陽性変時作用を有する薬物のQT延長評価に対するイソフルラン麻酔モルモットの有用性

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  • Utility of isoflurane-anesthetized guinea pigs for the assessment of the QT-interval prolongation induced by drugs with positive chronotropic action

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<p>[Background] The QT interval can be shortened by tachycardia, which may underestimate risks of the drug-induced QT-interval prolongation in the safety pharmacology studies.  To investigate utility of guinea pigs for the assessment of the QT-interval prolongation, we assessed cardiac effects of suspect drugs prolonging QT interval, sulpiride and aripiprazole, both of which exerted positive chronotropic actions in dogs.</p><p>[Methods] Under isoflurane-anesthesia, electrocardiogram and monophasic action potential (MAP) of right ventricle were continuously recorded from guinea pigs to measure the heart rate (HR) and the MAP duration (MAP90), respectively.  Sulpiride (2, 20, and 60 mg/kg) or aripiprazole (0.03, 0.3, and 3 mg/kg) were administered intravenously over 10 min.</p><p>[Results] Sulpiride at 2 mg/kg did not affect HR or MAP90, and increased MAP90 with decrement of HR at 20 and 60 mg/kg. Aripiprazole at 0.03 and 0.3 mg/kg did not affect HR or MAP90, and increased MAP90 with decrement of HR at 3 mg/kg. Meanwhile, positive chronotropic actions of sulpiride and aripiprazole were not observed. </p><p>[Conclusions] Since sulpiride and aripiprazole have been clinically reported to hardly induce tachycardia, anesthetized guinea pigs are useful for screening of drug-induced QT interval prolongation for safety pharmacology studies.</p>

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