Department of Biochemistry, University of Cambridge, Cambridge, UK.
Physiological Laboratory, University of Cambridge, Cambridge, UK.
Br J Pharmacol. 2018 Apr;175(8):1260-1278. doi: 10.1111/bph.13807. Epub 2017 May 12.
Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca -mediated, catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro-arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Na channel or intracellular ryanodine receptor (RyR2)-Ca channel function. Flecainide accesses its transmembrane Na 1.5 channel binding site during activated, open, states producing a use-dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak I related to activation of Na channels followed by rapid de-activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro-arrhythmic conditions reflecting loss of function of Na 1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro-arrhythmic effects attributed to prolonged AP recovery by abnormal late I following gain-of-function modifications of Na 1.5 channels in LQTS3 are reduced by flecainide. Anti-arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca release could arise from its primary actions on Na channels indirectly decreasing [Ca ] through a reduced [Na ] and/or direct open-state RyR2-Ca channel antagonism. The consequent [Ca ] alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Na 1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.
This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
氟卡尼可抑制包括阵发性心房颤动、室上性心动过速和心律失常性长 QT 综合征（LQTS）在内的心脏性快速性心律失常，以及钙介导的儿茶酚胺多形性室性心动过速（CPVT）。然而，氟卡尼也可能产生致心律失常作用，尤其是在心肌梗死时以及用于诊断 Brugada 综合征（BrS）时。这些不同的作用是由其在多个相互作用的细胞组织水平的生理和药理学作用引起的。在具有修饰的钠通道或细胞内 ryanodine 受体（RyR2）-Ca 通道功能的鼠基因模型中研究了这些作用。氟卡尼在激活、开放状态下进入其跨膜 Na + 1.5 通道结合位点，产生使用依赖性拮抗作用。关闭激活或失活门会将氟卡尼困在孔内。与钠通道激活相关的早期峰 I 随后迅速失活，驱动动作电位（AP）上升及其传播。这在致心律失常条件下会减弱，反映出 Na + 1.5 通道功能丧失，例如 BrS，因此氟卡尼的挑战会加剧这种情况。相反，在 LQTS3 中由于 Na + 1.5 通道的功能获得性改变导致异常晚期 I 后 AP 恢复延长而归因于致心律失常作用的氟卡尼作用减少。氟卡尼通过减少 [Na + ] 和/或直接开放状态 RyR2-Ca 通道拮抗作用间接降低 [Ca 2+ ] 来减少由肌浆网 Ca 释放介导的 CPVT 模型中的触发作用，从而产生抗心律失常作用。因此，[Ca 2+ ] 变化也可能通过其对 Na + 1.5 通道功能的作用来改变 AP 传播速度，从而改变心律失常基质。这与正常和增加的 RyR2 功能情况下氟卡尼对 Na 电流、AP 传导和心律失常发生的作用之间的矛盾差异一致。
本文是心血管疾病中聚焦小分子专题的一部分。要查看本部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
