TY - JOUR AU - Wang Xiang-chong AU - Jia Qing-zhong AU - Yu Yu-lou AU - Wang Han-dong AU - Guo Hui-cai AU - Ma Xin-di AU - Liu Chun-tong AU - Chen Xue-yan AU - Miao Qing-feng AU - Guan Bing-cai AU - Su Su-wen AU - Wei He-ming AU - Wang Chuan PY - 2021 TI - Inhibition of the I Na/K and the activation of peak I Na contribute to the arrhythmogenic effects of aconitine and mesaconitine in guinea pigs JF - Acta Pharmacologica Sinica; Vol 42, No 2 (February 2021): Acta Pharmacologica Sinica Y2 - 2021 KW - N2 - 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 I Na 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 ( I Na/K ) and increased peak I Na by accelerating the sodium channel activation with the EC 50 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 Ca 2+ concentrations. In conclusion, the current study demonstrates strong arrhythmogenic effects of ACO and MACO resulted from increasing the peak I Na via accelerating sodium channel activation and inhibiting the I Na/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. UR - http://www.chinaphar.com/article/view/10267