Effects of the histamine H1 receptor antagonist hydroxyzine on hERG K＋ channels and cardiac action potential duration  

作　　者：Byung Hoon LEE Seung Ho LEE Daehyun CHU Jin Won HYUN Han CHOE Bok Hee CHOI Su-Hyun JO 

机构地区：[1]Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University School of Medicine, Chuncheon 200- 701, Korea [2]Department of Radiology, Ilsan Paik Hospital, Inje University School of Medicine, Goyang 411- 706, Korea [3]Department of Pharmacology, Institute for Medical Sciences, Chonbuk National University Medical School, Jeonju, Jeonbuk 561-180, Korea [4]Department of Physiology, Bio-Medical Institute of Technology, University of Ulsan College of Medicine, Seou1138- 736, Korea [5]Department of Biochemistry, School of Medicine, Jeju National University, Jeju 690-756, Korea

出　　处：《Acta Pharmacologica Sinica》2011年第9期1128-1137,共10页中国药理学报（英文版）

摘　　要：Aim： To investigate the effects of hydroxyzine on human ether-a-go-go-related gene （hERG） channels to determine the electrolphysiological basis for its proarrhythmic effects. Methods： hERG channels were expressed in Xenopus oocytes and HEK293 cells, and the effects of hydroxyzine on the channels were examined using two-microelectrode voltage-clamp and patch-clamp techniques, respectively. The effects of hydroxyzine on action potential duration were examined in guinea pig ventricular myocytes using current clamp. Results： Hydroxyzine （0.2 and 2 μmol/L） significantly increased the action potential duration at 90% repolarization （APD9o） in both concentration- and time-dependent manners. Hydroxyzine （0.03-3 μmol/L） blocked both the steady-state and tail hERG currents. The block was voltage-dependent, and the values of IC50 for blocking the steady-state and tail currents at ＋20 mV was 0.18~0.02 pmol/L and 0.16±0.01 pmoVL, respectively, in HEK293 cells. Hydroxyzine （5 pmoVL） affected both the activated and the inactivated states of the channels, but not the closed state. The $6 domain mutation Y652A attenuated the blocking of hERG current by -6-fold. Conclusion： The results suggest that hydroxyzine could block hERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine.Aim： To investigate the effects of hydroxyzine on human ether-a-go-go-related gene （hERG） channels to determine the electrolphysiological basis for its proarrhythmic effects. Methods： hERG channels were expressed in Xenopus oocytes and HEK293 cells, and the effects of hydroxyzine on the channels were examined using two-microelectrode voltage-clamp and patch-clamp techniques, respectively. The effects of hydroxyzine on action potential duration were examined in guinea pig ventricular myocytes using current clamp. Results： Hydroxyzine （0.2 and 2 μmol/L） significantly increased the action potential duration at 90% repolarization （APD9o） in both concentration- and time-dependent manners. Hydroxyzine （0.03-3 μmol/L） blocked both the steady-state and tail hERG currents. The block was voltage-dependent, and the values of IC50 for blocking the steady-state and tail currents at ＋20 mV was 0.18~0.02 pmol/L and 0.16±0.01 pmoVL, respectively, in HEK293 cells. Hydroxyzine （5 pmoVL） affected both the activated and the inactivated states of the channels, but not the closed state. The $6 domain mutation Y652A attenuated the blocking of hERG current by -6-fold. Conclusion： The results suggest that hydroxyzine could block hERG channels and prolong APD. The tyrosine at position 652 in the channel may be responsible for the proarrhythmic effects of hydroxyzine.

关 键 词：histamine antagonists HYDROXYZINE CARDIOMYOCYTES hERG channels K~ channel proarrhythmic effects 

分 类 号：Q463[生物学—生理学] TQ463.5[化学工程—制药化工]