title: 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.
abstract: 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.
  
  
  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 alpha-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.
authors.affiliation: AstraZeneca Research and Development Mölndal, Integrative Pharmacology, S-431 83 Mölndal, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Johansson
authors.forename: L
authors.initials: L
authors.lastname: Carlsson
mesh_terms: D000367:Age Factors; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D011817:Rabbits; D012727:Sex Characteristics; D013449:Sulfonamides / Q000009:adverse effects*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D000889:Anti-Arrhythmia Agents; D013449:Sulfonamides; C067192:ibutilide