Biol Pharm Bull. 2026;49(1):34-39. doi: 10.1248/bpb.b25-00450.
ABSTRACT
We have established a proarrhythmic rabbit model of acute atrioventricular block (AVB) with severe bradycardia to detect delayed rectifier K+ channel current (IKr) blocker-induced torsade de pointes (TdP). To better understand the role of β-adrenoceptors in this model, we investigated the effect of the β-adrenoceptor blocker metoprolol against an IKr blocker dofetilide-induced TdP. AVB was induced by catheter ablation under isoflurane anesthesia, and the ventricles were electrically paced at a constant rate of 60 beats/min throughout the experiments. Monophasic action potentials (MAPs) were recorded from the right ventricle. In the non-treated control rabbits (n = 5), intravenous administration of an IKr blocker dofetilide (25 µg/kg) prolonged the MAP duration (MAP90) by 90 ± 38 ms, which led to the induction of TdP in four of the five animals. In rabbits receiving the β-adrenoceptor blocker metoprolol (10 µg/kg/min, n = 5), the same dose of dofetilide prolonged MAP90 by 205 ± 31 ms, whereas TdP did not occur in this group. Meanwhile, the incidence of dofetilide-induced R-on-T-type premature ventricular contractions, representing an arrhythmogenic trigger, was lower in metoprolol-treated rabbits than in non-treated control rabbits. These results indicate that metoprolol exerted an overall antiarrhythmic effect by strongly suppressing TdP generation induced by dofetilide, despite its proarrhythmic action of enhancing repolarization prolongation. This highlights the critical role of β-adrenoceptors in facilitating arrhythmogenic triggers under conditions of excessive repolarization delay.
PMID:41485989 | DOI:10.1248/bpb.b25-00450