title: Reduction in myocardial ischemic/reperfusion injury and neutrophil accumulation after therapeutic administration of streptokinase.
abstract: 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)
authors.affiliation: Department of Pharmacology, SmithKline Beecham Pharmaceuticals, plc, King of Prussia, PA 19406.
authors.forename: E F
authors.initials: EF
authors.lastname: Smith
authors.forename: A J
authors.initials: AJ
authors.lastname: Nichols
authors.forename: T S
authors.initials: TS
authors.lastname: Sellers
authors.forename: S R
authors.initials: SR
authors.lastname: O'Brien
authors.forename: D E
authors.initials: DE
authors.lastname: Griswold
authors.forename: J W
authors.initials: JW
authors.lastname: Egan
authors.forename: L M
authors.initials: LM
authors.lastname: Hillegass
authors.forename: J A
authors.initials: JA
authors.lastname: Vasko
authors.forename: M J
authors.initials: MJ
authors.lastname: Slivjak
authors.forename: P A
authors.initials: PA
authors.lastname: Davis
mesh_terms: D000818:Animals; D002449:Cell Aggregation / Q000187:drug effects; D003327:Coronary Disease / Q000503:physiopathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000502:physiology; D005528:Foot / Q000473:pathology; D016166:Free Radical Scavengers; D005966:Glucuronidase / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007249:Inflammation / Q000473:pathology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D009504:Neutrophils / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D010960:Plasminogen Activators / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013300:Streptokinase / Q000627:therapeutic use*; D013481:Superoxides / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D013481:Superoxides; D009195:Peroxidase; D005966:Glucuronidase; D013300:Streptokinase; D010960:Plasminogen Activators