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奈法唑酮在人诱导多能干细胞衍生心肌细胞中诱导心脏毒性的评估。

Evaluation of nefazodone-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes.

作者信息

Lee Sujeong, Lee Hyang-Ae, Choi Sung Woo, Kim Sung Joon, Kim Ki-Suk

机构信息

Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, South Korea.

Next-generation Pharmaceutical Research Center, Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 305-343, South Korea; Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 110-799, South Korea; Human and Environmental Toxicology Program, University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350, South Korea.

出版信息

Toxicol Appl Pharmacol. 2016 Apr 1;296:42-53. doi: 10.1016/j.taap.2016.01.015. Epub 2016 Jan 25.

Abstract

The recent establishment of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), which express the major cardiac ion channels and recapitulate spontaneous mechanical and electrical activities, may provide a possible solution for the lack of in vitro human-based cardiotoxicity testing models. Cardiotoxicity induced by the antidepressant nefazodone was previously revealed to cause an acquired QT prolongation by hERG channel blockade. To elucidate the cellular mechanisms underlying the cardiotoxicity of nefazodone beyond hERG, its effects on cardiac action potentials (APs) and ion channels were investigated using hiPSC-CMs with whole-cell patch clamp techniques. In a proof of principle study, we examined the effects of cardioactive channel blockers on the electrophysiological profile of hiPSC-CMs in advance of the evaluation of nefazodone. Nefazodone dose-dependently prolonged the AP duration at 90% (APD90) and 50% (APD50) repolarization, reduced the maximum upstroke velocity (dV/dtmax) and induced early after depolarizations. Voltage-clamp studies of hiPSC-CMs revealed that nefazodone inhibited various voltage-gated ion channel currents including IKr, IKs, INa, and ICa. Among them, IKr and INa showed relatively higher sensitivity to nefazodone, consistent with the changes in the AP parameters. In summary, hiPSC-CMs enabled an integrated approach to evaluate the complex interactions of nefazodone with cardiac ion channels. These results suggest that hiPSC-CMs can be an effective model for detecting drug-induced arrhythmogenicity beyond the current standard assay of heterologously expressed hERG K(+) channels.

摘要

最近建立的人诱导多能干细胞衍生的心肌细胞(hiPSC-CMs),其表达主要的心脏离子通道并重现自发的机械和电活动,可能为缺乏基于体外人体的心脏毒性测试模型提供一种可能的解决方案。先前已揭示,抗抑郁药奈法唑酮诱导的心脏毒性会通过阻断hERG通道导致获得性QT延长。为了阐明奈法唑酮除hERG之外的心脏毒性的细胞机制,使用全细胞膜片钳技术,研究了其对hiPSC-CMs心脏动作电位(APs)和离子通道的影响。在一项原理验证研究中,在评估奈法唑酮之前,我们预先研究了心脏活性通道阻滞剂对hiPSC-CMs电生理特征的影响。奈法唑酮剂量依赖性地延长了复极化90%(APD90)和50%(APD50)时的动作电位持续时间,降低了最大上升速度(dV/dtmax)并诱发了早期后去极化。对hiPSC-CMs的电压钳研究表明,奈法唑酮抑制了包括IKr、IKs、INa和ICa在内的各种电压门控离子通道电流。其中,IKr和INa对奈法唑酮表现出相对较高的敏感性,这与动作电位参数的变化一致。总之,hiPSC-CMs能够采用综合方法来评估奈法唑酮与心脏离子通道的复杂相互作用。这些结果表明,hiPSC-CMs可以成为一种有效的模型,用于检测超出当前异源表达hERG钾通道标准检测方法的药物诱导的致心律失常性。

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