Dilaveris Polychronis, Giannopoulos Georgios, Synetos Andreas, Gatzoulis Konstantinos, Stefanadis Christodoulos
1st Department of Cardiology, University of Athens Medical School, Hippokration Hospital, Athens, Greece.
Cardiovasc Hematol Agents Med Chem. 2006 Oct;4(4):313-8. doi: 10.2174/187152506778520709.
Several studies have demonstrated that resting heart rate is an important correlate of cardiovascular and all-cause mortality and that the mortality benefit of some cardiovascular drugs seems to be related in part to their heart rate-lowering effects. Since the currently available classes of drugs with heart-rate lowering effect (e.g. beta-blockers and calcium channel antagonists) also exert multiple structural and functional actions on the cardiovascular system, which may be in some cases undesired, the introduction of a new class of agents exclusively affecting the pacemaker activity of the sinus node is of particular interest. The first molecule of this class - sinus node modulators or I(f)-current inhibitors - to reach clinical application is ivabradine. Cardiac pacemaker cells generate a spontaneous slow diastolic depolarisation that drives the membrane voltage away from a hyperpolarised level towards the threshold level for initiating a subsequent action potential, generating rhythmic action potentials that propagate through the heart and trigger myocardial contraction. The I(f) current is an inward ionic current that determines the slope of diastolic depolarisation, which in turn controls the heart beating rate. Extensive work has amply demonstrated its involvement in the generation of spontaneous activity. The molecular basis of the generation of the pacemaker current was landmarked by the cloning of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, which constitute the structural units of the f-channels. This review addresses the major basic properties of cardiac f-channels, with a focus on the mode of action of I(f)-current inhibitors and outlines the therapeutic implications of the existing research data.
多项研究表明，静息心率是心血管疾病和全因死亡率的重要相关因素，一些心血管药物的死亡率获益似乎部分与其降低心率的作用有关。由于目前可用的具有降低心率作用的药物类别（如β受体阻滞剂和钙通道拮抗剂）也会对心血管系统产生多种结构和功能作用，在某些情况下可能是不理想的，因此引入一类专门影响窦房结起搏活动的新型药物备受关注。这类药物中首个进入临床应用的分子——窦房结调节剂或I(f)电流抑制剂——是伊伐布雷定。心脏起搏细胞产生自发性缓慢舒张期去极化，使膜电位从超极化水平向引发后续动作电位的阈值水平变化，产生有节律的动作电位，该动作电位通过心脏传播并触发心肌收缩。I(f)电流是一种内向离子电流，它决定舒张期去极化的斜率，进而控制心跳速率。大量研究充分证明其参与了自发活动的产生。起搏电流产生的分子基础以超极化激活的环核苷酸门控（HCN）通道的克隆为标志，HCN通道构成了I(f)通道的结构单元。本综述阐述了心脏I(f)通道的主要基本特性，重点关注I(f)电流抑制剂的作用方式，并概述了现有研究数据的治疗意义。
