Department of Biology, Gilead Sciences, 1651 Page Mill Road, Palo Alto, CA 94304, USA.
Circulation. 2011 Apr 26;123(16):1713-20. doi: 10.1161/CIRCULATIONAHA.110.000661. Epub 2011 Apr 11.
The reverse rate dependence (RRD) of actions of I(Kr)-blocking drugs to increase the action potential duration (APD) and beat-to-beat variability of repolarization (BVR) of APD is proarrhythmic. We determined whether inhibition of endogenous, physiological late Na(+) current (late I(Na)) attenuates the RRD and proarrhythmic effect of I(Kr) inhibition.
Duration of the monophasic APD (MAPD) was measured from female rabbit hearts paced at cycle lengths from 400 to 2000 milliseconds, and BVR was calculated. In the absence of a drug, duration of monophasic action potential at 90% completion of repolarization (MAPD(90)) and BVR increased as the cycle length was increased from 400 to 2000 milliseconds (n=36 and 26; P<0.01). Both E-4031 (20 nmol/L) and d-sotalol (10 μmol/L) increased MAPD(90) and BVR at all stimulation rates, and the increase was greater at slower than at faster pacing rates (n=19, 11, 12 and 7, respectively; P<0.01). Tetrodotoxin (1 μmol/L) and ranolazine significantly attenuated the RRD of MAPD(90,) reduced BVR (P<0.01), and abolished torsade de pointes in hearts treated with either 20 nmol/L E-4031 or 10 μmol/L d-sotalol. Endogenous late I(Na) in cardiomyocytes stimulated at cycle lengths from 500 to 4000 milliseconds was greater at slower than at faster stimulation rates, and rapidly decreased during the first several beats at faster but not at slower rates (n=8; P<0.01). In a computational model, simulated RRD of APD caused by E-4031 and d-sotalol was attenuated when late I(Na) was inhibited.
Endogenous late I(Na) contributes to the RRD of I(Kr) inhibitor-induced increases in APD and BVR and to bradycardia-related ventricular arrhythmias.
I(Kr)阻断剂增加动作电位时程（APD）和 APD 复极搏动间变异（BVR）的反向频率依赖性（RRD）是致心律失常的。我们确定抑制内源性生理晚期钠电流（late I(Na)）是否能减弱 I(Kr)抑制的 RRD 和致心律失常作用。
从雌性兔心起搏周长为 400 至 2000 毫秒的情况下，测量单相动作电位时程（MAPD），并计算 BVR。在无药物情况下，90%复极时单相动作电位时程（MAPD(90)）和 BVR 在起搏周长从 400 至 2000 毫秒时增加（n=36 和 26；P<0.01）。E-4031（20nmol/L）和 d-索他洛尔（10μmol/L）均在所有刺激率下增加 MAPD(90)和 BVR，且在较慢起搏率时增加更显著（n=19、11、12 和 7，分别；P<0.01）。河豚毒素（1μmol/L）和雷诺嗪显著减弱 MAPD(90)的 RRD，降低 BVR（P<0.01），并消除用 20nmol/L E-4031 或 10μmol/L d-索他洛尔处理的心脏中的尖端扭转型室性心动过速。在 500 至 4000 毫秒起搏周长下刺激的心肌细胞中的内源性晚期 I(Na)在较慢刺激率下大于较快刺激率，并且在较快但不是较慢刺激率下的最初几个搏动中迅速减少（n=8；P<0.01）。在计算模型中，当抑制晚期 I(Na)时，E-4031 和 d-索他洛尔引起的 APD 的模拟 RRD 减弱。
内源性晚期 I(Na)有助于 I(Kr)抑制剂引起的 APD 和 BVR 增加的 RRD，以及与心动过缓相关的室性心律失常。
