Get access

Electrophysiological effects of cetirizine, astemizole and d-sotalol in a canine model of long QT syndrome

Authors


Dr J. Weissenburger Pharmacology Laboratory, Faculté de Médecine St Antoine, 27, rue Chaligny 75571 Paris Cedex 12, France.

Abstract

Observations of torsades de pointes during therapy with terfenadine and astemizole has raised concern about the cardiac safety of non-sedating H1-antagonist agents. We compared cetirizine, another compound of that class, to d-sotalol and to astemizole in a model of acquired long QT syndrome.

Open-chest surgery was performed in adult beagle dogs anaesthetized with halothane and thiopental. Bradycardia was produced with β-adrenergic blockade and sinus node crush. Four left ventricular intramyocardial unipolar monophasic action potentials (MAP) were recorded during atrial pacing at basic cycle lengths (BCL) 400–1500 msec, before and during three successive 1-h drug infusions (0.14, 0.45 and 1.4 mg/kg/h for astemizole and cetirizine and 1.1, 2.2 and 4.5 mg/kg/h for d-sotalol).

Dose- and bradycardia-dependent prolongations of MAP duration (MAPD) were produced by d-sotalol (P < 0.001) and astemizole (P < 0.001) but not by cetirizine. At BCL 1500 ms, the three infusions of astemizole prolonged endocardial MAPD from 323 ± 8 msec (mean ± SE) at baseline to 343 ± 10, 379 ± 13 and 468 ± 26 msec, respectively (n = 9). Sotalol prolonged that MAPD from 339 ± 6 msec to 377 ± 7, 444 ± 15 and 485 ± 24 msec (n = 7). In contrast, cetirizine did not prolong MAPD: 341 ± 8 msec at baseline Vs 330 ± 8, 324 ± 9 and 323 ± 11 msec (n = 9). Drug-induced increase in transmural dispersion reached +79 ± 19 msec after astemizole, +59 ± 21 msec after d-sotalol and only +7 ± 11 msec after cetirizine. Runs of ventricular tachycardias and torsades de pointes occurred during dose three of astemizole (5/9 dogs) and d-sotalol (4/7 dogs) but never during cetirizine.

In the present model, astemizole and d-sotalol but not cetirizine prolonged MAPD and transmural dispersions of repolarization and produced torsades de pointes. These results suggest that the halothane-anaesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies.

Ancillary