Clemizole hydrochloride blocks cardiac potassium currents stably expressed in HEK 293 cells.
Br J Pharmacol
; 174(3): 254-266, 2017 02.
Article
em En
| MEDLINE
| ID: mdl-27886373
ABSTRACT
BACKGROUND AND PURPOSE:
Clemizole, a histamine H1 receptor 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. EXPERIMENTALAPPROACH:
Whole-cell patch techniques was used to examine the effects of clemizole on hERG channel current, IKs and Kv 1.5 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. KEYRESULTS:
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 IKs and human Kv 1.5 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). CONCLUSION AND IMPLICATIONS 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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Benzimidazóis
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Bloqueadores dos Canais de Potássio
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Canais de Potássio Éter-A-Go-Go
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Antagonistas dos Receptores Histamínicos H1
Limite:
Animals
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Female
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Humans
/
Male
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article