新Ⅲ类抗心律失常化合物CPUY11066对心肌缺血的保护作用及抗心律失常作用

Protective Effect of the Novel Class III Antiarrhythmic Compound CPUY11066 against Myocardial Ischemia and Its Antiarrhythmic Activity

目的:考察新Ⅲ类抗心律失常化合物CPUY11066对心肌缺血的保护作用和抗心律失常作用。方法:建立实验性异丙肾上腺素诱导小鼠急性心肌缺血模型和乌头碱致大鼠心律失常模型。于造模前,给予动物使用CPUY11066预治疗,并以阿奇利特和胺碘酮作为阳性对照,测量受试动物造模前后的心电图和心率。同时,观察CPUY11066对正常豚鼠心电图和心率的影响。结果:在异丙肾上腺素诱发小鼠急性心肌缺血模型实验中,造模后,与模型组相比,CPUY11066组和阿奇利特组小鼠心电图中ST段、T波和QT间期以及心率显著改善(P<0.05或P<0.01),且血清中一氧化氮含量以及总一氧化氮合酶和内皮型一氧化氮合酶活性显著回升(P<0.01),接近正常组;在乌头碱致大鼠心律失常模型实验中,造模后,与模型组相比,CPUY11066高剂量(6 mg·kg-1)组、胺碘酮组和阿奇利特组大鼠出现室性早搏、室性心动过速、室性纤颤及心脏停搏的时间明显延迟(P<0.05或P<0.01),且CPUY11066高剂量组和阿奇利特组大鼠的房颤发生率明显下降,房颤持续时间也显著缩短(P<0.01和P<0.001);在药物心脏安全性实验中,与阿奇利特不同,CPUY11066虽可致正常豚鼠心电图中QT间期延长,但其作用并不随浓度的增加而增强,即存在平台效应,且不同浓度的CPUY11066对豚鼠心率的影响均较小。结论:CPUY11066对异丙肾上腺素诱导的急性心肌缺血具有保护作用,并能有效对抗乌头碱引起的心律失常,且安全性良好。

Objective： To investigate the protective effects of CPUY11066, a novel Class III anti- arrhythmic compound, against myocardial ischemia and its antiarrhythmic activity. Methods： The experi- mental isoproterenol （ISO）-induced acute myocardial isehemia model in mice and aconitine-induced arrhythmia model in rats were made. Before making models, the test animals were administrated CPUY11066 for pre-treatment with azimilide and amiodarone used as positive controls. Moreover, theeffects of CPUY11066 on induced acute myocardial ECG and heart rate were ECG and heart rate in normal guinea ischemia model experiment, after pigs were observed. Results： In the ISO- making model ST segment, T wave and QTc in significantly improved （P 〈 0. 05 or （P 〈 0. 01） and NO level and NOS activity in serum significantly returned nearly to normal group （P 〈0. 01） in mice in CPUY11066 group and azi- milide group compared with those in model group. In the aconitine-induced arrhythmia model experiment, after making model the onset of ventricular premature beat, ventricular tachycardia, ventricular fibrillation and cardiac arrest was significantly delayed （ P 〈 0. 05 or P 〈 0. 01） in rats in CPUY11066 high dose （6 rag-kg-1） group, amiodarone group and azimilide group and the atrial fibrillation rate was significantly decreased and the atrial fibrillation duration was significantly shortened （P 〈 0. 01 and P 〈 0. 001） in rats in CPUY11066 high dose group and azimilide group compared with those in model group. In the drug cardiac safety test, unlike azimilide CPUYl1066-induced QTc prolongation displayed a concentration- independent ＂platform＂ effect and CPUYl1066 in any concentration had less effect on heart rate. Conclusion： CPUYl1066 could protect against ISO-induced acute myocardial ischemia and effectively antagonize aconitine-induced arrhythmias. Besides, it has high cardiac safety.