The Electrophysiological Effects of Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and in Guinea Pig Isolated Hearts
The Electrophysiological Effects of Cardiac Glycosides in Human iPSC-derived Cardiomyocytes and in Guinea Pig Isolated Hearts
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DOI：
10.1159/000329966
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发表时间：
2011-01-01
影响因子：
--
通讯作者：
Kolaja, Kyle L.
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文献类型：
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作者：
Guo, Liang;Qian, Jian-Yong;Kolaja, Kyle L.
背景/目的：监测人诱导多能干细胞衍生心肌细胞（hiPSC-CM）在化合物给药后场电位（FP）的变化已被提议作为评估心脏离子通道相互作用和 QT 责任的新型筛选工具。在这里，我们扩展了 FP 的用途来评估强心苷的药理和毒理特性。方法：使用微电极阵列 (MEA) 在自发跳动的 hiPSC-CM 中记录 FP。将哇巴因和地高辛对 FP 的体外影响与豚鼠 Langendorff 心脏中血流动力学和心电图参数生成的数据进行比较。结果：在 hiPSC-CM 中，哇巴因和地高辛降低了 Na(+) 尖峰幅度，缩短了 FP 持续时间 (FPD)，增加了 Ca(2+) 波幅度，并导致剂量依赖性心律失常。在 hiPSC-CM 中观察到的哇巴因诱导的变化与在离体心脏中观察到的效果密切相关，显示 QT 缩短、收缩力增强和心律失常发生。硝苯地平是一种 L 型 Ca(2+) 通道阻滞剂，可降低 hiPSC-CM 中的 Ca(2+) 波振幅和 FPD，并导致离体心脏中心室收缩力降低和 QT 间期缩短的平行效应。此外，硝苯地平减弱了两种糖苷的 Ca(2+) 峰值幅度和促心律失常作用。这些结果表明，FPD 和Ca(2+) 波振幅分别是QT 间期和完整心脏收缩力的可比替代指标。结论：hiPSC-CM 反映了与分离的心脏制剂相似的心脏药理学，因此是研究心脏活性离子通道和转运蛋白调节剂的药理学和毒理学的合适模型。版权所有 (C) 2011 S. Karger AG，巴塞尔
Background/aims: Monitoring changes in the field potential (FP) of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) following compound administration has been proposed as a novel screening tool to evaluate cardiac ion channel interactions and QT liability. Here we extended the use of FP to evaluate the pharmacological and toxicological properties of cardiac glycosides. Methods: FPs were recorded using microelectrode arrays (MEAs) in spontaneously beating hiPSC-CMs. The in vitro effects of ouabain and digoxin on FPs were compared with data generated on hemodynamic and ECG parameters in guinea pig Langendorff hearts. Results: In hiPSC-CMs, ouabain and digoxin reduced Na(+)-spike amplitude, shortened FP duration (FPD), increased Ca(2+)-wave amplitude, and dose-dependently induced arrhythmic beats. The ouabain-induced changes observed in hiPSC-CMs correlated well with the effects seen in isolated hearts which revealed QT shortening, enhancement of contractility, and arrhythmogenesis. Nifedipine, an L-type Ca(2+) channel blocker, reduced Ca(2+)-wave amplitude and FPD in hiPSC-CMs, and led to parallel effects of decreased ventricular contractility and shortened QT interval in isolated hearts. Further, nifedipine attenuated the Ca(2+)-peak amplitude and proarrhythmic effect of both glycosides. These results suggested that FPD and Ca(2+)-wave amplitude are comparable surrogates of QT interval and contractility of intact hearts, respectively. Conclusion: hiPSC-CMs reflect similar cardiac pharmacology as seen in isolated cardiac preparations and thus are a suitable model in study of the pharmacology and toxicology of cardioactive ion channel and transporter modulators. Copyright (C) 2011 S. Karger AG, Basel