Program

PO3-11-6

Sensitivity of the acute atrioventricular block rabbit as a novel model for detecting drug-induced Torsade de Pointes arrhythmias

[Speaker] Yoshinobu Nagasawa:1
[Co-author] Mihoko Hagiwara-Nagasawa:1,2, Seiji Shibuta:1, Kazuhiro Takada:1, Ryuichi Kambayashi:1, Misako Nakajo:1, Xin Cao:1, Megumi Aimoto:1, Akira Takahara:1
1:Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, Japan, 2:Department of Pharmacology, Faculty of Medicine, Toho University, Japan

[Background] The acute atrioventricular block (AAVB) rabbit has been known as a novel model for detecting drug-induced Torsade de Pointes (TdP) arrhythmias with high specificity for proarrhythmic drugs. In this study, we assess sensitivity of the model to detect the drug-induced TdP by comparing proarrhythmic effects of dofetilide, a representative torsadogenic drug, on the AAVB rabbit with those on the methoxamine-sensitized rabbit, the firstly established proarrhythmia model.
[Methods] All experiments were performed under isoflurane anesthesia. In the AAVB rabbit group, bradycardia was induced by combination of atrioventricular node ablation and ventricular electrical stimulation at 60 beats/min throughout the experiment. Dofetilide (1, 10, and 100 µg/kg) was intravenously infused over 10 min, and its electrophysiological and proarrhythmic effects were monitored for 30 or 60 min. In the methoxamine-sensitized rabbit group, dofetilide was similarly administered under the continuous infusion of methoxamine at rate of 15 µg/kg/min (i.v.).
[Results] Dofetilide prolonged the monophasic action potential duration (MAP90) of the right ventricle and QT interval both in AAVB and methoxamine-sensitized rabbits. In the AAVB rabbit, the premature ventricular contractions with R on T phenomenon were observed at the low, middle and high dose, of which numbers during the observation period were 2.8, 92.7 and 629.2 beats, respectively. The effects were greater than those in the methoxamine-sensitized rabbit (0, 27.3, and 85.4 beats, respectively). At the middle and high dose, TdP was observed in 4 out of 6 rabbits and 5 out of 6 rabbits with AAVB, and the numbers of its episodes during the observation period were 4.0 and 24.0 episodes, respectively. The potency of its proarrhythmic effects was greater than those in the methoxamine-sensitized rabbit showing that TdP was observed in 3 out of 6 rabbits (degenerated into ventricular fibrillation in 1 rabbit) and 2 out of 5 rabbits and that numbers of its episodes were 1.3 and 0.4 episodes at the middle and high dose, respectively.
[Conclusions] The sensitivity of the AAVB rabbit to detect the drug-induced TdP is higher than that of the methoxamine-sensitized rabbit, which can be a useful test system for the detection of proarrhythmic potential of drugs.
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