title: Predictors of torsades de pointes in rabbit ventricles perfused with sedating and nonsedating histamine H1-receptor antagonists.
abstract: Several nonsedating histamine H1-receptor antagonists are associated with torsades de pointes ventricular tachycardia. The objectives of this study were to: (i) compare electrocardiographic, monophasic action potential, and arrhythmogenic effects of sedating and nonsedating H1-receptor antagonists, and (ii) identify correlates of drug-induced torsades de pointes in an isolated ventricle model. Isolated, electrically paced (1-3 Hz) rabbit ventricles were Langendorff-perfused with either drug-free Tyrode's solution or one of the following: (i) the sedating H1-receptor antagonist hydroxyzine (0.1-30 microM), (ii) cetirizine, a nonsedating metabolite of hydroxyzine (1-300 microM), and (iii) the nonsedating, putatively arrhythmogenic H1-receptor antagonist astemizole (0.1-30 microM). Volume conducted electrocardiographic signals and monophasic action potentials from the periapical left ventricular endocardium and epicardium were recorded. There were no apparent changes in control (n = 15) or hydroxyzine-perfused (n = 7) hearts. Cetirizine (n = 13) produced a mild biphasic electrocardiographic QT interval prolongation and was associated with early afterdepolarizations, but not with torsades de pointes. Astemizole (n = 11) lengthened QT intervals, and at high concentration (30 microM) induced torsades de pointes in 10 of 11 hearts (P < 0.001 vs. all other groups). These findings are consistent with previously reported repolarizing current inhibition by cetirizine, but may additionally indicate "compensatory" inhibition of inward currents at higher concentrations. By contrast, astemizole-induced changes are consistent with unopposed repolarizing current inhibition.
authors.affiliation: Department of Paediatrics and Child Health, University of Manitoba, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Canada.
authors.forename: J D
authors.initials: JD
authors.lastname: Gilbert
authors.forename: S A
authors.initials: SA
authors.lastname: Cahill
authors.forename: D G
authors.initials: DG
authors.lastname: McCartney
authors.forename: A
authors.initials: A
authors.lastname: Lukas
authors.forename: G J
authors.initials: GJ
authors.lastname: Gross
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D016589:Astemizole / Q000494:pharmacology; D017332:Cetirizine / Q000494:pharmacology; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006919:Hydroxyzine / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D010477:Perfusion; D011817:Rabbits; D016171:Torsades de Pointes / Q000503:physiopathology*
chemical_list: D006634:Histamine H1 Antagonists; D006993:Hypnotics and Sedatives; D006919:Hydroxyzine; D016589:Astemizole; D017332:Cetirizine