Guo Liang, Qian Jian-Yong, Abrams Rory, Tang Hai-Ming, Weiser Thomas, Sanders Martin J, Kolaja Kyle L
Global Early & Investigative Safety, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ, USA.
Cell Physiol Biochem. 2011;27(5):453-62. doi: 10.1159/000329966. Epub 2011 Jun 15.
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.
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.
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.
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.
背景/目的：监测化合物给药后人诱导多能干细胞衍生心肌细胞（hiPSC-CMs）的场电位（FP）变化，已被提议作为一种新型筛选工具，用于评估心脏离子通道相互作用和QT间期易损性。在此，我们扩展了FP的用途，以评估强心苷的药理和毒理特性。
使用微电极阵列（MEA）在自发跳动的hiPSC-CMs中记录FP。将哇巴因和地高辛对FP的体外作用与豚鼠Langendorff心脏血流动力学和心电图参数的数据进行比较。
在hiPSC-CMs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，并剂量依赖性地诱发心律失常搏动。在hiPSC-CMs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应密切相关，后者显示QT间期缩短、收缩力增强和心律失常发生。硝苯地平，一种L型Ca(2+)通道阻滞剂，降低了hiPSC-CMs中的Ca(2+)波幅度和FPD，并在离体心脏中导致心室收缩力降低和QT间期缩短的平行效应。此外，硝苯地平减弱了两种强心苷的Ca(2+)峰值幅度和促心律失常作用。这些结果表明，FPD和Ca(2+)波幅度分别是完整心脏QT间期和收缩力的可比替代指标。
hiPSC-CMs反映了与离体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体调节剂药理和毒理学的合适模型。
