Halothane-anaesthetized, closed-chest, guinea-pig model for assessment of drug-induced QT-interval prolongation

Abstract

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. © 2008 The Authors.