Comparison of effects of dofetilide derivative V03(CPU228) and dofetilide on coronary occlusion and reperfusion arrhythmia, vascular contractions and proarrhythmic potential of torsade de pointes / 中国药理学通报

ABSTRACT

AIM To investigate the cardiovascular activity of new compound V03(CPU228) derived from dofetilide. METHODS Arrhythmias was induced by the occlusion and reperfusion of left anterior descending coronary artery. The effects of CPU228 and dofetilide on QT interval and inducing Tdp were compared in anesthetized rabbits during stimulation with methoxamine. The contractions of thoracic aortic rings induced by KCl (rat) and Phe (guinea pig) in Ca 2+-free and calcium recovered K-H solution was studied to determinate the activity of CPU228 on intracellular calcium mobilization and calcium entry. RESULTS ① CPU228 suppressed the maximal arrhythmia scores, decreased the AUC of arrhythmia score( reduced the duration of VF and VT significantly). PU228 is more potent than dofetilide.②The potency of CPU228 of inducing Tdp is significantly weaker than that of dofetilide.③There were significantly inhibitions of CPU228 on the contractions of aortic rings induced by KCl and Phe in Ca 2+-free solution and dofetilide only had a inhibition on the former. CPU228 inhibited contractions of aortic ring by adding calcium which influx via L-type calcium channel while dofetilide had no effects on these. CONCLUSION CPU228 has stronger inhibition on coronary occlusion and reperfusion arrhythmia and lower potency of inducing Tdp than dofetilide. All the results suggest that CPU228 is a nonselective I Kr-blocker combined with a blockade on the L-type Ca 2+ channel and?adrenergic receptor.