A gender-independent proarrhythmic action of 17beta-estradiol in anaesthetized rabbits.
Women are at increased risk of having drug-induced arrhythmias such as torsade de pointes but less susceptible to arrhythmias associated with myocardial ischaemia. We have shown previously that 17beta-estradiol had greater antiarrhythmic activity in female rats than in male rats subject to myocardial ischaemia. The aim of this work was to investigate the effects of acute administration of 17beta-estradiol in both sexes in an established in vivo model of drug-induced arrhythmias. In alpha(1)-adrenoceptor-stimulated, pentobarbital-anaesthetized rabbits, 17beta-estradiol (100, 300 or 1000 ng/kg bolus followed by 10, 30 or 100 ng/kg/min infusion) tended to increase the incidence of torsade de pointes, induced by clofilium, in both sexes: from 50% in controls to 80%, 70% and 80% in females; from 40% in controls to 60%, 70% and 80% in males with increasing doses of 17beta-estradiol (n=10 per group). The total duration of all episodes of torsade de pointes was increased significantly by the highest dose of 17beta-estradiol compared to vehicle in both female and male rabbits: from 9+/-4 s to 93+/-26 s in females; from 26+/-14 s to 96+/-20 s in males. There were no baseline differences between the sexes in heart rate, QTc interval or epicardial monophasic action potential duration. The proarrhythmic effect of acute administration of 17beta-estradiol in the alpha(1)-adrenoceptor-stimulated anaesthetized rabbit model was independent of gender. This indicates that the underlying mechanism differs from that involved in the gender-selective reduction of ischaemia-induced arrhythmias by 17beta-estradiol.
Philp
Karen L
KL
Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, UK.
Hart
George
G
Coker
Susan J
SJ
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000777:Anesthetics / Q000008:administration & dosage*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D008297:Male; D017202:Myocardial Ischemia / Q000139:chemically induced* / Q000473:pathology; D011817:Rabbits; D012727:Sex Characteristics; D013997:Time Factors; D016171:Torsades de Pointes / Q000175:diagnosis
D000777:Anesthetics; D000889:Anti-Arrhythmia Agents; D004958:Estradiol