Temporal response of ectopic activity in guinea pig ventricular myocardium in response to isoproterenol and acetylcholine.

Amara Greer-Short,Steven Poelzing

doi:10.3389/fphys.2015.00278

Abstract

Both β adrenergic and muscarinic receptor stimulation independently potentiate arrhythmogenesis. However, the effect of simultaneous stimulation on arrhythmogenesis is not well known. The purpose of this study was to determine the temporal response of arrhythmia risk to individual and combined autonomic agonists. Guinea pig hearts were excised and Langendorff-perfused. The β adrenergic receptor and muscarinic receptor agonists were isoproterenol (ISO, 0.6 μM) and acetylcholine (ACh, 10 μM), respectively. All measurements with agonists occurred over 21 min. ISO induced ectopic activity for the first 8 min. ISO also transiently shortened and then prolonged R-R interval over a similar time course. ACh added after ISO transiently induced ectopic activity for 12 min, while R-R interval invariantly prolonged. ACh alone produced few ectopic beats, while invariantly prolonging R-R interval. In contrast to ISO alone, ISO following ACh significantly increased ectopic activity and shortened R-R interval for the duration of the experiment. Animals aged 17–19 months exhibited sustained arrhythmogenesis while those aged 11–14 did not. When ACh was removed in older hearts while ISO perfused, a transient increase in ectopic activity and decreased R-R interval was observed, similar to ISO alone. These data suggest that pre-treating with and maintaining ACh perfusion can sustain ISO sensitivity, in contrast to ISO perfusion alone.

Highlights

Sympathetic stimulation by β adrenergic receptor (β-AR) agonists, such as isoproterenol or noradrenaline, or by direct stimulation of the stellate ganglion have all been previously used to induce ventricular arrhythmias or precursors to arrhythmias such as spontaneous calcium releases (Opthof et al, 1993; Brodde and Michel, 1999; Xiang, 2011; Lee et al, 2012; Myles et al, 2012)
The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No 85-23, revised 1996) and has been approved by Institutional Animal Care and Use Committee (IACUC) at Virginia Polytechnic Institute& State University
A temporal relationship exists for ISO-induced ectopic beats

Summary

Introduction

Sympathetic stimulation by β adrenergic receptor (β-AR) agonists, such as isoproterenol or noradrenaline, or by direct stimulation of the stellate ganglion have all been previously used to induce ventricular arrhythmias or precursors to arrhythmias such as spontaneous calcium releases (Opthof et al, 1993; Brodde and Michel, 1999; Xiang, 2011; Lee et al, 2012; Myles et al, 2012). Parasympathetic stimulation via vagus nerves or muscarinic receptor agonists has previously been demonstrated to have opposing effects on calcium handling in myocytes (Gilmour and Zipes, 1985; Nagata et al, 2000), but has been linked to increase risk of arrhythmias (He et al, 2013). Both β–AR and muscarinic receptor stimulation can independently. Prolonged exposure to agonists (minutes to hours) can modulate responsiveness (Dessy et al, 2000; Obayashi et al, 2006; Whalen et al, 2007; Liu et al, 2012). Arrhythmogenic risk due to independent β– AR or muscarinic receptor agonists exhibits multiple time scale dependencies

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