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

Xiang-Chong Wang; Qing-Zhong Jia; Yu-Lou Yu; Han-Dong Wang; Hui-Cai Guo; Xin-di Ma; Chun-Tong Liu; Xue-Yan Chen; Qing-Feng Miao; Bing-Cai Guan; Su-Wen Su; He-Ming Wei; Chuan Wang

doi:10.1038/s41401-020-0467-6

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

Acta Pharmacol Sin. 2021 Feb;42(2):218-229. doi: 10.1038/s41401-020-0467-6. Epub 2020 Aug 3.

Authors

Xiang-Chong Wang^#^{1

2

3}, Qing-Zhong Jia^#^{1

2}, Yu-Lou Yu^{1

2}, Han-Dong Wang^{1

2}, Hui-Cai Guo⁴, Xin-di Ma^{1

2}, Chun-Tong Liu^{1

2}, Xue-Yan Chen^{1

2}, Qing-Feng Miao^{1

2}, Bing-Cai Guan^{1

2}, Su-Wen Su^{5

6}, He-Ming Wei⁷, Chuan Wang^{8

9}

Affiliations

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 Department of Pharmacology, The Key Laboratory of Pharmacology and Toxicology for New Drugs, Hebei Medical University, Shijiazhuang, 050017, China. suswmk@hebmu.edu.cn.
⁶ The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, China. suswmk@hebmu.edu.cn.
⁷ Research Laboratory, KK Women's & Children's Hospital, Singapore, 229899, Singapore. wei.heming@kkh.com.sg.
⁸ Department of Pharmacology, The Key Laboratory of Pharmacology and Toxicology for New Drugs, Hebei Medical University, Shijiazhuang, 050017, China. wangchuan@hebmu.edu.cn.
⁹ The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, China. wangchuan@hebmu.edu.cn.

^# Contributed equally.

Abstract

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 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 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.

Keywords: Na+/K+ pump current; aconitine; action potential; arrhythmia; mesaconitine; voltage-gated sodium channel current.

MeSH terms

Aconitine / analogs & derivatives*
Aconitine / isolation & purification
Aconitine / toxicity*
Aconitum / chemistry
Action Potentials / drug effects
Animals
Arrhythmias, Cardiac / chemically induced*
Arrhythmias, Cardiac / physiopathology
Cardiotoxicity / etiology*
Cardiotoxicity / physiopathology
Electrocardiography
Guinea Pigs
Male
Membrane Potentials / drug effects
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / pathology
Patch-Clamp Techniques
Sodium Channels / drug effects
Sodium Channels / metabolism

Substances

Sodium Channels
mesaconitine
Aconitine