Thrombolysis with Recombinant Human Single-Chain Urokinase-Type Plasminogen Activator (rscu-PA): Dose-Response in Dogs with Coronary Artery Thrombosis

Abstract

The dose-response of an intravenous i.v. infusion for 30 min of recombinant human single-chain urokinase-type plasminogen activator (rscu-PA) was investigated in dogs with 1-h-old clots in the left anterior descending coronary artery. The clots were induced with a copper coil, and thrombolysis was monitored by repeated coronary angiography. Intravenous infusion of rscu-PA at a rate of 2 micrograms/kg/min did not induce lysis within 30 min (n = 4). Infusion at a rate of 4 micrograms/kg/min in 7 dogs produced complete lysis in 2 (within 25 and 27 min), partial lysis in 2 (within 18 and 25 min), and no lysis in 3. Infusion at 8 micrograms/kg/min in four dogs caused complete lysis in three dogs within 18 +/- 3 min (mean +/- SD) and partial lysis in the fourth animal. Infusion at 20 micrograms/kg/min in four dogs induced complete lysis within 14 +/- 3 min. A linear correlation was observed between the infusion rate and the plateau level of rscu-PA in blood. At the highest infusion rate (20 micrograms/kg/min), the concentration of rscu-PA in blood was 2.5 +/- 0.45 microgram/ml, but this was not associated with systemic fibrinolytic activation because the alpha 2-antiplasmin and fibrinogen levels remained essentially unchanged. It is concluded that i.v. infusion of recombinant single-chain urokinase-type plasminogen activator (rscu-PA) at a sufficiently high rate (greater than or equal to 8 micrograms/kg/min) produces coronary thrombolysis without systemic fibrinolysis in dogs.