Shijiazhuang Yiling Pharmaceutical Co., Ltd, No.238, the South of Tianshan street, Shijiazhuang 050035, Hebei, China.
Department of Pharmacy, The Fourth Hospital of Shijiazhuang, No.16, the North of Tangu street, Shijiazhuang 050031, Hebei, China.
Biomed Pharmacother. 2021 Jul;139:111581. doi: 10.1016/j.biopha.2021.111581. Epub 2021 Apr 23.
Resibufogenin (RBG) is a chemical ingredient of Chan Su. In our research, we found RBG affected cardiac rhythm in a negative chronotropic way in vivo. The cardiac Mapping system ex vivo and the patch clamp in vitro were used to explore how RBG influenced the cardiac electrophysiological properties. The negative chronotropic action of RBG at 100 μM might be attribute to prolongation in the atrioventricular conduction time and reduction in the ventricular conduction velocity. Using whole-cell patch clamp in ventricular myocytes of adult rats, we found that RBG prolonged the action potential duration (APD) in APD, APD, and APD at 100 μM and inhibited calcium currents (I), total outward potassium currents (I), and transient outward potassium current (I) in a concentration-dependent manner, but not on the inward rectifying potassium current (I). Notably, RBG had a potent proarrhythmic action ex vivo in the isolated perfused guinea pig hearts at 10 μM, but not in rats. To avoid the potential cardiotoxicity derived from the distributional differences of ion channels among species, the effect of RGB on I in hERG-HEK293 cells was detected. The IC of RGB on I was more than 100 μM. In summary, all these results indicated that the negative chronotropic action of RBG relied on the blocking activities on multiple ion channels, and the species-difference of proarrhythmic effects might result from lack of the I on the myocardial membrane of guinea pigs. Anyhow, the cardiotoxicity observed in guinea pigs required further detailed studies to mitigate the potential risks in the clinical application of Chan Su.
瑞布芬辛（RBG）是蟾酥的一种化学成分。在我们的研究中，我们发现 RBG 在体内以负性变时作用影响心率。我们使用心脏Mapping 系统在体和膜片钳技术在离体来探讨 RBG 如何影响心脏电生理特性。100μM 的 RBG 的负性变时作用可能归因于房室传导时间延长和心室传导速度降低。在成年大鼠心室肌细胞中使用全细胞膜片钳技术，我们发现 RBG 在 100μM 时延长动作电位时程（APD）、APD 和 APD，并且以浓度依赖的方式抑制钙电流（I）、总外向钾电流（I）和瞬间外向钾电流（I），但不影响内向整流钾电流（I）。值得注意的是，10μM 的 RBG 在离体灌注豚鼠心脏中具有很强的致心律失常作用，但在大鼠中没有。为避免由于物种间离子通道分布差异而导致的潜在心脏毒性，我们检测了 RBG 对 hERG-HEK293 细胞中 I 的影响。RBG 对 I 的半数抑制浓度（IC）大于 100μM。总之，这些结果表明 RBG 的负性变时作用依赖于对多种离子通道的阻断活性，而致心律失常作用的种属差异可能是由于豚鼠心肌膜上缺乏 I。无论如何，在豚鼠中观察到的心脏毒性需要进一步的详细研究，以减轻蟾酥在临床应用中的潜在风险。
