Inhibition of the INa/K and the activation of peak INa contribute to the arrhythmogenic effects of aconitine and mesaconitine in guinea pigs

Authors: Xiang-chong Wang1,2,3, Qing-zhong Jia1,2, Yu-lou Yu1,2, Han-dong Wang1,2, Hui-cai Guo4, Xin-di Ma1,2, Chun-tong Liu1,2, Xue-yan Chen1,2, Qing-feng Miao1,2, Bing-cai Guan1,2, Su-wen Su1,2, He-ming Wei5, Chuan Wang1,2
1 Department of Pharmacology, The Key Laboratory of Pharmacology and Toxicology for New Drugs, Hebei Medical University, Shijiazhuang 050017, China
2 The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China
3 Department of Pharmacology, Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Hebei Higher Education Institute Applied Technology Research Center on TCM Formula Preparation, Hebei University of Chinese Medicine, Shijiazhuang 050091, China
4 Depatment of Toxicology, Hebei Medical University, Shijiazhuang 050017, China
5 Research Laboratory, KK Women’s & Children’s Hospital, Singapore 229899, Singapore
Correspondence to: Su-wen Su:, He-ming Wei:, Chuan Wang:,
DOI: 10.1038/s41401-020-0467-6
Received: 29 December 2019
Accepted: 23 June 2020
Advance online: 3 August 2020


Aconitine (ACO), a main active ingredient of Aconitum, is well-known for its cardiotoxicity. However, the mechanisms of toxic action of ACO remain unclear. In the current study, we investigated the cardiac effects of ACO and mesaconitine (MACO), a structurally related analog of ACO identified in Aconitum with undocumented cardiotoxicity in guinea pigs. We showed that intravenous administration of ACO or MACO (25 μg/kg) to guinea pigs caused various types of arrhythmias in electrocardiogram (ECG) recording, including ventricular premature beats (VPB), atrioventricular blockade (AVB), ventricular tachycardia (VT), and ventricular fibrillation (VF). MACO displayed more potent arrhythmogenic effect than ACO. We conducted whole-cell patch-clamp recording in isolated guinea pig ventricular myocytes, and observed that treatment with ACO (0.3, 3 μM) or MACO (0.1, 0.3 μM) depolarized the resting membrane potential (RMP) and reduced the action potential amplitude (APA) and durations (APDs) in a concentration-dependent manner. The ACO- and MACO-induced AP remodeling was largely abolished by an INa blocker tetrodotoxin (2 μM) and partly abolished by a specific Na+/K+ pump (NKP) blocker ouabain (0.1 μM). Furthermore, we observed that treatment with ACO or MACO attenuated NKP current (INa/K) and increased peak INa by accelerating the sodium channel activation with the EC50 of 8.36 ± 1.89 and 1.33 ± 0.16 μM, respectively. Incubation of ventricular myocytes with ACO or MACO concentration-dependently increased intracellular Na+ and Ca2+ concentrations. In conclusion, the current study demonstrates strong arrhythmogenic effects of ACO and MACO resulted from increasing the peak INa via accelerating sodium channel activation and inhibiting the INa/K. These results may help to improve our understanding of cardiotoxic mechanisms of ACO and MACO, and identify potential novel therapeutic targets for Aconitum poisoning.
Keywords: aconitine; mesaconitine; arrhythmia; action potential; Na+/K+ pump current; voltage-gated sodium channel current

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