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Female Gender Does Not Influence the Magnitude of Ibutilide-Induced Repolarization Delay and Incidence of Torsades de Pointes in an In Vivo Rabbit Model of the Acquired Long QT Syndrome

Leif Carlsson, PhD

AstraZeneca Research and Development Moindal, Integrative Phannacology, Moindal, Sweden

Background: Clinical and experimental in vitro observations indicate that female gender is associated with a higher risk of developing torsades de pointes with repolarizing-delaying agents. The present study addressed the question of gender difference in the susceptibility towards developing torsades de pointes in a rabbit model of the acquired long QT syndrome in vivo.

Methods and Results: Female (F, n = 40) or male (M, n = 40) NZW rabbits, characterized as young (Y, n = 20) or adult (A, n = 20) were anesthetized with oc-chloralose and sensitized to developing torsades de pointes by a continuous infusion of methoxamine. The class III antiarrhythmic agent ibutilide was subsequently infused at a rate of 8 nmol/kg/min for 30 minutes maximum. Before commencement of drug infusion, no gender-related differences in the QT interval were observed (121 ± 1.9 msec and 126 ± 3.3 msec in FA and in MA and 116 ± 1.6 msec and 113 ± 1.7 msec in the FY and MY, respectively). Infusion of ibutilide was associated with a rapid and marked increase in the QT interval, which did not differ significantly between the groups. Hence, the maximal QT lengthening observed was 39 ± 3.1% in FA, 46 ± 5.7% in MA, 38 ± 3.9% in FY and 36 ± 3.4% in MY, respectively (p > 0.05 between gender). In the adults, the incidence of torsades de pointes in F was 70% and in M 90% (p = 0.235), whereas in the young, the incidence in F was 45% and in M 70% (p = 0.200). The cumulative doses of ibutilide causing torsades de pointes were not statistically significantly different between the four groups of rabbits (70 ± 15.5 nmol/kg in FA, 50 ± 5.3 nmol/kg in MA, 59 ± 17.2 nmol/kg in FY and 61 ± 15.9 nmol/kg in MY, respectively).

Conclusions: In this in vivo rabbit model of the acquired long QT syndrome, female gender was not associated with a longer repolarization time (QT interval), an excessive change in the baseline QT interval or a higher incidence of torsades de pointes in response to ibutilide challenge.

Key Words: drugs • gender • QT interval • proarrhythmias

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 6, No. 3, 247-254 (2001)
DOI: 10.1177/107424840100600305


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