Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University.
Biol Pharm Bull. 2021;44(11):1796-1799. doi: 10.1248/bpb.b21-00605.
Torsadogenic effects of ivabradine, an inhibitor of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, were assessed in an in vivo proarrhythmia model of acute atrioventricular block rabbit. Ivabradine at 0.01, 0.1, and 1 mg/kg was intravenously administered to isoflurane-anesthetized rabbits (n = 5) in the stable idioventricular rhythm. Ivabradine at 0.01 and 0.1 mg/kg hardly affected the atrial and ventricular automaticity, QT interval, or the monophasic action potential duration of the ventricle. Additionally administred ivabradine at 1 mg/kg decreased the atrial and ventricular rate significantly but increased the QT interval and duration of the monophasic action potential. Meanwhile, torsade de pointes arrhythmias were detected in 1 out of 5 animals and in 2 out of 5 animals after the administration of 0.1 and 1 mg/kg, respectively. Importantly, torsade de pointes arrhythmias could be observed only in 2 rabbits showing more potent suppressive effects on ventricular automaticity. These results suggest that the torsadogenic potential of ivabradine may become evident when its expected bradycardic action appears more excessively.
在急性房室传导阻滞兔的体内致心律失常模型中评估了伊伐布雷定（一种超极化激活环核苷酸门控（HCN）通道抑制剂）的致扭转型作用。在异氟烷麻醉的兔子（n=5）稳定的自身节律下，静脉内给予伊伐布雷定 0.01、0.1 和 1mg/kg。伊伐布雷定 0.01 和 0.1mg/kg 几乎不影响心房和心室自动性、QT 间期或心室单相动作电位的持续时间。此外，给予 1mg/kg 的伊伐布雷定可显著降低心房和心室率，但增加 QT 间期和单相动作电位的持续时间。同时，在 5 只动物中有 1 只，在给予 0.1 和 1mg/kg 后有 2 只动物中检测到尖端扭转型室性心动过速。重要的是，尖端扭转型室性心动过速仅在 2 只显示对心室自动性更强烈抑制作用的兔子中观察到。这些结果表明，当伊伐布雷定预期的缓慢性作用表现得更加过度时，其致扭转型作用的可能性就会变得明显。
