Effect of Azelastine on Cardiac Repolarization of Guinea-Pig Cardiomyocytes, hERG K+ Channel, and Human L-type and T-type Ca2+ Channel

Journal of Pharmacological Sciences

Seung Ho Lee²  Mi-Hyeong Park¹  Bok Hee Choi²  Dae Hyun Chu³  Kwang Hee Won³  Su-Hyun Jo¹  Han Choe³ 

[1] Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University College of Medicine, Korea;Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School, Korea;Department of Physiology, Research Institute for Biomacromolecules, University of Ulsan College of Medicine, Korea

关键词: action potential duration;    antipsychotic drug;    azelastine;    hERG channel;    rapidly-activating delayed rectifier K+ channel;   

DOI  :  10.1254/jphs.12239FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(38)Cited-By(1)Azelastine is a second generation histamine H1–receptor antagonist used as an anti-asthmatic and anti-allergic drug that can induce QT prolongation and torsades de pointes. We investigated the acute effects of azelastine on human ether-a-go-go-related gene (hERG) channels, action potential duration (APD), and L-type (ICa,L) and T-type Ca2+ current (ICa,T) to determine the electrophysiological basis for its proarrhythmic potential. Azelastine increased the APD at 90% of repolarization concentration dependently, with an IC50 of 1.08 nM in guinea-pig ventricular myocytes. We examined the effects of azelastine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Azelastine induced a concentration-dependent decrease of the hERG current amplitude at the end of the voltage steps and tail currents. The IC50 for the azelastine-induced block of the hERG currents expressed in HEK293 cells was 11.43 nM, while the drug inhibited ICa,L and ICa,T with IC50 values of 7.60 and 26.21 μM, respectively. The S6 domain mutations, Y652A partially attenuated and F656A abolished hERG current block. These results suggest that azelastine is a potent blocker of hERG channels rather than ICa,L or ICa,T, providing molecular mechanisms for the arrhythmogenic side effects during the clinical administration of azelastine.

【 授权许可】

Unknown