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Cardiovascular Research 2001 49(2):361-370; doi:10.1016/S0008-6363(00)00265-0
© 2001 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Antiarrhythmic drug carvedilol inhibits HERG potassium channels

Christoph A Karlea, Volker A.W Kreyeb, Dierk Thomasa, Katja Röckla, Sven Kathöfera, Wei Zhanga and Johann Kiehna,*

a3rd Department of Internal Medicine (Cardiology), University of Heidelberg Medical School, Bergheimerstrasse 58, D-69115 Heidelberg, Germany
bDepartment of Physiology and Pathophysiology University of Heidelberg Medical School, Bergheimerstrasse 58, D-69115 Heidelberg, Germany

* Corresponding author. Tel.: +49-622-156-8682; fax: +49-622-156-5515 johann_kiehn{at}ukl.uni-heidelberg.de

Objective: The aryloxypropanolamine carvedilol is a multiple action cardiovascular drug with blocking effects on {alpha}-receptors, β-receptors, Ca2+-channels, Na+-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 β-blocking agents in reducing total mortality. Given the multiple pharmacological actions of carvedilol, this may be due to specific channel blockade rather than β-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 µM 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.

KEYWORDS Adrenergic (ant)agonists; Antiarrhythmic agents; K-channel; Single channel currents; Ion channels


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