title: Clemizole hydrochloride blocks cardiac potassium currents stably expressed in HEK 293 cells.
abstract: Clemizole, a histamine H1receptor antagonist has a potential therapeutic effect on hepatitis C infection and also potently inhibits TRPC5 ion channels. The aim of the present study was to investigate whether clemizole blocks cardiac K+currents and thus affects cardiac repolarization.
  
  
  
  Whole-cell patch techniques was used to examine the effects of clemizole on hERG channel current, IKsand Kv1.5 channel current in HEK 293 cell expression systems as well as on ventricular action potentials of guinea pig hearts. Isolated hearts from guinea pigs were used to determine the effect on the ECG.
  
  
  
  Clemizole decreased hERG current by blocking both open and closed states of the channel in a concentration-dependent manner (IC50: 0.07 μM). The S631A, S636A, Y652A and F656V hERG mutant channels reduced the inhibitory effect of clemizole (IC50: 0.82, 0.89, 1.49 and 2.98 μM, respectively), suggesting that clemizole is a pore blocker of hERG channels. Clemizole also moderately decreased IKsand human Kv1.5 channel current. Moreover, clemizole increased the duration of the ventricular action potential in guinea pig hearts and the QTc interval in isolated perfused hearts from guinea pigs, in a concentration-dependent manner (0.1-1.0 μM).
  
  
  
  Our results provide the first evidence that clemizole potently blocks hERG channels, moderately inhibits cardiac IKs, delays cardiac repolarization and thereby prolongs QT interval. Thus, caution should be taken when clemizole is used as a TRPC5 channel blocker or for treating hepatitis C infection.
authors.affiliation: Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, China.
authors.forename: Ling-Jun
authors.initials: LJ
authors.lastname: Jie
authors.affiliation: Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, China.
authors.forename: Wei-Yin
authors.initials: WY
authors.lastname: Wu
authors.affiliation: Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, China.
authors.forename: Guo-Sheng
authors.initials: GS
authors.lastname: Xiao
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Canada.
authors.forename: Shetuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, China.
authors.forename: Gui-Rong
authors.identifier: 0000-0002-9437-2280
authors.initials: GR
authors.lastname: Li
authors.affiliation: Xiamen Cardiovascular Hospital, Xiamen University, Xiamen, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005260:Female; D006168:Guinea Pigs; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001562:Benzimidazoles; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; D026902:Potassium Channel Blockers; C084582:clemizole