Swansea University Medical School, Swansea University, Swansea, UK.
National Heart and Lung Institute, Imperial College, Hammersmith Hospital, London, UK.
Br J Pharmacol. 2022 Jun;179(11):2558-2563. doi: 10.1111/bph.15718. Epub 2021 Dec 2.
Flecainide is used to treat catecholaminergic polymorphic ventricular tachycardia (CPVT), an arrhythmia caused by disrupted cellular Ca handling following β-adrenergic stimulation. The clinical efficacy of flecainide in this context involves complex effects on multiple ion channels that may be influenced by the disease state. A compelling narrative has been constructed around flecainide's nonselective block of sarcoplasmic reticulum (SR) lumen-to-cytoplasm Ca release through intracellular calcium release channels (RyR2). However, ion fluxes across the SR membrane during heart contraction are bidirectional, and here, we review experimental evidence that flecainide's principal action on RyR2 involves the partial block of ion flow in the cytoplasm-to-lumen direction (i.e., flecainide inhibits RyR2-mediated SR 'countercurrent'). Experimental approaches that could advance new knowledge on the mechanism of RyR2 block by flecainide are proposed. Some impediments to progress in this area, that must be overcome to enable the development of superior drugs to treat CPVT, are also considered.
氟卡尼用于治疗儿茶酚胺多形性室性心动过速（CPVT），这是一种由β肾上腺素刺激后细胞内钙处理紊乱引起的心律失常。氟卡尼在这种情况下的临床疗效涉及对多种离子通道的复杂影响，这些影响可能受疾病状态的影响。围绕氟卡尼通过细胞内钙释放通道（RyR2）对肌浆网（SR）腔到细胞质 Ca 释放的非选择性阻断，已经构建了一个引人注目的叙述。然而，在心脏收缩期间，SR 膜上的离子流是双向的，在这里，我们回顾了实验证据，表明氟卡尼对 RyR2 的主要作用涉及细胞质到腔方向的离子流的部分阻断（即，氟卡尼抑制 RyR2 介导的 SR“逆流”）。提出了一些可以推进关于氟卡尼对 RyR2 阻断机制的新知识的实验方法。还考虑了一些在该领域取得进展的障碍，这些障碍必须克服，才能开发出治疗 CPVT 的更好药物。
