Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG
Application of human stem cell-derived cardiomyocytes in safety pharmacology requires caution beyond hERG
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DOI：
10.1016/j.yjmcc.2012.02.002
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发表时间：
2012-05-01
影响因子：
5
通讯作者：
van Veen, Toon A. B.
中科院分区：
文献类型：
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作者：
Jonsson, Malin K. B.;Vos, Marc A.;van Veen, Toon A. B.
人胚胎干细胞来源的心肌细胞(hESC-CM)被认为是一种新的安全药理学模型。到目前为止，对它们的基本电生理学和广泛的测试有了透彻的描述。对它们的整体促心律失常能力缺乏机械性的解释。在标准化条件下，我们评估了hESC-CM对阻断HERG和其他通道引起的心律失常刺激的敏感性。在电压膜片钳下，hESC-CM的某些离子电流密度(pA/pF)与成年CM相当：I-Kr(-12.5+/-6.9)，I-Ks(0.65+/-0.12)，I-Na峰(-72+/-21)，I-Na，I-Late(-1.10+/-0.36)，I-Ca，I-L(-4.3+/-0.6)。I-f密度较大(-10+/-1.1)，I-K1不存在或很小(-2.67+/-0.3)。KCNJ2mRNA的低表达证实了低I-K1密度。抗心律失常化合物对动作电位(AP)参数和早期后除极激发(EADS)的影响显示，Chrool293B(100mU/L)和BAY K8644(1mU/L)均显著延长动作电位(AP)(90)。ATX-II(
Human embryonic stem cell-derived cardiomyocytes (hESC-CM) have been proposed as a new model for safety pharmacology. So far, a thorough description of their basic electrophysiology and extensive testing. and mechanistic explanations, of their overall pro-arrhythmic ability is lacking. Under standardized conditions, we have evaluated the sensitivity of hESC-CM to proarrhythmic provocations by blockade of hERG and other channels. Using voltage patch clamp, some ion current densities (pA/pF) in hESC-CM were comparable to adult CM:I-Kr (-12.5+/-6.9), I-Ks (0.65 +/- 0.12), I-Na.peak (-72 +/- 21), I-Na,I-late (-1.10 +/- 0.36), and I-Ca,I-L (-4.3 +/- 0.6). I-f density was larger (-10 +/- 1.1) and I-K1 not existent or very small (-2.67 +/- 0.3). The low I-K1 density was corroborated by low KCNJ2 mRNA levels. Effects of pro-arrhythmic compounds on action potential (AP) parameters and provocation of early afterdepolarizations (EADs) revealed that Chromanol293B (100 mu mol/l) and Bay K8644 (1 mu mol/l) both significantly prolonged APD(90). ATX-II (