Cardioprotection and thrombolysis by anistreplase in anesthetized dogs

Anistreplase is a thrombolytic agent comprising a complex of streptokinase, lys-plasminogen, and a p-anisoyl group, which temporarily protects the catalytic center of the enzyme complex. Streptokinase was previously shown to reduce infarct size (IS) in dogs with a fibrin-rich clot in the left anterior descending coronary artery (LAD) without necessarily producing reperfusion. Therefore, we hypothesized that IS in this model would be reduced by anistreplase. In addition, we studied the effect of tissue-type plasminogen activator (t-PA) on IS, testing our hypothesis in anesthetized dogs in which thrombin (100 U) and calcium (50 μl, 0.05 h were sequentially injected into the LAD to form a thrombus, anistreplase [0.01, 0.05, or 0.10 U/kg intravenous (i.v.) bolus], t-PA (0.1, 0.5, 2, or 8 μg/kg/min infusion for 60 min) or vehicle (VEH) was administered 55 min later. Anistreplase (0.05 or 0.10 U/kg) significantly (p<0.05) reduced clot weight (VEH 22±3 mg; anistreplase 0.05 U/kg, 13±4 mg; anistreplase 0.10 U/kg, 0.7±0.6 mg), increased incidence of reperfusion (VEH 0%; anistreplase 0.05 U/kg, 42%; anistreplase 0.10 U/kg, 100%) and reduced IS (VEH 23±3%; anistreplase, 0.05 U/kg, 14±2%; anistreplase 0.10 U/kg, 15±2%). t-PA reduced thrombin weight (VEH 26±3 mg; 2 μg/kg/min t-PA 12± 4; 8 μg/kg/min t-PA 2±2 mg) and increased incidence of reperfusion (VEH 0%; 2 μg/kg/min 75%; 8 μg/kg/min 100%), but IS was not altered (VEH 19±3%; 0.1 μg/kg/ min 18±3%; 0.5 μg/kg/min 23±2%; 2 μg/kg/min 16± 5%; 8 μg/kg/min: 19±3%). Moreover, anistreplasetreated dogs who did not reperfuse also had a smaller infarct. Because anistreplase but not t-PA reduced IS in animals that did not reperfuse or exhibit reduction in clot weight, the cardioprotective effect of anistreplase is independent of early reperfusion of the ischemic myocardium