Antiarrhythmic drug carvedilol inhibits HERG potassium channels

Objective: The aryloxypropanolamine carvedilol is a multiple action cardiovascular drug with blocking effects on a-receptors, beta -receptors, Ca2+-channels, N+-channels and various native cardiac K+ channels, thereby prolonging the cardiac action potential. In a number of clinical trials with patients suffering from congestive heart failure, carvedilol appeared to be superior to other beta -blocking agents in reducing total mortality. Given the multiple pharmacological actions of carvedilol, this may be due to specific channel blockade rather than beta -antagonistic activity. Since human ether-a-go-go related gene (HERG) K+ channels play a critical role in the pathogenesis of cardiac arrhythmias and sudden cardiac death, the effects of carvedilol on HERG K+ channels were investigated. Methods: Double-electrode voltage-clamp experiments were performed on HERG potassium channels which were expressed heterologously in Xenopus oocytes. Results: Carvedilol at a concentration of 10 muM blocked HERG potassium tail currents by 47%. The electrophysiological characteristics of HERG, i.e. activation, steady-state inactivation and recovery from inactivation were not affected by carvedilol. Inhibition of current gradually increased from 0% immediately after the test pulse to about 80% at 600 ms with subsequent marginal changes of current kinetics during the resting 29 s, indicating a very fast open channel block by carvedilol as the major blocking mechanism. Conclusion: This is the first study demonstrating that carvedilol blocks HERG potassium channels. The biophysical data presented in this study with a potentially antiarrhythmic effect may contribute to the positive outcome of clinical trials with carvedilol. (C) 2001 Elsevier Science B.V. All rights reserved.