Lu H R, Mariën R, Saels A, De Clerck F
Department of Cardiovascular Safety Pharmacology, Janssen Research Foundation, Beerse, Belgium.
J Cardiovasc Pharmacol. 2000 Jul;36(1):132-9. doi: 10.1097/00005344-200007000-00018.
Women are known to have a longer QT interval than men and a greater propensity toward drug-induced "torsades de pointes" (TdPs). However, little is known about these sex differences in isolated cardiac tissues. We evaluated potential sex differences in repolarization in isolated rabbit Purkinje fibers using a microelectrode technique. Isolated male or female Purkinje fibers were perfused in a Tyrode's solution with solvent, dofetilide (1 x 10(-8) M) or quinidine (1 x 10(-5) M), and stimulated at 1 or 0.2 Hz. Female Purkinje fibers with solvent (n = 11) tended to have a longer duration of the action potential at 90% repolarization (APD90) than male fibers with solvent (n = 10): 331 (median) vs. 272 ms at 1 Hz (p > 0.05); 473 vs. 367 ms at 0.2 Hz (p < 0.05). Dofetilide (1 x 10(-8) M) significantly increased APD90 more in female Purkinje fibers (n = 11) than in male fibers (n = 10): 670 vs. 385 ms at 1 Hz, at 20 min after the infusion (p < 0.05), and 1,000 vs. 937 ms at 0.2 Hz at the end of the 25-min infusion (p < 0.05), respectively. Quinidine (1 x 10(-5) M) tended to increase APD90 more in female Purkinje fibers (n = 11) than in male fibers (n = 10): 705 vs. 500 ms at 1 Hz, at 20 min after the infusion (p > 0.05). Furthermore, dofetilide (1 x 10(-8) M) and quinidine (1 x 10(-5) M) elicited a higher incidence of early afterdepolarizations in female Purkinje fibers than in male fibers at 0.2 Hz (100 vs. 60%, p < 0.05; and 91 vs. 50%, p > 0.05). Our data indicate that female Purkinje fibers tend to have longer ventricular repolarization and are at higher risk of drug-induced early afterdepolarizations at a slow stimulation rate than male fibers. This may contribute to a sex difference in QT interval and to a greater tendency on the part of women to the development of drug-induced TdPs.
已知女性的QT间期比男性长，且更易发生药物诱导的“尖端扭转型室性心动过速”（TdP）。然而，关于这些性别差异在孤立心脏组织中的情况却知之甚少。我们使用微电极技术评估了孤立兔浦肯野纤维复极化过程中的潜在性别差异。将孤立的雄性或雌性浦肯野纤维置于含有溶剂、多非利特（1×10⁻⁸ M）或奎尼丁（1×10⁻⁵ M）的台氏液中进行灌注，并以1或0.2 Hz的频率进行刺激。使用溶剂的雌性浦肯野纤维（n = 11）在90%复极化时的动作电位时程（APD90）往往比使用溶剂的雄性纤维（n = 10）更长：在1 Hz时为331（中位数）对272 ms（p > 0.05）；在0.2 Hz时为473对367 ms（p < 0.05）。多非利特（1×10⁻⁸ M）使雌性浦肯野纤维（n = 11）的APD90增加幅度显著大于雄性纤维（n = 10）：在输注后20分钟，1 Hz时为670对385 ms（p < 0.05），在25分钟输注结束时，0.2 Hz时为1000对937 ms（p < 0.05）。奎尼丁（1×10⁻⁵ M）使雌性浦肯野纤维（n = 11）的APD90增加幅度往往大于雄性纤维（n = 10）：在输注后20分钟，1 Hz时为705对500 ms（p > 0.05）。此外，在0.2 Hz时，多非利特（1×10⁻⁸ M）和奎尼丁（1×10⁻⁵ M）在雌性浦肯野纤维中诱发早期后除极的发生率高于雄性纤维（分别为100%对60%，p < 0.05；91%对50%，p > 0.05）。我们的数据表明，雌性浦肯野纤维往往具有更长的心室复极化时间，并且在缓慢刺激频率下比雄性纤维更易发生药物诱导的早期后除极。这可能导致QT间期的性别差异，并使女性更易发生药物诱导的TdP。
