Current-dependent block of rabbit sino-atrial node I(f) channels by ivabradine.
Current-dependent block of rabbit sino-atrial node I(f) channels by ivabradine.
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DOI：
10.1085/jgp.20028593
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发表时间：
2002-07
影响因子：
3.8
通讯作者：
DiFrancesco, Dario
中科院分区：
文献类型：
--
作者：
Bucchi, Annalisa;Baruscotti, Mirko;DiFrancesco, Dario
“有趣”（f-）通道在起搏细胞自发活动的产生中起关键作用，并介导心率的自主控制; f-通道和相关的神经元h-通道由超极化激活的环核苷酸门控（HCN）通道亚基组成。我们研究了伊伐布雷定（一种新型心率降低剂）对兔心脏窦房结细胞f通道的阻断作用。伊伐布雷定是一种开放通道阻滞剂;然而，当通道在去极化时失活时，优先发挥阻滞作用，并通过长超极化步骤缓解。这些特征导致使用依赖性行为。在这方面，伊伐布雷定对f通道的作用与其他降速率剂（如UL-FS 49和ZD 7288）报告的作用相似。然而，伊伐拉定诱导的阻断的其他特征是独特的，并且不符合阻断的电压依赖性完全归因于伊伐拉定带电分子对通道孔中电场的敏感性或对不同通道状态的不同亲和力的假设，如已针对UL-FS 49提出的（DiFrancesco，D. 1994. Pflugers Arch.427：64-70）和ZD 7288（Shin，S.K.，B.S. Rotheberg和G.耶伦2001. 117：91-101）。在不改变膜电压的情况下改变流经通道的电流的实验表明，伊伐布雷定阻滞依赖于电流驱动力，而不仅仅是电压，这是细胞内阳离子在内向整流K+通道中诱导阻滞的典型特征。在没有通过通道的内向电流的情况下，结合的药物分子不会从结合位点分离，即使通道是开放的，药物因此不会被关闭的门“捕获”。我们的数据表明，通过f通道孔的渗透是根据多离子、单列机制发生的，伊伐布雷定的阻断/解除阻断与离子流偶联。伊伐布雷定If阻滞的特定特征导致的使用依赖性放大了其在高自发心率下的心率降低能力，可能对临床应用有用。
“Funny” (f-) channels have a key role in generation of spontaneous activity of pacemaker cells and mediate autonomic control of cardiac rate; f-channels and the related neuronal h-channels are composed of hyperpolarization-activated, cyclic nucleotide–gated (HCN) channel subunits. We have investigated the block of f-channels of rabbit cardiac sino-atrial node cells by ivabradine, a novel heart rate-reducing agent. Ivabradine is an open-channel blocker; however, block is exerted preferentially when channels deactivate on depolarization, and is relieved by long hyperpolarizing steps. These features give rise to use-dependent behavior. In this, the action of ivabradine on f-channels is similar to that reported of other rate-reducing agents such as UL-FS49 and ZD7288. However, other features of ivabradine-induced block are peculiar and do not comply with the hypothesis that the voltage-dependence of block is entirely attributable to either the sensitivity of ivabradine-charged molecules to the electrical field in the channel pore, or to differential affinity to different channel states, as has been proposed for UL-FS49 (DiFrancesco, D. 1994. Pflugers Arch. 427:64–70) and ZD7288 (Shin, S.K., B.S. Rotheberg, and G. Yellen. 2001. J. Gen. Physiol. 117:91–101), respectively. Experiments where current flows through channels is modified without changing membrane voltage reveal that the ivabradine block depends on the current driving force, rather than voltage alone, a feature typical of block induced in inwardly rectifying K+ channels by intracellular cations. Bound drug molecules do not detach from the binding site in the absence of inward current through channels, even if channels are open and the drug is therefore not “trapped” by closed gates. Our data suggest that permeation through f-channel pores occurs according to a multiion, single-file mechanism, and that block/unblock by ivabradine is coupled to ionic flow. The use-dependence resulting from specific features of If block by ivabradine amplifies its rate-reducing ability at high spontaneous rates and may be useful to clinical applications.