independent of adrenergic innervation in a group of catecholamine depleted animals (6-hydroxydopamine). We conclude that 1) the enhanced ventricular electrical stability produced by vagal stimulation in dogs is mediated by cholinergic nerve fibers which supply the ventricular conduction system, and 2) this anatomic pathway is present in human hearts. were 1) to determine definitely whether the beneficial effects of vagal stimulation in dogs are in fact due to cholinergic innervation of the ventricle and 2) to determine whether cholinergic pathways exist in the human heart that could provide a basis for possible beneficial effects of increased vagal tone on the genesis of arrhythmias in man.Methods Human tissue was obtained at autopsy within 12 hours of death from five patients without known cardiac disease. Tissue from the sinoatrial (SA) node region, the atrioventricular (A-V) node, the His bundle, the left bundle branch, and the free wall of the left ventricle was examined. To determine whether postmortem time was a factor in the disappearance of acetylcholinesterase (AChE) activity in human tissue, fresh samples of atrial myocardium (atrial appendage removed at the time of cannulation for extracorporeal circulation) and ventricular myocardium (removed at time of myectomy for asymmetric septal hypertrophy) were obtained at the time of operation, frozen on dry ice, and analyzed immediately.In canine experiments tissue blocks of the SA node, A-V node with bundle of His and proximal left bundle branch, and left ventricular myocardium were placed on specimen

Effects of intracoronary acetylcholine and atropine on basal and dobutamine-stimulated left ventricular contractility.

“…(7) Atropine was infused at a rate of 12 gg/min. (8) After hemodynamic measurements had been made during atropine infusion, atropine was continued with the concurrent infusion of dobutamine at the rate used for the first dobutamine infusion. (9) After completion of the drug infusions, radiographic contrast was injected to confirm the continued position of the catheter in the left main coronary ostium.…”

“…However, changes in parasympathetic tone can substantially attenuate the positive inotropic response to a variety of sympathetic stimuli in anesthetized2-5 and conscious6,7 dogs, and vagal fibers can be seen to innervate the human left ventricle, albeit to a lesser density than the sinoatrial or atrioventricular nodes. 8 The purpose of this study was to determine whether cholinergic pathways in the human heart modulate basal left ventricular contractility or the positive inotropic response to 8-adrenergic stimulation. Acetylcholine, a cholinergic agonist; atropine, a cholinergic antagonist; and dobutamine, a 3-adrenergic agonist, were infused directly into the left main coronary artery of patients with angiographically normal coronary arteries, and left ventricular peak +dP/dt was measured to assess changes in contractility.9 We studied six subjects with normal left ventricular function and, to address a po-tential action of acetylcholine or atropine to affect cardiac function by modulating presynaptic norepinephrine release, seven subjects who had undergone cardiac transplantation from 1 to 3 years previously.…”

Vagus nerve stimulation decreases left ventricular contractility in vivo in the human and pig heart

“…These studies show that in the human and pig heart the left vagus nerve can profoundly decrease the inotropic state of the left ventricular myocardium independent of its bradycardic effect. et al 1974;Loffelholz & Pappano, 1985;Du et al 1995) as well as a dense distribution of muscarinic M 2 receptors (Fields et al 1978;Goyal, 1989;Deighton et al 1990). However, a load-independent assessment of the influences of vagal nerve stimulation on contractility, in mammals other than the dog, is lacking.…”

Physiological Society Symposium ‐ Vagal Control: From Axolotl to Man

“…In humans, there is evidence for an efferent parasympathetic innervation of the LV myocardium (Kent et al 1974) and for the presence of muscarinic M2 cholinoreceptors (Deighton et al 1990). Positron emission tomography with the "C-labelled muscarinic antagonist methiodide quinuclidinyl benzilate has shown that the highest binding density in the human heart is in the ventricular septum and in the left ventricle (Syrota e f al.…”