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Block of hERG $K^+$ Channel by Classic Histamine $H_1$ Receptor Antagonist Chlorpheniramine  

Hong, Hee-Kyung (Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University College of Medicine)
Jo, Su-Hyun (Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University College of Medicine)
Publication Information
The Korean Journal of Physiology and Pharmacology / v.13, no.3, 2009 , pp. 215-220 More about this Journal
Abstract
Chlorpheniramine is a potent first-generation histamine $H_1$ receptor antagonist that can increase action potential duration and induce QT prolongation in several animal models. Since block of cardiac human ether-a-go-go-related gene (hERG) channels is one of leading causes of acquired long QT syndrome, we investigated the acute effects of chlorpheniramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of chlorpheniramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Chlorpheniramine induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The $IC_{50}$ of chlorpheniramine-dependent hERG block in Xenopus oocytes decreased progressively relative to the degree of depolarization. Chlorpheniramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG current block. These results suggest that the $H_1$ antihistamine, chlorpheniramine is a blocker of the hERG channels, providing a molecular mechanism for the drug-induced arrhythmogenic side effects.
Keywords
Antihistamine; HERG channel; Chlorpheniramine; Rapidly-activating delayed rectifier $K^+$ channel;
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