Smith E F, Nichols A J, Sellers T S, O'Brien S R, Griswold D E, Egan J W, Hillegass L M, Vasko J A, Slivjak M J, Davis P A
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, plc, King of Prussia, PA 19406.
J Cardiovasc Pharmacol. 1991 Nov;18(5):729-38. doi: 10.1097/00005344-199111000-00011.
The benefit of thrombolytic agents to reduce myocardial infarct size, improve left ventricular (LV) function, and prolong survival in human subjects is generally recognized, although the precise mechanism is poorly defined. This study was designed to evaluate the cardioprotective effects of streptokinase (SK) in rats, a species less responsive to plasminogen activators, using a model of mechanical occlusion and release of the left coronary artery. Myocardial injury and polymorphonuclear leukocyte (PMN) infiltration were determined by measuring creatine phosphokinase (CPK) specific activity and myeloperoxidase (MPO) activity, respectively, in the LV free wall (LVFW). After coronary artery occlusion for 0.5 h and reperfusion for 24 h (myocardial ischemia, MI/R), CPK specific activity decreased from 7.0 +/- 0.3 U/mg protein in the sham + vehicle group to 5.6 +/- 0.5 U/mg protein in the MI/R + vehicle group (n = 19, p less than 0.01), while MPO activity increased from 0.14 +/- 0.03 U/g tissue in the sham + vehicle group to 2.8 +/- 0.7 U/g in the MI/R + vehicle group (p less than 0.001). Administration of SK (100,000 IU/kg + 50,000 IU/kg/h for 2 h beginning 15 min before coronary artery reperfusion) reduced the loss of CPK specific activity from reperfused myocardium (6.8 +/- 0.5 U/mg protein, n = 23, p less than 0.05 as compared with the MI/R + vehicle group) and attenuated the increase in MPO activity (1.3 +/- 0.4 U/g tissue, p less than 0.05 as compared with the MI/R + vehicle group). This dose of SK did not change plasma fibrinogen concentration, slightly reduced plasminogen activity (i.e., 20% from control value), and markedly reduced alpha 2-antiplasmin activity (i.e., 60% from control values). A lower dose of SK (i.e., 10,000 IU/kg + 5,000 IU/kg/h for 2 h) did not reduce myocardial injury, did not attenuate the increase in MPO activity, and had no effect on the measured hemostatic parameters. Survival in all MI/R groups ranged from 62 to 66%, and there were no differences in survival between any of the groups (p greater than 0.05). In a model of arachidonic acid-induced rat hindpaw inflammation, SK had no effect on the increase in MPO activity, suggesting that the increase in myocardial MPO activity was not due to a direct effect on inflammatory cell accumulation. In in vitro studies, SK (1-1,000 U/ml) did not scavenge superoxide anion produced by purine (10 mM) and xanthine oxidase (10 mU/ml), nor did it reduce superoxide release, beta-glucuronidase release, or neutrophil aggregation of rabbit peritoneal neutrophils activated with fMLP.(ABSTRACT TRUNCATED AT 400 WORDS)
尽管溶栓剂减少人类受试者心肌梗死面积、改善左心室（LV）功能及延长生存期的确切机制尚不清楚，但溶栓剂的益处已得到普遍认可。本研究旨在使用左冠状动脉机械性闭塞和再灌注模型，评估链激酶（SK）对大鼠的心脏保护作用，大鼠对纤溶酶原激活剂的反应性较低。通过分别测量左心室游离壁（LVFW）中的肌酸磷酸激酶（CPK）比活性和髓过氧化物酶（MPO）活性来确定心肌损伤和多形核白细胞（PMN）浸润。冠状动脉闭塞0.5小时并再灌注24小时（心肌缺血，MI/R）后，CPK比活性从假手术+赋形剂组的7.0±0.3 U/mg蛋白降至MI/R+赋形剂组的5.6±0.5 U/mg蛋白（n = 19，p<0.01），而MPO活性从假手术+赋形剂组的0.14±0.03 U/g组织增至MI/R+赋形剂组的2.8±0.7 U/g（p<0.001）。在冠状动脉再灌注前15分钟开始给予SK（100,000 IU/kg + 50,000 IU/kg/h，持续2小时），可减少再灌注心肌中CPK比活性的损失（6.8±0.5 U/mg蛋白，n = 23，与MI/R+赋形剂组相比p<0.05），并减弱MPO活性的增加（(1.3±0.4 U/g组织，与MI/R+赋形剂组相比p<0.05）。该剂量的SK未改变血浆纤维蛋白原浓度，轻度降低纤溶酶原活性（即较对照值降低20%），并显著降低α2-抗纤溶酶活性（即较对照值降低60%）。较低剂量的SK（即10,000 IU/kg + 5,000 IU/kg/h，持续2小时）未减轻心肌损伤，未减弱MPO活性的增加，且对所测止血参数无影响。所有MI/R组的生存率在62%至66%之间，各实验组间生存率无差异（p>0.05）。在花生四烯酸诱导的大鼠后爪炎症模型中，SK对MPO活性的增加无影响，提示心肌MPO活性的增加并非由于对炎症细胞聚集的直接作用。在体外研究中，SK（1 - 1000 U/ml）不能清除由嘌呤（10 mM）和黄嘌呤氧化酶（10 mU/ml）产生的超氧阴离子，也不能减少用fMLP激活的兔腹腔中性粒细胞的超氧阴离子释放、β-葡萄糖醛酸酶释放或中性粒细胞聚集。（摘要截断于400字）
