Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation
Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation
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DOI：
10.1016/j.jelectrocard.2009.07.007
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发表时间：
2009-11-01
影响因子：
1.3
通讯作者：
Burashnikov, Alexander
中科院分区：
文献类型：
--
作者：
Antzelevitch, Charles;Burashnikov, Alexander
房颤(AF)的药物治疗仍然是一个重要的未得到满足的医学需求。由于现有的房颤节律控制药物往往与发生室性心律失常或心外毒性的显著风险相关，因此最近的药物开发集中在具有心房选择性的药物上。抑制心房特有的超快延迟整流钾电流(I-Kur)就是一种心房选择性的方法。然而，最近的研究表明，编码I-Kur通道a亚单位K-V1.5的基因KCNA5的功能丧失突变与房颤的发生有关，抑制I-Kur可以促进实验性模型房颤的诱发。最近发现了另一种潜在的心房选择方法。实验研究表明，钠通道的生物物理特性存在着重要的房室差异，并发现了可利用房室电生理差异的钠通道阻滞剂。心房选择性/主要钠通道阻滞剂，如雷诺嗪，在犬分离的右房制剂的实验模型中有效地抑制房颤，其浓度对心室肌的电生理参数几乎没有影响。长期给药胺碘酮也被发现对心房选择性抑制I-Na依赖的参数，从而阻止房颤的诱发。雷诺嗪和胺碘酮有共同的能力，可以迅速从钠通道解离，并通过抑制I-Kr来延长心房动作电位时程。我们的观察表明，心房选择性钠通道阻滞剂可能是治疗房颤的有效策略。(C)2009 Elsevier Inc.保留所有权利。
Pharmacological management of atrial fibrillation (AF) remains an important unmet medical need. Because available drugs for rhythm control of AF are often associated with a significant risk for development of ventricular arrhythmias or extracardiac toxicity, recent drug development has focused on agents that are atrial selective. Inhibition of the ultrarapid delayed rectifier potassium current (I-Kur), a current exclusive to atria, is an example of an atrial-selective approach. Recent studies, however, have shown that loss-of-function mutations in KCNA5, the gene that encodes K-V1.5, the a subunit of the I-Kur channel, is associated with the development of AF and that inhibition of I-Kur can promote the induction of AF in experimental models. Another potential atrial-selective approach has recently been identified. Experimental Studies have demonstrated important atrioventricular differences in the biophysical properties of the sodium channel and have identified sodium channel blockers that can exploit electrophysiological distinctions between atria and ventricles. Atrial-selective/predominant sodium channel blockers such as ranolazine effectively suppress AF in experimental models involving canine-isolated right atrial preparations at concentrations that produce little to no effect on electrophysiological parameters in ventricular myocardium. Chronic administration of amiodarone was also found to exert atrial-selective depression of I-Na-dependent parameters and thus to prevent the induction of AF. Ranolazine and amiodarone have in common the ability to rapidly dissociate from the sodium channel and to prolong the atrial action potential duration via inhibition of I-Kr. Our observations suggest that atrial-selective sodium channel block may be a fruitful strategy for the management of AF. (C) 2009 Elsevier Inc. All rights reserved.