Electrophysiological effects of nicotinic and electrical stimulation of intrinsic cardiac ganglia in the absence of extrinsic autonomic nerves in the rabbit heart

Emily Allen,John H Coote,Blair D Grubb,Trevor F.C Batten,Dainius H Pauza,G André Ng,Kieran E Brack

doi:10.1016/j.hrthm.2018.05.018

Abstract

BackgroundThe intrinsic cardiac nervous system is a rich network of cardiac nerves that converge to form distinct ganglia and extend across the heart and is capable of influencing cardiac function.ObjectiveThe goals of this study were to provide a complete picture of the neurotransmitter/neuromodulator profile of the rabbit intrinsic cardiac nervous system and to determine the influence of spatially divergent ganglia on cardiac electrophysiology.MethodsNicotinic or electrical stimulation was applied at discrete sites of the intrinsic cardiac nerve plexus in the Langendorff-perfused rabbit heart. Functional effects on sinus rate and atrioventricular conduction were measured. Immunohistochemistry for choline acetyltransferase (ChAT), tyrosine hydroxylase, and/or neuronal nitric oxide synthase (nNOS) was performed using whole mount preparations.ResultsStimulation within all ganglia produced either bradycardia, tachycardia, or a biphasic brady-tachycardia. Electrical stimulation of the right atrial and right neuronal cluster regions produced the largest chronotropic responses. Significant prolongation of atrioventricular conduction was predominant at the pulmonary vein-caudal vein region. Neurons immunoreactive (IR) only for ChAT, tyrosine hydroxylase, or nNOS were consistently located within the limits of the hilum and at the roots of the right cranial and right pulmonary veins. ChAT-IR neurons were most abundant (1946 ± 668 neurons). Neurons IR only for nNOS were distributed within ganglia.ConclusionStimulation of intrinsic ganglia, shown to be of phenotypic complexity but predominantly of cholinergic nature, indicates that clusters of neurons are capable of independent selective effects on cardiac electrophysiology, therefore providing a potential therapeutic target for the prevention and treatment of cardiac disease.

Highlights

In recent decades, a rich network of intrinsic cardiac nerves that converge to form distinct ganglia and extend across the heart has been documented in mammalian species including dog, cat, pig, guinea pig, mouse, as well as human.[1]
Nicotine was applied in a total of 14 hearts at a number of sites within the regions shown in Figure 1: left neuronal complex (LNC) in all 14 animals; right neuronal complex (RNC), right atrial ganglionated plexi (RAGP), and PVCV in 13, 11, and 6 animals, respectively
Nicotine applied to RAGP produced the strongest bradycardia or tachycardia, while LNC produced the smallest heart rate (HR) decrease and PVCV the smallest HR increase (Figure 2)

Summary

Introduction

A rich network of intrinsic cardiac nerves that converge to form distinct ganglia and extend across the heart has been documented in mammalian species including dog, cat, pig, guinea pig, mouse, as well as human.[1] Evidence suggests that activity within these ganglia may result in cardiac changes both locally and in other regions of the myocardium, independent of extrinsic autonomic nerves.[1,2,3,4] This has given rise to the notion that such an intrinsic cardiac nervous system (ICNS) acts as the heart’s “little brain,” capable of influencing cardiac function[5,6] even in the absence of extrinsic autonomic input, this has not been directly tested. The intrinsic cardiac nervous system is a rich network of cardiac nerves that converge to form distinct ganglia and extend across the heart and is capable of influencing cardiac function

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Conclusion