Hirudin and sulotroban improve coronary blood flow after reperfusion induced by the novel recombinant plasminogen activator BM 06.022 in a canine model of coronary artery thrombosis.

Thrombus formation in anesthetized, open-chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery. One-hour postocclusion, administration of vehicle to heparinized dogs (n = 12) did not induce reperfusion despite concomitant treatment with acetylsalicylic acid (ASA), sulotroban, or saline. Intravenous bolus injection of 140 kU/kg (= 0.24 mg/kg) of the unglycosylated t-PA variant BM 06.022 induced reperfusion in 4 out of 6 dogs, followed by flow deterioration. Pretreatment with i.v. ASA did not improve coronary blood flow (CBF). Conjunctive treatment with the thromboxane A2-receptor antagonist, sulotroban, (10 mg/kg i.v. bolus, followed by 10 mg/kg/h) or with recombinant hirudin, a specific thrombin inhibitor, (1 mg/kg/h) 30 min prior to i.v. injection of BM 06.022, prolonged (p < 0.01) the cumulative patency time (sum of time-intervals in which the coronary artery was patent) to 147.4 +/- 9.2 min in 4 out of 6 reperfused dogs and 129.9 +/- 12.3 min in 7 out of 8 dogs, respectively, compared to the saline plus BM 06.022 treatment (47.5 +/- 13.1 min) in 4 out of 6 dogs. The terminal CBF was higher (p < 0.01) after sulotroban plus BM 06.022 (7.0 +/- 1.7 ml/min) and hirudin plus BM 06.022 (6.3 +/- 1.5 ml/min) than after saline plus BM 06.022 (0.8 ml/min). These findings demonstrate that drugs with antithromboxane or antithrombin activity may improve CBF after reperfusion.