title: Effects of the histamine H(1) receptor antagonist hydroxyzine on hERG K(+) channels and cardiac action potential duration.
abstract: OBJECTIVE
  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 (APD(90)) 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 IC(50) for blocking the steady-state and tail currents at +20 mV was 0.18±0.02 μmol/L and 0.16±0.01 μmol/L, respectively, in HEK293 cells. Hydroxyzine (5 μmol/L) affected both the activated and the inactivated states of the channels, but not the closed state. The S6 domain mutation Y652A attenuated the blocking of hERG current by ~6-fold.
  
  
  CONCLUSIONS
  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.
authors: Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University School of Medicine, Chuncheon 200-701, Korea.
authors: Byung Hoon
authors: BH
authors: Lee
authors: Seung Ho
authors: SH
authors: Lee
authors: Daehyun
authors: D
authors: Chu
authors: Jin Won
authors: JW
authors: Hyun
authors: Han
authors: H
authors: Choe
authors: Bok Hee
authors: BH
authors: Choi
authors: Su-Hyun
authors: SH
authors: Jo
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D006919:Hydroxyzine / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D014982:Xenopus laevis
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; D006919:Hydroxyzine