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Title: Predictors of Torsades de Pointes in rabbit ventricles perfused with sedating and nonsedating histamine H-1-receptor antagonists
Authors: Gilbert, JD
Cahill, SA
McCartney, DG
Lukas, A
Gross, GJ
Keywords: Langendorff preparation
rabbit ventricle
H-1-receptor antagonists
QT interval
ventricular arrhythmias
Issue Date: 31-May-2000
Citation: 0008-4212; CAN J PHYSIOL PHARMACOL, MAY 2000, vol. 78, no. 5, p.407 to 414.
Abstract: Several nonsedating histamine H-1-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 H-1-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 H-1-receptor antagonist hydroxyzine (0.1-30 mu M), (ii) cetirizine, a nonsedating metabolite of hydroxyzine (1-300 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 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 mu M) 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.
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