-Original-

Antagonistic Effects of Tetrodotoxin on Aconitine-induced Cardiac Toxicity

Takiyoshi Ono¹, Makiko Hayashida¹, Akito Tezuka², Hideyuki Hayakawa³ and Youkichi Ohno¹

¹Department of Legal Medicine, Nippon Medical School
²Division of Regenerative Medicine and Cardiology, Department of Internal Medicine, Nippon Medical School
³Tsukuba Medical Examiner's Office

Aconitine, well-known for its high cardiotoxicity, causes severe arrhythmias, such as ventricular tachycardia and ventricular fibrillation, by opening membrane sodium channels. Tetrodotoxin, a membrane sodium-channel blocker, is thought to antagonize aconitine activity. Tetrodotoxin is a potent blocker of the skeletal muscle sodium-channel isoform Na_v1.4 (IC₅₀ 10 nM), but micromolar concentrations of tetrodotoxin are required to inhibit the primary cardiac isoform Na_v1.5. This suggests that substantial concentrations of tetrodotoxin are required to alleviate the cardiac toxicity caused by aconitine. To elucidate the interaction between aconitine and tetrodotoxin in the cardiovascular and respiratory systems, mixtures of aconitine and tetrodotoxin were simultaneously administered to mice, and the effects on electrocardiograms, breathing rates, and arterial oxygen saturation were examined. Compared with mice treated with aconitine alone, some mice treated with aconitine-tetrodotoxin mixtures showed lower mortality rates and delayed appearance of arrhythmia. The decreased breathing rates and arterial oxygen saturation observed in mice receiving aconitine alone were alleviated in mice that survived after receiving the aconitine-tetrodotoxin mixture; this result suggests that tetrodotoxin is antagonistic to aconitine. When the tetrodotoxin dose is greater than the dose that can block tetrodotoxin-sensitive sodium channels, which are excessively activated by aconitine, tetrodotoxin toxicity becomes prominent, and the mortality rate increases because of the respiratory effects of tetrodotoxin. In terms of cardiotoxicity, mice receiving the aconitine-tetrodotoxin mixture showed minor and shorter periods of change on electrocardiography. This finding can be explained by the recent discovery of tetrodotoxin-sensitive sodium-channel cardiac isoforms (Na_v1.1, 1.2, 1.3, 1.4 and 1.6).

J Nippon Med Sch 2013; 80: 350-361

Keywords
aconitine, tetrodotoxin, arrhythmia, tetrodotoxin-sensitive channel, tetrodotoxin-resistant channel, breathing rate, arterial oxygen saturation

Correspondence to
Takiyoshi Ono, Department of Legal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
takiono@nms.ac.jp

Received, February 4, 2013
Accepted, May 7, 2013