Effects of selective IKr channel blockade by E-4031 on ventricular electro-mechanical relationship in the halothane-anesthetized dogs.
Effects of selective IKr channel blockade by E-4031 on ventricular electro-mechanical relationship in the halothane-anesthetized dogs.
复制标题
E-4031 选择性 IKr 通道阻断对氟烷麻醉狗心室机电关系的影响。
DOI：
10.1016/j.ejphar.2014.06.064
复制
发表时间：
2014
影响因子：
5
通讯作者：
Sugiyama A
中科院分区：
文献类型：
--
作者：
Izumi-Nakaseko H;Nakamura Y;Cao X;Ohara H;Yamazaki Y;Ueda N;Ando K;Sugiyama A
机电耦合的反转：即电复极之前的机械松弛，已被提议作为预测药物引起的心律失常发生的替代标记。本研究旨在定性和定量阐明 E-4031 快速激活延迟整流 K+电流 (IKr) 选择性阻断对体内机电关系的影响。我们采用氟烷麻醉犬模型（n=4）。 0.01 和 0.1 mg/kg 剂量的 E-4031 可以在体外提供有效抑制 IKrin 的血浆浓度，显着延迟舒张开始后的复极，导致机电耦合反转，提供理想的致心律失常基质，同时左心室收缩和舒张持续时间保持不变。由于这些观察到的变化仅由复极延迟引起，因此机电耦合的反转可能对 QT 间期延长具有相似程度的敏感性，作为预测 IK 抑制剂诱导的心律失常发作的替代标记。
An inversion of electro-mechanical coupling: namely, mechanical relaxation which precedes electrical repolarization, has been proposed as a surrogate marker to predict the occurrence of drug-induced arrhythmias. The present study was designed to qualitatively and quantitatively clarify the effects of rapidly activating delayed rectifier K+current (IKr)-selective blockade by E-4031 on the electro-mechanical relationshipin vivo. We adopted the halothane-anesthetized canine model (n=4). E-4031 in doses of 0.01 and 0.1 mg/kg that can provide the plasma concentrations effectively to inhibitIKrin vitrosignificantly delayed the repolarization beyond the initiation of diastole, resulting in the inversion of electro-mechanical coupling, which provides an ideal proarrhythmic substrate, while the durations of left ventricular systole and diastole remained the same. Since these observed changes were solely caused by the repolarization delay, the inversion of electro-mechanical coupling may have a similar extent of sensitivity to QT-interval prolongation as a surrogate marker in predicting the onset ofIKrinhibitor-induced arrhythmias.