Gender-related differences in drug-induced prolongation of cardiac repolarization in prepubertal guinea pigs.
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 (I(Kr) ) or/and the slow (I(Ks)) components of the delayed rectifier potassium current in prepubertal male and female guinea pigs (n = 120) treated with or without verapamil. Indapamide (I(Ks) 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, MAPD(90) prolongation induced by domperidone or dofetilide (I(Kr) 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 MAPD(90) 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 I(Kr) or I(Ks) block, although it augmented prolongation of cardiac repolarization by I(Kr) blockers.
Hreiche
Raymond
R
Faculty of Pharmacy, Université de Montréal, Montréal, Québec, Canada.
Morissette
Pierre
P
Zakrzewski-Jakubiak
Hubert
H
Turgeon
Jacques
J
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004294:Domperidone / Q000633:toxicity; D005260:Female; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism; D007190:Indapamide / Q000633:toxicity; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D010627:Phenethylamines / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000633:toxicity*; D012737:Sex Factors; D046468:Sexual Development; D013449:Sulfonamides / Q000633:toxicity; D013997:Time Factors; D014700:Verapamil / Q000633:toxicity
D000889:Anti-Arrhythmia Agents; D051668:Delayed Rectifier Potassium Channels; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D004294:Domperidone; D014700:Verapamil; D007190:Indapamide; C063533:dofetilide