Johansson M, Carlsson L
AstraZeneca Research and Development Mölndal, Integrative Pharmacology, S-431 83 Mölndal, Sweden.
J Cardiovasc Pharmacol Ther. 2001 Jul;6(3):247-54. doi: 10.1177/107424840100600305.
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.
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).
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.
临床和体外实验观察表明，女性使用复极延迟剂时发生尖端扭转型室速的风险更高。本研究探讨了在体内获得性长QT综合征兔模型中，发生尖端扭转型室速易感性的性别差异问题。
将40只雌性（F，n = 40）或40只雄性（M，n = 40）新西兰白兔分为青年组（Y，n = 20）和成年组（A，n = 20），用α-氯醛糖麻醉，通过持续输注甲氧明使其对发生尖端扭转型室速敏感。随后以8 nmol/kg/min的速率输注Ⅲ类抗心律失常药伊布利特，最长输注30分钟。在开始药物输注前，未观察到QT间期存在性别相关差异（FA组和MA组分别为121±1.9毫秒和126±3.3毫秒，FY组和MY组分别为116±1.6毫秒和113±1.7毫秒）。输注伊布利特与QT间期迅速且显著增加相关，各组之间无显著差异。因此，观察到的最大QT延长在FA组为39±3.1%，MA组为46±5.7%，FY组为38±3.9%，MY组为36±3.4%（性别间p>0.05）。在成年兔中，F组尖端扭转型室速的发生率为70%，M组为90%（p = 0.235），而在青年兔中，F组发生率为45%，M组为70%（p = 0.200）。四组兔发生尖端扭转型室速时伊布利特的累积剂量无统计学显著差异（FA组为70±15.5 nmol/kg，MA组为50±5.3 nmol/kg，FY组为59±17.2 nmol/kg，MY组为61±15.9 nmol/kg）。
在这个获得性长QT综合征的体内兔模型中，女性与复极时间（QT间期）延长、基线QT间期过度变化或对伊布利特激发试验发生尖端扭转型室速的更高发生率无关。
