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Journal of Cardiovascular Pharmacology and Therapeutics
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Gender-related Differences in Drug-induced Prolongation of Cardiac Repolarization in Prepubertal Guinea Pigs

Raymond Hreiche, PharmD, PhD

Faculty of Pharmacy, Université de Montréal, and CRCHUM, Centre Hospitalier de l'Université de Montréal Montréal, Québec, Canada

Pierre Morissette, PhD

Faculty of Pharmacy, Université de Montréal, and CRCHUM, Centre Hospitalier de l'Université de Montréal Montréal, Québec, Canada

Hubert Zakrzewski-Jakubiak, BPharm

Faculty of Pharmacy, Université de Montréal, and CRCHUM, Centre Hospitalier de l'Université de Montréal Montréal, Québec, Canada

Jacques Turgeon, BPharm, PhD

Faculty of Pharmacy, Université de Montréal, and CRCHUM, Centre Hospitalier de lUniversité de Montréal Montréal, Québec, Canada, jacques.turgeon.chum{at}ssss.gouv.qc.ca

Underlying mechanisms of drug-induced long QT syndrome are not fully understood. Our objective was to evaluate gender-related differences for block of the rapid (IKr ) or/and the slow (IKs) components of the delayed rectifier potassium current in prepubertal male and female guinea pigs (n = 120) treated with or without verapamil. Indapamide (IKs blocker) prolonged the monophasic action potential duration at 90% repolarisation (MAPD 90) in females more than in males (15.1 + 0.5 vs 9.7 + 1.3 msec; P < .05) in verapamil treated animals. In contrast, MAPD90 prolongation induced by domperidone or dofetilide (IKr blockers) was not different between genders. Verapamil treatment augmented prolongation of MAPD 90 caused by dofetilide or domperidone (P < .01). In conclusion, 1) females exhibited greater prolongation of MAPD90 when exposed to indapamide, 2) no gender-related differences were observed for I Kr blockers, and 3) verapamil treatment did not uncover gender-related differences in IKr or IKs block, although it augmented prolongation of cardiac repolarization by IKr blockers.

Key Words: drug-induced long QT syndrome • potassium channel blockers • cardiac repolarization • gender • membrane transporters

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 14, No. 1, 28-37 (2009)
DOI: 10.1177/1074248408331018
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