Smith E F, Griswold D E, Hillegass L M, Slivjak M J, Davis P A, DiMartino M J
SmithKline Beecham Pharmaceuticals, Department of Pharmacology, King of Prussia, PA 19406.
Pharmacology. 1992;44(6):297-305. doi: 10.1159/000138934.
The purpose of this study was to evaluate the cardioprotective effects of carvedilol, a beta-adrenergic blocker and vasodilator, in two models of ischemic myocardial damage in the rat. Following coronary artery occlusion for 0.5 h and reperfusion for 24 h (MI/R group), left ventricular (LV) injury was determined by planimetric analysis of triphenyltetrazolium chloride-stained tissue, and polymorphonuclear leukocyte infiltration was assessed by measuring myeloperoxidase (MPO) activity. In the vehicle-treated MI/R group, infarct size was 14.2 +/- 1.3% of the LV (n = 16), and MPO activity was increased to 2.8 +/- 0.7 from 0.14 +/- 0.03 U/g tissue in the vehicle-treated sham-occluded group (p less than 0.01). Carvedilol (1 mg/kg i.v., 15 min prior to coronary artery occlusion and at 3.5 h following reperfusion) reduced myocardial infarct size to 7.5 +/- 1.2% of the LV (n = 14; p less than 0.01) and attenuated the increase in MPO activity to 1.4 +/- 0.4 U/g tissue (p less than 0.05). A lower dose of carvedilol (i.e. 0.3 mg/kg i.v.) did not limit myocardial infarct size or the increase in MPO activity. In a model of permanent coronary artery occlusion, 24-hour survival was reduced from 85% in sham-occluded animals (n = 38) to 44% in the vehicle-treated MI group (n = 84; p less than 0.01). In comparison to the vehicle-treated MI group, carvedilol (0.3 mg/kg i.v., 15 min prior to coronary artery occlusion and 1 mg/kg 4 h after occlusion) improved survival by 55% (n = 64; p less than 0.05, compared to the vehicle-treated MI group), whereas the same dose of propranolol (n = 42) had no significant effect on survival. These results indicate that carvedilol reduces myocardial ischemia/reperfusion injury, and significantly improves survival in a permanent coronary artery occlusion model of myocardial infarction.
本研究旨在评估β-肾上腺素能阻滞剂兼血管扩张剂卡维地洛对大鼠两种缺血性心肌损伤模型的心脏保护作用。冠状动脉闭塞0.5小时并再灌注24小时后（心肌梗死/再灌注组），通过对氯化三苯基四氮唑染色组织进行平面测量分析来确定左心室（LV）损伤，并通过测量髓过氧化物酶（MPO）活性来评估多形核白细胞浸润情况。在给予赋形剂处理的心肌梗死/再灌注组中，梗死面积为左心室的14.2±1.3%（n = 16），且MPO活性从给予赋形剂处理的假闭塞组中的0.14±0.03 U/g组织增加至2.8±0.7 U/g组织（p < 0.01）。卡维地洛（静脉注射1 mg/kg，在冠状动脉闭塞前15分钟及再灌注后3.5小时给药）可将心肌梗死面积减小至左心室的7.5±1.2%（n = 14；p < 0.01），并使MPO活性增加减弱至1.4±0.4 U/g组织（p < 0.05）。较低剂量的卡维地洛（即静脉注射0.3 mg/kg）并未限制心肌梗死面积或MPO活性的增加。在永久性冠状动脉闭塞模型中，24小时生存率从假闭塞动物的85%（n = 38）降至给予赋形剂处理的心肌梗死组的44%（n = 84；p < 0.01）。与给予赋形剂处理的心肌梗死组相比，卡维地洛（静脉注射0.3 mg/kg，在冠状动脉闭塞前15分钟给药，闭塞后4小时给予1 mg/kg）可使生存率提高55%（n = 64；与给予赋形剂处理的心肌梗死组相比，p < 0.05），而相同剂量的普萘洛尔（n = 42）对生存率无显著影响。这些结果表明，卡维地洛可减轻心肌缺血/再灌注损伤，并显著提高心肌梗死永久性冠状动脉闭塞模型中的生存率。
