Successful coronary thrombolysis depends on rapidly restoring blood flow and maintaining patency of the infarct-related artery. Although widely used as an adjunct to lytic therapy, heparin is limited in its ability to produce these effects. Since the limitations of heparin may reflect its inability to inactivate clot-bound thrombin, we developed a rat model of tissue plasminogen activator (t-PA) induced thrombolysis to compare doses of heparin, hirudin, hirulog (a synthetic hirudin-derived peptide), and D-Phe-Pro-ArgCH2Cl (PPACK) that produced a 4-fold prolongation of the baseline activated partial thromboplastin time (APTT) with saline in terms of their ability to accelerate thrombolysis and to prevent reocclusion. A thrombus rich in red cells and fibrin was formed in the distal aorta by applying an external constrictor after denuding the endothelium with a balloon catheter. Thrombolysis was induced with t-PA (1 mg/kg bolus, followed by 1 mg kg-1 h-1 over 30 min) and the rats were then randomized to receive a concomitant 80 min infusion of a thrombin inhibitor or saline. By continuously monitoring blood flow and pre- and post-stenotic blood pressures, the time to clot lysis, and the number of reocclusions were determined. Compared to saline, heparin had no significant effect on these variables.(ABSTRACT TRUNCATED AT 250 WORDS)