Enhanced Repolarization Capacity: New Potential Antiarrhythmic Strategy Based on hERG Channel Activation

G.      Szabo; V.      Farkas; M.      Grunnet; A.      Mohacsi; P.      P. Nanasi

Abstract

The delayed rectifier potassium current (IK) is the major outward current responsible for ventricular repolarization in cardiac tissues. Based on kinetic properties and drug sensitivity it is composed of a slow (IKs) and a rapid (IKr) component, the latter is mediated by hERG channels. Suppression of IKr is the common mechanism of action of all class III antiarrhythmics, causing prolongation of the refractory period. However, lengthening of repolarization - either by a pathological factor or due to a pharmacological intervention - threatens with an increased risk of EAD generation and the concomitant sudden cardiac death. Therefore, a new potential anti-arrhythmic strategy, based on augmentation of the repolarization reserve, has been emerged. Recently a new class of compounds has been introduced as activators of the hERG channel. In this article we systematically review the chemical structures found to enhance IKr. Since the majority of previous experiments were performed in expression systems or in rodent cardiac preparations (neither is relevant to the human heart), in the second part of this article we present some results obtained with NS1643, the best examined hERG activator, in canine ventricular cardiomyocytes. This preparation is believed to have electrophysiological parameters most resembling those of human. NS1643 shortened the duration of canine ventricular action potential and was shown to interact with several transmembrane ion currents, including ICa, IKr, IKs, and Ito. However, the action potential shortening effect of NS1643 is likely related to inhibition of ICa, in addition to the enhancement of IKr. Although the multiple ion channel activity of NS1643 may carry proarrhythmic risk, the rationale of antiarrhythmic strategy based on IKr activation is not questioned.

Keywords: hERG channel activation, IKr, long QT syndrome, NS1643, cardiac electrophysiology, action potential, repolarization reserve, cardiac tissues, hERG channels, class III antiarrhythmics