Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation - Differences in sodium channel inactivation between atria and ventricles and the role of ranolazine
Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation - Differences in sodium channel inactivation between atria and ventricles and the role of ranolazine
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DOI：
10.1161/circulationaha.107.704890
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发表时间：
2007-09-25
期刊：
影响因子：
37.8
通讯作者：
Antzelevitch, Charles
中科院分区：
文献类型：
--
作者：
Burashnikov, Alexander;Di Diego, Jose M.;Antzelevitch, Charles
背景-选择性心房抗心律失常药物的开发是目前抑制心房颤动（AF）的策略。方法和结果-全细胞膜片钳技术被用于评估从犬心房和心室分离的肌细胞中峰值钠通道电流（I-Na）的失活。在犬离体冠状动脉灌注的心房和心室制备物中，评价了治疗浓度的雷诺嗪（1至10 μ mol/L）和利多卡因（2.1至21 μ mol/L）的电生理效应。在对照条件下，心房细胞的I-Na半失活电压比心室细胞的I-Na半失活电压负约15 mV;暴露于雷诺嗪后，这种差异增加。雷诺嗪对钠通道参数产生明显的使用依赖性抑制，包括动作电位上行程的最大上升速率、传导速度和舒张期兴奋阈值，以及心房（而非心室）诱导的复极后不应性。利多卡因也优先抑制心房与心室的这些参数，但程度远低于雷诺嗪。雷诺嗪使心房动作电位时程（APD（90））延长，对心室肌APD（90）无影响，使浦肯野纤维APD（90）缩短。利多卡因缩短了心房和心室APD（90）。雷诺嗪在终止持续性AF和预防AF诱导方面比利多卡因更有效。结论-我们的研究证明了心房与心室钠通道失活特征的重要差异，雷诺嗪产生使用依赖性钠通道阻滞的作用具有显著的心房选择性，我们的研究结果表明心房选择性钠通道阻滞是治疗房颤的一种新策略。
Background-The development of selective atrial antiarrhythmic agents is a current strategy for suppression of atrial fibrillation (AF).Methods and Results-Whole-cell patch clamp techniques were used to evaluate inactivation of peak sodium channel current (I-Na) in myocytes isolated from canine atria and ventricles. The electrophysiological effects of therapeutic concentrations of ranolazine (1 to 10 mu mol/L) and lidocaine (2.1 to 21 mu mol/L) were evaluated in canine isolated coronary-perfused atrial and ventricular preparations. Half-inactivation voltage of I-Na was approximate to 15 mV more negative in atrial versus ventricular cells under control conditions; this difference increased after exposure to ranolazine. Ranolazine produced a marked use-dependent depression of sodium channel parameters, including the maximum rate of rise of the action potential upstroke, conduction velocity, and diastolic threshold of excitation, and induced postrepolarization refractoriness in atria but not in ventricles. Lidocaine also preferentially suppressed these parameters in atria versus ventricles, but to a much lesser extent than ranolazine. Ranolazine produced a prolongation of action potential duration (APD(90)) in atria, no effect on APD(90) in ventricular myocardium, and an abbreviation of APD(90) in Purkinje fibers. Lidocaine abbreviated both atrial and ventricular APD(90). Ranolazine was more effective than lidocaine in terminating persistent AF and in preventing the induction of AF.Conclusions-Our study demonstrates important differences in the inactivation characteristics of atrial versus ventricular sodium channels and a striking atrial selectivity for the action of ranolazine to produce use-dependent block of sodium channels, leading to suppression of AF. Our results point to atrium-selective sodium channel block as a novel strategy for the management of AF.