Department of Electrical, Electronic, and Communication Engineering, Faculty of Science and Engineering, Chuo University, Tokyo, Japan.
Department of Electrical, Electronic, and Communication Engineering, Faculty of Science and Engineering, Chuo University, Tokyo, Japan.
J Pharmacol Sci. 2021 Sep;147(1):95-103. doi: 10.1016/j.jphs.2021.05.014. Epub 2021 Jun 5.
Several false-positive results in the human ether-à-gogo-related gene test suggest that blockers of the rapid component of delayed rectifier K current (I) do not necessarily produce drug-induced arrhythmias. Specifically, the occurrence of early afterdepolarization (EAD) differs among I blockers, even if the prolonged action potential duration is in the same range. To predict EAD in drug-induced arrhythmias, we proposed a prediction method based on the mechanisms underlying the difference in frequency of EAD among nonselective I blockers. The mechanisms were elucidated by examining how different blockade kinetics of L-type Ca current (I) affect the frequency of EAD, using mathematical models of human ventricular myocytes. Addition of voltage-independent I blockade resulted in the suppression of EAD. However, when voltage-dependent I blockade kinetics of amiodarone, bepridil, and terfenadine were incorporated into I in the model, bepridil and terfenadine induced EAD more than the voltage-independent I blockade, while amiodarone suppressed EAD more effectively. Opposite effects were accounted for by the difference in I blockade at negatively polarized potential. EAD occurrence was found to be associated with I blockade measured at -20 mV. These results suggest that voltage dependence of I blockade may be useful in predicting the different risks of nonselective I blockers.
几种人 Ether-à-gogo 相关基因测试的假阳性结果表明，延迟整流钾电流（I）的快速成分阻断剂不一定会产生药物诱导的心律失常。具体来说，即使动作电位时程延长在相同范围内，I 阻断剂也会导致早期后除极（EAD）的发生不同。为了预测药物诱导的心律失常中的 EAD，我们提出了一种基于非选择性 I 阻断剂之间 EAD 频率差异的机制的预测方法。通过检查 L 型钙电流（I）的不同阻断动力学如何影响 EAD 的频率，使用人心室肌细胞的数学模型阐明了这些机制。添加非电压依赖性 I 阻断会抑制 EAD。然而，当将胺碘酮、贝普地尔和特非那定的电压依赖性 I 阻断动力学纳入模型中的 I 时，贝普地尔和特非那定诱导的 EAD 比非电压依赖性 I 阻断更多，而胺碘酮更有效地抑制 EAD。这种相反的效果是由负极化电位下 I 阻断的差异引起的。发现 EAD 的发生与在-20 mV 测量的 I 阻断有关。这些结果表明，I 阻断的电压依赖性可能有助于预测非选择性 I 阻断剂的不同风险。
