Abstract
Gap junctions and sodium channels are the major molecular determinants of normal and abnormal electrical conduction through the myocardium, however, their exact contributions to arrhythmogenesis are unclear. We examined conduction and recovery properties of regular (S1) and extrasystolic (S2) action potentials (APs), S1S2 restitution and ventricular arrhythmogenicity using the gap junction and sodium channel inhibitor heptanol (2 mM) in Langendorff-perfused mouse hearts (n=10). Monophasic action potential recordings obtained during S1S2 pacing showed that heptanol increased the proportion of hearts showing inducible ventricular tachycardia (0/10 vs. 5/8 hearts (Fisher’s exact test, P < 0.05), prolonged activation latencies of S1 and S2 APs, thereby decreasing S2/S1 activation latency ratio (ANOVA, P < 0.05) despite prolonged ventricular effective refractory period (VERP). It did not alter S1 action potential duration at 90% repolarization (APD90) but prolonged S2 APD90 (P < 0.05), thereby increasing S2/S1 APD90 ratio (P < 0.05). It did not alter maximum conduction velocity (CV) restitution gradient or maximum CV reductions but decreased the restitution time constant (P < 0.05). It increased maximal APD90 restitution gradient (P < 0.05) without altering critical diastolic interval or maximum APD90 reductions. Pro-arrhythmic effects of 2 mM heptanol are explicable by delayed conduction and abnormal electrical restitution. We concluded that gap junctions modulated via heptanol (0.05 mM) increased arrhythmogenicity through a delay in conduction, while sodium channel inhibition by a higher concentration of heptanol (2 mM) increased arrhythmogenicity via additional mechanisms, such as abnormalities in APDs and CV restitution.
Highlights
Gap junctions and sodium channels are the major molecular determinants of conduction velocity (CV) of action potentials (APs) travelling through the myocardium [1,2,3,4]
Callans and his colleagues demonstrated in a canine myocardial infarction model, that heptanol had a bimodal effect on ventricular arrhythmogenicity, with 0.5 mM heptanol increasing, and 1 mM heptanol decreasing, the incidence of induced Ventricular tachycardia (VT) [6]
We showed that heptanol at 0.05 mM reduced CV without altering effective refractory period (ERP) or action potential duration (APD), leading to a reduction in excitation wavelength (λ = CV x ERP)
Summary
Gap junctions and sodium channels are the major molecular determinants of conduction velocity (CV) of action potentials (APs) travelling through the myocardium [1,2,3,4]. Heptanol is a pharmacological agent that uncouples gap junctions at concentrations < 2 mM and inhibits sodium channels > 2 mM [5]. A number of investigators have examined the effects of this agent on ventricular arrhythmogenicity, demonstrating different effects in various model systems [6,7,8,9]. Callans and his colleagues demonstrated in a canine myocardial infarction model, that heptanol had a bimodal effect on ventricular arrhythmogenicity, with 0.5 mM heptanol increasing, and 1 mM heptanol decreasing, the incidence of induced VT [6]. 1 mM heptanol reduced CV, increased the excitable gap and to a lesser extent the effective refractory period (ERP) as well as prolonged the cycle length during ventricular tachycardia [7]
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