多非替利衍生物V03(CPU228)与多非替利对再灌注性心律失常、血管收缩和诱发尖端扭转室速(TdP)作用的比较

目的　研究多非替利衍生物V0 3(CPU2 2 8)心血管活性。方法　结扎麻醉大鼠冠状动脉左前降支及再灌 ,建立再灌注心律失常模型 ;用甲氧胺给药的家兔模型考察诱发TdP作用 ;以无钙、复钙液中KCl(大鼠 )和苯肾上腺素 (豚鼠 )引起的胸主动脉环的收缩 ,考察对内钙动员和外钙内流的影响。结果　①CPU2 2 8可降低最大心律失常分数 ,明显缩短VF和VT持续时间 ,减少心律失常分数 -时间曲线下面积 ,作用强于多非替利。②CPU2 2 8的TdP诱发率低于多非替利。③CPU2 2 8可浓度依赖性地抑制无钙液中的KCl和Phe引起的血管收缩 ,亦抑制复钙后KCl引起的血管收缩但对Phe的复钙收缩无影响 ,多非替利仅高浓度对无钙液中的KCl引起的血管收缩具有抑制作用。结论　CPU2 2 8增强了抗再灌注性心律失常作用 ,减弱了诱发Tdp作用 ,新增了对L 型钙通道的拮抗作用和α受体的阻断作用 ,具有复合型Ⅲ类药物的特点

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

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 andαadrenergic receptor.