A novel method of selecting human embryonic stem cell-derived cardiomyocyte clusters for assessment of potential to influence QT interval.
A novel method of selecting human embryonic stem cell-derived cardiomyocyte clusters for assessment of potential to influence QT interval.
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一种选择人胚胎干细胞来源的心肌细胞簇以评估影响 QT 间期的潜力的新方法。
DOI：
10.1016/j.tiv.2011.12.005
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
K. Sawada
中科院分区：
文献类型：
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作者：
K. Yamazaki;Taro Hihara;Tomohiko Taniguchi;N. Kohmura;T. Yoshinaga;Masashi Ito;K. Sawada
延迟复极的生理相关评估在药物开发中是必要的。在我们使用多电极记录系统进行评价的初步实验中，我们发现场电位时程（FPD）（作为QT样间期）对hERG通道阻滞剂的反应性在人胚胎干细胞衍生的心肌细胞簇中从无反应者到过度反应者有很大差异。因此，我们报告了一种新的方法，选择集群适合评估化合物的评估。用西沙必利（一种hERG通道阻滞剂）以100 nM处理簇，并以5-20%的校正FPD（FPDc）延长标准进行选择。然后，用参比化合物处理选定的簇。通过阻断hERG通道（E-4031和dl-索他洛尔）和KvLQT 1通道（色原烷醇293 B和HMR 1556）以及激活钠通道（藜芦碱）和钙通道（Bay K8644）延长FPDc。钙通道阻滞剂（维拉帕米、硝苯地平和地尔硫卓）和KATP通道激活剂（吡那地尔）可缩短FPDc。Ia类抗肿瘤药物，奎尼丁和丙吡胺，延长FPDc。所选簇适用于评估化合物对影响QT间期的离子通道的影响。这是第一个报告的建立一个评估系统的潜在影响QT间期，使用随机选择的集群。
Physiologically relevant assessment of delayed repolarization is necessary in drug development. In our preliminary experiments on the evaluation using a multielectrode recording system, we had found that the responsiveness of field potential duration (FPD), as QT-like intervals, to hERG channel blockers differed greatly from non-responders to excessive responders in human embryonic stem cell-derived cardiomyocyte clusters. Thus, we report a novel method of selecting clusters suitable for evaluating compounds for the assessment. Clusters were treated with cisapride, a hERG channel blocker, at 100nM, and selected with criteria of 5–20% of corrected FPD (FPDc) prolongation. Then, selected clusters were treated with reference compounds. FPDc was prolonged by blockade of the hERG channel (E-4031 and dl-sotalol) and KvLQT1 channel (chromanol 293B and HMR1556), and by activation of the sodium channel (veratridine) and calcium channel (Bay K8644). FPDc was shortened by calcium channel blockage (verapamil, nifedipine and diltiazem) and by KATPchannel activation (pinacidil). Class Ia antiarrhythmic drugs, quinidine and disopyramide, prolonged FPDc. Selected clusters are appropriate for assessing the effects of compounds on ion channels affecting QT intervals. This is the first report of the establishment of an assessment system of potential to influence QT interval, using pharmacologically selected clusters.