Department of Physiology, University of Debrecen, Nagyerdei Krt. 98. H-4012 Debrecen, Hungary.
Curr Med Chem. 2011;18(24):3607-21. doi: 10.2174/092986711796642382.
The delayed rectifier potassium current (I(K)) 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 (I(Ks)) and a rapid (I(Kr)) 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 I(Ca), I(Kr), I(Ks), and I(to). 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 I(Kr) activation is not questioned.
延迟整流钾电流（I(K))是心肌复极化的主要外向电流。根据动力学特性和药物敏感性，它由慢（I(Ks))和快（I(Kr))成分组成，后者由 hERG 通道介导。抑制 IKr 是所有 III 类抗心律失常药物的共同作用机制，导致不应期延长。然而，复极化的延长 - 无论是由于病理因素还是由于药物干预 - 都有增加 EAD 产生和随之而来的心脏性猝死的风险。因此，出现了一种基于增强复极化储备的新的潜在抗心律失常策略。最近，已经引入了一类新的化合物作为 hERG 通道的激活剂。在本文中，我们系统地回顾了发现增强 IKr 的化学结构。由于大多数先前的实验都是在表达系统或啮齿动物心脏制剂中进行的（两者都与人类心脏无关），在本文的第二部分，我们介绍了用 NS1643 （研究最充分的 hERG 激活剂）在犬心室心肌细胞中获得的一些结果。该制剂被认为具有与人类最相似的电生理参数。NS1643 缩短了犬心室动作电位的持续时间，并被证明与几种跨膜离子电流相互作用，包括 I(Ca)、I(Kr)、I(Ks)和 I(to)。然而，NS1643 的动作电位缩短作用可能与 ICa 的抑制有关，除了增强 IKr 之外。尽管 NS1643 的多种离子通道活性可能存在致心律失常风险，但基于 I(Kr)激活的抗心律失常策略的基本原理并未受到质疑。
