Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties
Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties
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DOI：
10.1161/01.cir.0000139333.83620.5d
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发表时间：
2004-08-24
期刊：
影响因子：
37.8
通讯作者：
Thomas, G
中科院分区：
文献类型：
--
作者：
Antzelevitch, C;Belardinelli, L;Thomas, G
背景-雷诺嗪是一种新型的抗心绞痛药物，在血浆浓度为2 - 6 μ mol/L时能够产生抗缺血作用，而不会降低心率或血压。本研究考察了其在分离的犬心室肌细胞、组织和动脉灌注左心室楔形制剂中的电生理效应。方法和结果-同时记录楔形制剂心外膜和心肌中区跨膜动作电位（APs）和假心电图。心外膜和M组织也记录了ap。心外膜和M肌细胞记录全细胞电流。雷诺嗪抑制I-Kr （IC50 = 11.5 μ mol/L）、晚期I-Na、晚期I-Ca、峰值I-Ca和INa-Ca （IC50分别为5.9、50、296和91 μ mol/L）和I-Ks (IC50为30 μ mol/L时为17%)，但对I-to和I-K1的抑制作用较小或无抑制作用。在组织和楔形制剂中，雷诺嗪使心外膜AP持续时间呈浓度依赖性延长，但使M细胞AP持续时间缩短，导致跨壁复极化弥散度（TDR）减少或无变化。在[K+](o) = 4 mmol/L时，10 μ mol/L雷诺嗪可使QT间期延长20 ms，但未增加TDR。未观察到心脏收缩外活动和自发性扭转点（TdP），刺激诱导的TdP在任何浓度的雷诺嗪（正常或低[K+]）下都不能诱导。Ranolazine （5 ~ 20 μ mol/L）抑制早期后去极化（EADs），降低选择性I-Kr阻滞剂d-sotalol诱导的TDR增加。结论：雷诺嗪产生的离子通道效应类似于慢性胺碘酮治疗后观察到的离子通道效应（减少I-Kr、I-Ks、晚期I-Na和I-Ca）。雷诺嗪抑制EADs和降低TDR的作用表明，除了其抗心绞痛作用外，该药物可能具有抗心律失常活性。
Background - Ranolazine is a novel antianginal agent capable of producing antiischemic effects at plasma concentrations of 2 to 6 mumol/L without reducing heart rate or blood pressure. The present study examines its electrophysiological effects in isolated canine ventricular myocytes, tissues, and arterially perfused left ventricular wedge preparations.Methods and Results - Transmembrane action potentials (APs) from epicardial and midmyocardial ( M) regions and a pseudo-ECG were recorded simultaneously from wedge preparations. APs were also recorded from epicardial and M tissues. Whole-cell currents were recorded from epicardial and M myocytes. Ranolazine inhibited I-Kr (IC50 = 11.5 mumol/L), late I-Na, late I-Ca, peak I-Ca, and INa-Ca (IC50 = 5.9, 50, 296, and 91 mumol/L, respectively) and I-Ks (17% at 30 mumol/L), but caused little or no inhibition of I-to or I-K1. In tissues and wedge preparations, ranolazine produced a concentration-dependent prolongation of AP duration of epicardial but abbreviation of that of M cells, leading to reduction or no change in transmural dispersion of repolarization (TDR). At [K+](o) = 4 mmol/L, 10 mumol/L ranolazine prolonged QT interval by 20 ms but did not increase TDR. Extrasystolic activity and spontaneous torsade de pointes (TdP) were never observed, and stimulation-induced TdP could not be induced at any concentration of ranolazine, either in normal or low [K+](o). Ranolazine ( 5 to 20 mumol/L) suppressed early afterdepolarizations (EADs) and reduced the increase in TDR induced by the selective I-Kr blocker d-sotalol.Conclusions - Ranolazine produces ion channel effects similar to those observed after chronic amiodarone ( reduced I-Kr, I-Ks, late I-Na, and I-Ca). The actions of ranolazine to suppress EADs and reduce TDR suggest that, in addition to its antianginal actions, the drug may possess antiarrhythmic activity.