Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels
Antiarrhythmic Properties of Ranolazine: Inhibition of Atrial Fibrillation Associated TASK-1 Potassium Channels
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DOI：
10.3389/fphar.2019.01367
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发表时间：
2019-11-26
影响因子：
5.6
通讯作者：
Schmidt, Constanze
中科院分区：
文献类型：
--
作者：
Ratte, Antonius;Wiedmann, Felix;Schmidt, Constanze
背景：心房颤动（AF）是最常见的持续性心律失常，也是心血管疾病发病和死亡的主要原因之一。尽管在过去几年中取得了良好的进展，但安全有效的房颤治疗仍然是一个未满足的临床需求。抗心绞痛剂雷诺嗪主要通过晚期I-Na和I-Kr阻断表现出抗心律失常的特性。这导致心房动作电位持续时间（APD）和有效不应期（ERP）延长，但对心室电生理的影响较小。此外，雷诺嗪已被证明在房颤治疗中有效。TASK-1是一种双孔结构域钾（K-2P）通道，在人类心脏中几乎显示心房特异性表达，并在房颤中被发现上调，导致房颤患者心房APD缩短。我们假设抑制TASK-1有助于观察到雷诺嗪的电生理和临床效果。方法：以非洲爪蟾卵母细胞和cho细胞作为异源表达系统，研究雷诺嗪对TASK-1的抑制作用，并通过分子药物对接模拟研究雷诺嗪的结合位点和结合特性。结果：Ranolazine作为TASK-1钾通道抑制剂，抑制TASK-1电流，在哺乳动物细胞中IC50为30.6 3.7 μ M，在褐毛鼠卵母细胞中IC50为198.4 +/- 1.1 μ M。雷诺嗪对TASK-1的抑制不是频率依赖的，而是电压依赖的，在去极化膜电位越高时抑制效力越高。雷诺嗪结合在TASK-1内孔的中心空腔内，在选择性过滤器的底部。结论：在本研究中，我们发现雷诺嗪抑制TASK-1通道。我们认为抑制TASK-1可能有助于观察到雷诺嗪的抗心律失常作用。因此，雷诺嗪可作为治疗心房性心律失常的原型药物，其对心房电生理的综合疗效和较低的心室副作用风险。
Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and one of the major causes of cardiovascular morbidity and mortality. Despite good progress within the past years, safe and effective treatment of AF remains an unmet clinical need. The anti-anginal agent ranolazine has been shown to exhibit antiarrhythmic properties via mainly late I-Na and I-Kr blockade. This results in prolongation of the atrial action potential duration (APD) and effective refractory period (ERP) with lower effect on ventricular electrophysiology. Furthermore, ranolazine has been shown to be effective in the treatment of AF. TASK-1 is a two-pore domain potassium (K-2P) channel that shows nearly atrial specific expression within the human heart and has been found to be upregulated in AF, resulting in shortening the atrial APD in patients suffering from AF. We hypothesized that inhibition TASK-1 contributes to the observed electrophysiological and clinical effects of ranolazine.Methods: We used Xenopus laevis oocytes and CHO-cells as heterologous expression systems for the study of TASK-1 inhibition by ranolazine and molecular drug docking simulations to investigate the ranolazine binding site and binding characteristics.Results: Ranolazine acts as an inhibitor of TASK-1 potassium channels that inhibits TASK-1 currents with an IC50 of 30.6 3.7 mu M in mammalian cells and 198.4 +/- 1.1 mu M in X. laevis oocytes. TASK-1 inhibition by ranolazine is not frequency dependent but shows voltage dependency with a higher inhibitory potency at more depolarized membrane potentials. Ranolazine binds within the central cavity of the TASK-1 inner pore, at the bottom of the selectivity filter.Conclusions: In this study, we show that ranolazine inhibits TASK-1 channels. We suggest that inhibition of TASK-1 may contribute to the observed antiarrhythmic effects of Ranolazine. This puts forward ranolazine as a prototype drug for the treatment of atrial arrhythmia because of its combined efficacy on atrial electrophysiology and lower risk for ventricular side effects.