Predictors of Torsades de Pointes in rabbit ventricles perfused with sedating and nonsedating histamine H-1-receptor antagonists

Several nonsedating histamine H-1-receptor antagonists are associated with torsades de pointes ventricular tachycardia. The objectives of this study w ere to: (i) compare electrocardiographic, monophasic action potential, and arrhythmogenic effects of sedating and nonsedating H-1-receptor antagonists , and (ii) identify correlates of drug-induced torsades de pointes in an is olated ventricle model. Isolated, electrically paced (1-3 Hz) rabbit ventri cles were Langendorff-perfused with either drug-free Tyrode's solution or o ne of the following: (i) the sedating H-1-receptor antagonist hydroxyzine ( 0.1-30 mu M), (ii) cetirizine, a nonsedating metabolite of hydroxyzine (1-3 00 mu M), and (iii) the nonsedating, putatively arrhythmogenic H-1-receptor antagonist astemizole (0.1-30 mu M). Volume conducted electrocardiographic signals and monophasic action potentials from the periapical left ventricu lar endocardium and epicardium were recorded. There were no apparent change s in control (n = 15) or hydroxyzine-perfused (n = 7) hearts. Cetirizine (n = 13) produced a mild biphasic electrocardiographic QT interval prolongati on and was associated with early afterdepolarizations, but not with torsade s de pointes. Astemizole (n = 11) lengthened QT intervals, and at high conc entration (30 mu M) induced torsades de pointes in 10 of 11 hearts (P < 0.0 01 vs. all other groups). These findings are consistent with previously rep orted repolarizing current inhibition by cetirizine, but may additionally i ndicate "compensatory" inhibition of inward currents at higher concentratio ns. By contrast, astemizole-induced changes are consistent with unopposed r epolarizing current inhibition.