Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, PC21

Poster Communications

The acute inotropic and electrophysiological response during cardiac contractility modulation is mediated by local post-synaptic transmission in the isolated innervated rabbit heart

J. Winter1, K. E. Brack1, G. Ng1,2

1. Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom. 2. Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester, United Kingdom.

  • Figure 1. Effect of hexamethonium on the inotropic and electrophysiological responses to CCM. BL=Baseline, CCM=Cardiac Contractility Modulation, LVP=Left ventricular pressure, dPdtmax=maximal rate of change of pressure, MAPD= Mono-phasic action potential duration. *P<0.05, **P<0.01, ***P<0.001.

The cardiac ventricle is richly innervated by both efferent and afferent sympathetic fibres. The latter relays sensory information from the myocardium to the intracardiac and intrathoracic ganglia, spinal cord and the brain for integration and is known to be involved in the regulation of cardiac function. We have previously demonstrated in isolated hearts that application of electrical signals to the rabbit ventricle during the absolute refractory period enhances inotropy by stimulating the release of noradrenaline - so-called cardiac contractility modulation (CCM) (1). The aim of the present study was to investigate the potential role of the intracardiac, intrathoracic ganglia and afferent sympathetic nerves in the inotropic and electrophysiological responses seen during CCM. Experiments were conducted in the isolated innervated New Zealand white rabbit hearts (n=4). Following pre-sedation (ketamine (10mg/kg), medetomidine hydrochloride (0.2mg/kg) and butorphanol (0.05mg/kg) (i.m.)) general anaesthesia was established with propofol (1%w/v ad libitum, i.v.) during which vessels were ligated and cervico-thoracic tissues isolated to give the innervated heart preparation. Animals were euthanised with pentobarbitone overdose (160mg/kg, i.v.). The resulting ex vivo preparation was perfused via the descending aorta with constant flow. Left ventricular (LV) performance was measured iso-volumetrically with a fluid filled balloon. Bi-phasic square wave electrical pulses (amplitude=15mA, duration=20ms) were applied to the LV using wire electrodes and timed to coincide with the absolute refractory period measured from locally recorded monophasic action potentials. Local action potential duration (APD) was calculated both immediately before CCM and immediately after the cessation of stimulation. The inotropic and electrophysiological effects of CCM were assessed before and during perfusion of the nicotinic ganglionic transmission inhibitor hexamethonium (HX, 0.5mM) and following removal of the spinal cord. Data (mean±SEM) were compared using paired Students T-Tests. CCM enhanced LV pressure (LVP, Fig1A), rate of pressure development (Fig 1B) and promoted the shortening of local APD (Fig1C). The CCM induced increase in LVP (Fig. 1A), dP/dtmax (Fig. 1B) and shortening of APD (Fig. 1C) was unaffected by HX perfusion. The effect of CCM was comparable before and after removal of the spinal cord (data not shown). Our data provides functional evidence that CCM does not engage the intracardiac or intrathoracic ganglion and that afferent nerve transmission is not required to modulate the acute ventricular response during CCM. These data support the notion that the acute inotropic and electrophysiological effects of CCM are mediated through local post-synaptic noradrenaline release.

Where applicable, experiments conform with Society ethical requirements