Mangoni M E, Marger L, Nargeot J
CNRS UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France.
Adv Cardiol. 2006;43:17-30. doi: 10.1159/000095403.
The slow diastolic depolarization phase in cardiac pacemaker cells is the electrical basis of cardiac automaticity. The hyperpolarization-activated current (I(f)) is one of the key mechanisms underlying diastolic depolarization. Particularly, I(f) is unique in being activated on membrane hyperpolarization following the repolarization phase of the action potential. I(f) has adapted biophysical properties and voltage-dependent gating to initiate pacemaker activity. I(f) possibly constitutes the first voltage-dependent trigger of the diastolic depolarization. For these reasons, I(f) is a natural pharmacological target for controlling heart rate in cardiovascular disease. In this view, I(f) inhibitors have been developed in the past, yet the only molecule to have reached the clinical development is ivabradine. At the cellular level, the remarkable success of ivabradine is to be ascribed to its relatively high affinity for f-channels. Furthermore, ivabradine is the most I(f)-specific inhibitor known to date, since moderate inhibition of other voltage-dependent ionic currents involved in automaticity can be observed only at very high concentrations of ivabradine, more than one order of magnitude from that inhibiting I(f). Finally, the mechanism of block of f-channels by ivabradine has particularly favorable properties in light of controlling heart rate under variable physiological conditions. In this article, we will discuss how I(f) inhibition by ivabradine can lead to reduction of heart rate. To this aim, we will comment on the role of I(f) in cardiac automaticity and on the mechanism of action of ivabradine on f-channels. Some aspects of the cardiac pacemaker mechanism that improve the degree of security of ivabradine will also be highlighted.
心脏起搏细胞的舒张期缓慢去极化阶段是心脏自动节律性的电基础。超极化激活电流（I(f)）是舒张期去极化的关键机制之一。特别地，I(f)的独特之处在于它在动作电位复极化阶段后的膜超极化时被激活。I(f)具有适应性的生物物理特性和电压依赖性门控，以启动起搏活动。I(f)可能构成舒张期去极化的首个电压依赖性触发因素。基于这些原因，I(f)是心血管疾病中控制心率的天然药理学靶点。从这个角度来看，过去已经开发了I(f)抑制剂，但唯一进入临床开发阶段的分子是伊伐布雷定。在细胞水平上，伊伐布雷定取得显著成功的原因在于它对f通道具有相对较高的亲和力。此外，伊伐布雷定是迄今为止已知的最具I(f)特异性的抑制剂，因为只有在非常高的伊伐布雷定浓度下才能观察到对其他参与自动节律性的电压依赖性离子电流的适度抑制，该浓度比抑制I(f)的浓度高出一个数量级以上。最后，鉴于在可变生理条件下控制心率，伊伐布雷定阻断f通道的机制具有特别有利的特性。在本文中，我们将讨论伊伐布雷定抑制I(f)如何导致心率降低。为此，我们将评论I(f)在心脏自动节律性中的作用以及伊伐布雷定对f通道的作用机制。还将强调心脏起搏机制中提高伊伐布雷定安全性的一些方面。
