Sakaguchi Yasue, Takahara Akira, Nakamura Yuji, Akie Yasuki, Sugiyama Atsushi
Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi,Shimokato, Chuo, Yamanashi, Japan.
Basic Clin Pharmacol Toxicol. 2009 Jan;104(1):43-8. doi: 10.1111/j.1742-7843.2008.00312.x.
For the halothane-anaesthetized, closed-chest, guinea-pig model, corrected QT interval (QTc) has been empirically used to estimate the extent of drug-induced QT-interval prolongation. In the present study, we employed an atrial pacing method to clarify a net effect of a drug on the QT interval in this model. The atrial pacing catheter was inserted via the jugular vein with a minimal surgical invasion, and the effects of d-sotalol (0.3 and 3 mg/kg, intravenously) and verapamil (0.01 and 0.1 mg/kg, intravenously) on electrocardiogram parameters were assessed under the sinus rhythm and during the atrial pacing of 200 and 240 beats/min. d-Sotalol significantly prolonged the QT interval in a reverse use-dependent manner and decreased the heart rate, while verapamil prolonged the PR interval without affecting the heart rate or QT interval, indicating the sensitivity and specificity of this model in assessing the pharmacodynamics of the drug-induced QT-interval prolongation. Using the QT/RR relationship under the sinus rhythm, we obtained the following two types of QT-interval correcting formulae; namely, QTc = QT - 0.207(RR - 300) by a linear regression method; and QTc = QT/(RR/300)0.332 by a non-linear regression method, the latter of which is equal to 0.67 times of Fridericia's formula, providing rationale for the use of mathematical correction in this model. Thus, the halothane-anaesthetized, closed-chest, guinea-pig model may be highly useful for assessing the drug-induced QT-interval prolongation, which may become an alternative to current models for the in vivo QT assay.
对于氟烷麻醉、闭胸豚鼠模型，校正QT间期（QTc）已被经验性地用于估计药物诱导的QT间期延长程度。在本研究中，我们采用心房起搏方法来阐明该模型中药物对QT间期的净效应。通过颈静脉插入心房起搏导管，手术创伤最小，评估了d - 索他洛尔（0.3和3 mg/kg，静脉注射）和维拉帕米（0.01和0.1 mg/kg，静脉注射）在窦性心律以及200和240次/分钟心房起搏期间对心电图参数的影响。d - 索他洛尔以反向使用依赖方式显著延长QT间期并降低心率，而维拉帕米延长PR间期但不影响心率或QT间期，表明该模型在评估药物诱导的QT间期延长的药效学方面具有敏感性和特异性。利用窦性心律下的QT/RR关系，我们得到了以下两种类型的QT间期校正公式；即，通过线性回归方法得到QTc = QT - 0.207(RR - 300)；通过非线性回归方法得到QTc = QT/(RR/300)^0.332，后者等于弗里德里西亚公式的0.67倍，为该模型中使用数学校正提供了理论依据。因此，氟烷麻醉、闭胸豚鼠模型对于评估药物诱导的QT间期延长可能非常有用，这可能成为当前体内QT测定模型的替代方法。
