Bufalin-induced cardiotoxicity: new findings into mechanisms.
10.1016/S1875-5364(20)30065-0
- Author:
Min LI
1
;
Xi-Jie WANG
1
;
Qi ZHAO
1
;
Jia-Xian WANG
2
;
Hong-Yan XING
1
;
Yi-Zhe ZHANG
1
;
Xue-Xia ZHANG
1
;
Yang-Yang ZHI
1
;
Hua LI
3
;
Jing MA
3
Author Information
1. China State Institutes of Pharmaceutical Industry National Shanghai Center for New Drug Safety Evaluation and Research, Shanghai 201203, China; Shanghai InnoStar Bio-Tech Co., Ltd., Shanghai 201203, China.
2. Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing 211100, China; Department of Research and Development, HELP Stem Cell Therapeutics, Nanjing 211100, China.
3. China State Institutes of Pharmaceutical Industry National Shanghai Center for New Drug Safety Evaluation and Research, Shanghai 201203, China; Shanghai InnoStar Bio-Tech Co., Ltd., Shanghai 201203, China. Electronic address: hli@ncdser.com.
- Publication Type:Journal Article
- Keywords:
Bufalin;
Cardiomyocytes;
Cardiotoxicity;
Ion channels;
Stem cell
- From:
Chinese Journal of Natural Medicines (English Ed.)
2020;18(7):550-560
- CountryChina
- Language:English
-
Abstract:
Bufalin is one of the main pharmacological and toxicological components of Venenum Bufonis and many traditional Chinese medicine preparations. The cardiotoxicity clearly limits its application to patients living in countries. Hence, an investigation of its toxicological mechanism is helpful for new drug development and treatment of the related clinical adverse reactions. We investigate the cardiotoxicity of bufalin using human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) (0.003-0.1 μmol·L), human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) (0.03-0.3 μmol·L) and eight human cardiac ion channel currents (0.01-100 μmol·L) combined with an impedance-based bioanalytical and patch clamp method. Biphasic effect of bufalin on the contractility in hiPSC-CMs, which has been shown to strengthen myocardial contractility, accelerate conduction, and increase beating rate at the earlier stage of administration, whereas weakened myocardial contractility, abolished conduction, and ceased beating rate at the later stage of administration. Bufalin decreased the action potential duration (Action potential duration at 30%, 50% and 90% repolarization), cardiac action potential amplitude, and maximal depolarization rate and depolarized the resting membrane potential of hiPSC-CMs. Spontaneous beating rates of hiPSC-CMs were markedly increased at 0.03 μmol·L, while were weakened at 0.3 μmol·L after application. Bufalin blocks I in a concentration-dependent manner with half maximal inhibitory concentration of 74.5 μmol·L. Bufalin respectively increased the late sodium current and Na-Ca exchange current with a concentration for 50% of maximal effect of 2.48 and 66.06 μmol·L in hiPSC-CMs. Whereas, bufalin showed no significant effects on other cardiac ion channel currents. The enhancement of the late sodium current is one of the main mechanism for cardiotoxicity of bufalin.
