Transient outward current inhibition by propafenone and 5-hydroxypropafenone in cultured neonatal rat ventricular myocytes.

The antiarrhythmic agent propafenone and its primary electropharmacologically active metabolite, 5-hydroxypropafenone, are known inhibitors of cardiac myocyte repolarizing currents. We recently documented potent propafenone inhibition of the transient outward potassium current (Ito) in human atrial myocytes from patients in the newborn and infant age range. In the current study we characterized ventricular Ito inhibition by propafenone and 5-hydroxypropafenone in neonatal myocytes enzymatically isolated from 2-day-old Sprague-Dawley rat pups. Using the whole-cell patch-clamp technique in ventricular myocytes kept in primary culture for 1-4 days, we observed comparably potent Ito inhibition by both agents, yielding 50% maximal inhibitory concentration (IC50) values of 2.1 +/- 0.5 and 1.5 +/- 0.2 microM for propafenone and 5-hydroxypropafenone, respectively. Ito blockade by both of these agents was time, concentration, and voltage dependent, but use independent. There was no drug effect on steady-state voltage dependence of Ito inactivation, or on the time course of Ito recovery from inactivation. These findings are consistent with an open channel-blocking mechanism as suggested by other models. We conclude that both propafenone and 5-hydroxypropafenone are potent Ito inhibitors in neonatal rat ventricular myocytes, with potencies exceeding those demonstrated for propafenone in adult rat ventricular myocytes or in human atrial myocytes from patients of all ages.

Predictors of torsades de pointes in rabbit ventricles perfused with sedating and nonsedating histamine H1-receptor antagonists.

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.