Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai, 200127, China.
Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
Cardiovasc Toxicol. 2022 Feb;22(2):141-151. doi: 10.1007/s12012-021-09709-3. Epub 2021 Nov 24.
Yohimbine is a highly selective and potent α-adrenoceptor antagonist, which is usually treated as an adjunction for impotence, as well for weight loss and natural bodybuilding aids. However, it was recently reported that Yohimbine causes myocardial injury and controversial results were reported in the setting of cardiac diseases. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a model system to explore electrophysiologic characterization after exposure to Yohimbine. HiPSC-CMs were differentiated by employment of inhibitory Wnt compounds. For analysis of electrophysiological properties, conventional whole-cell patch-clamp recording was used. Specifically, spontaneous action potentials, pacemaker currents (I), sodium (Na) channel (I), and calcium (Ca) channel currents (I) were assessed in hiPSC-CMs after exposure to Yohimbine. HiPSC-CMs expressed sarcomeric-α-actinin and MLC2V proteins, as well as exhibited ventricular-like spontaneous action potential waveform. Yohimbine inhibited frequency of hiPSC-CMs spontaneous action potentials and significantly prolonged action potential duration in a dose-dependent manner. In addition, rest potential, threshold potential, amplitude, and maximal diastolic potential were decreased, whereas APD/APD was prolonged. Yohimbine inhibited the amplitude of I in low doses (IC = 14.2 μM, n = 5) and inhibited I in high doses (IC = 139.7 μM, n = 5). Whereas Yohimbine did not affect the activation curves, treatment resulted in left shifts in inactivation curves of both Na and Ca channels. Here, we show that Yohimbine induces direct cardiotoxic effects on spontaneous action potentials of I and I in hiPSC-CMs. Importantly, these effects were not mediated by α-adrenoceptor signaling. Our results strongly suggest that Yohimbine directly and negatively affects electrophysiological properties of human cardiomyocytes. These findings are highly relevant for potential application of Yohimbine in patients with atrioventricular conduction disorder.
育亨宾是一种高度选择性和有效的α肾上腺素能受体拮抗剂，通常被用作治疗阳痿的辅助药物，也用于减肥和自然健美。然而，最近有报道称育亨宾会导致心肌损伤，并且在心脏病患者中也有争议的结果。在这里，我们使用人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）作为模型系统，来研究暴露于育亨宾后电生理特征的变化。我们通过使用抑制 Wnt 化合物来分化 hiPSC-CMs。为了分析电生理特性，我们使用了传统的全细胞膜片钳记录技术。具体来说，我们评估了暴露于育亨宾后 hiPSC-CMs 的自发性动作电位、起搏电流（I）、钠（Na）通道电流（I）和钙（Ca）通道电流（I）。hiPSC-CMs 表达肌球蛋白重链-α-肌动蛋白和肌球蛋白轻链 2V 蛋白，并表现出心室样自发性动作电位波形。育亨宾以剂量依赖性方式抑制 hiPSC-CMs 自发性动作电位的频率，并显著延长动作电位时程。此外，静息电位、阈电位、幅度和最大舒张电位降低，而 APD/APD 延长。育亨宾在低剂量（IC=14.2 μM，n=5）下抑制 I 的幅度，在高剂量（IC=139.7 μM，n=5）下抑制 I。虽然育亨宾不影响激活曲线，但处理导致 Na 和 Ca 通道的失活曲线向左移动。在这里，我们表明育亨宾对 hiPSC-CMs 的 I 和 I 的自发性动作电位直接产生心脏毒性作用。重要的是，这些作用不是由α肾上腺素能受体信号介导的。我们的结果强烈表明育亨宾直接且负性地影响人心肌细胞的电生理特性。这些发现对于育亨宾在房室传导障碍患者中的潜在应用具有重要意义。
