Different voltage dependence of ICaL blockade in nonselective IKr blockers causes their opposite effects on early afterdepolarization in drug-induced arrhythmia
Different voltage dependence of ICaL blockade in nonselective IKr blockers causes their opposite effects on early afterdepolarization in drug-induced arrhythmia
复制标题
非选择性 IKr 阻滞剂中 ICaL 阻滞剂的不同电压依赖性导致其对药物性心律失常的早期后除极产生相反的作用
DOI：
10.1016/j.jphs.2021.05.014
复制
发表时间：
2021
影响因子：
3.5
通讯作者：
Murakami Shingo
中科院分区：
文献类型：
--
作者：
Kimura Akira;Murakami Shingo
人醚-à-gogo-related基因测试的几个假阳性结果表明，延迟整流K+电流（IKr）快速组分的阻滞剂不一定会产生药物性心律失常。具体来说，即使延长的动作电位持续时间在相同的范围内，不同的ik阻滞剂的早期后去极化（EAD）的发生也是不同的。为了预测药物性心律失常的EAD，我们提出了一种基于非选择性ik阻滞剂之间EAD频率差异机制的预测方法。利用人心室肌细胞的数学模型，研究了l型Ca2+电流（ICaL）的不同阻断动力学如何影响EAD的频率，从而阐明了其机制。添加电压无关的ICaLblockade导致EAD的抑制。然而，当将电压依赖性的胺碘酮、贝普利地尔和特非那定的ICaLblockade动力学纳入ICaLin模型时，贝普利地尔和特非那定诱导的EAD比电压依赖性的ICaLblockade更严重，而胺碘酮更有效地抑制EAD。相反的效果由负极化电位的ICaLblockade的差异来解释。发现EAD的发生与−20 mV时测量的ICaLblockade相关。这些结果表明，ICaLblockade的电压依赖性可能有助于预测非选择性ik阻滞剂的不同风险。
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 (IKr) do not necessarily produce drug-induced arrhythmias. Specifically, the occurrence of early afterdepolarization (EAD) differs among IKrblockers, 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 IKrblockers. The mechanisms were elucidated by examining how different blockade kinetics of L-type Ca2+current (ICaL) affect the frequency of EAD, using mathematical models of human ventricular myocytes. Addition of voltage-independent ICaLblockade resulted in the suppression of EAD. However, when voltage-dependent ICaLblockade kinetics of amiodarone, bepridil, and terfenadine were incorporated into ICaLin the model, bepridil and terfenadine induced EAD more than the voltage-independent ICaLblockade, while amiodarone suppressed EAD more effectively. Opposite effects were accounted for by the difference in ICaLblockade at negatively polarized potential. EAD occurrence was found to be associated with ICaLblockade measured at −20 mV. These results suggest that voltage dependence of ICaLblockade may be useful in predicting the different risks of nonselective IKrblockers.