ELSEVIER Life Sciences, Vol. 63, No. 14, pp. 1205-1219, 1998 Copyright 0 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0024-32OS/y8$19.00 + .I0 PII 800243205(98)00383-X ELECTROPHYSIOLOGICAL MECHANISMS FOR THE ANTIARRHYTHMIC ACTIVITIES OF NALOXONE ON CARDIAC TISSUES Chi-Feng Hung, Mei-Hwan Wut , Chang-Her Tsai’, Shu-Hsun Chu’, Jo-Feng Chi and Ming-Jai Su Institute of Pharmacology, Department of Pediatrics+ and Surgery*, College of Medicine, National Taiwan University, Taipei, Taiwan (Received in final form July 16, 1~8) Summary It has been reported that naloxone. an opioid antagonist, has antiarrhythmic activity in vivo. In Langendorff perfused rat hearts, we found that ischemia-reperfusion-induced ventricular tachyarrhythmia reverted to normal sinus rhythm after the treatment with naloxone (3-10 PM). The method of voltage and current clamp were used to study the underlying mechanism of its antiarrhythmic activity on isolated cardiac myocytes. In isolated rat ventricular and in guinea-pig and human atria1 myocytes. naloxone prolonged the action potential duration reversibly. In rat ventricular myocytes, naloxone (l-30 @I) inhibited sodium current (I&, transient outward potassium current (Ito). and calcium current (lea). On the contrary, the addition of naloxone significantly increased inward rectifier potassium current (1~1). For the effect on INS, naloxone did not shift the inactivation curve of 1~~but retarded the 1~~ recovery rate from inactivation state. Naloxone suppressed I,, with a significant left-shift of the inactivation curve. however. the time course of I,, recovery from inactivation was not affected. In guinea pig atria1 myocytes, naloxone (10 PM) decreased the delayed rectifier K’ current (1~). These results show that naloxone exert various extent of inhibition on 1~~. I,,, lk and lea. The prolongation of cardiac action potential is related to the inhibition of I,, and lk The antiatrhythmic activity of naloxone is more closely related to the inhibition of Na’ and K’ currents rather than the blockade of myocardial opioid receptors. KeyWords: naloxone, action potential, Nat current, Ca*’ current, Kf current, arrhythmia Naloxone is an opioid receptor antagonist which has been shown to have antiarrhythmic effect and positive inotropic effect in many animal models. In vivo studies in both anesthetized and conscious rats, naloxone has been reported to reduce the incidence and severity of early ventricular arrhythmias induced by coronary artery ligation (1). Naloxone is also effective in reducing the incidence of ventricular arrhythmias and mortality rate after coronary artery occlusion and reperfusion in the anesthetized dog (2). In various models of experimental shock, naloxone reverses the hypotension that results from bacterial endotoxemia, haemorrhage, and spinal shock Corresnondence Author: Ming-Jai Su, Ph.D.: Institute of Pharmacology; College of Medicine; National Taiwan University; No. 1, Sec. 1, Jen-Ai Rd. Taipei. 10018, Taiwan.; Tel: 886-2- 23562221; Fax: 886-2-23971403; E-mail address: mjsu@ha.mc.ntu.edu.tw