We investigated effects of two dosing regimes of recombinant tissue plasminogen activator (rt-PA) and sodium heparin on pulmonary thrombolysis in a canine model of pulmonary hypertension, induced by injection of radioactive blood clots. By continuously counting over both lung fields with a mobile gamma camera, we correlated rate and extent of pulmonary thrombolysis with corresponding pulmonary hemodynamics. Treatment with heparin, over a 3-hour interval, did not result in significant thrombolysis or in a decrease in mean pulmonary artery pressure (PAP). In contrast, rt-PA caused marked pulmonary thrombolysis. While total clot lysis was similar when 1 mg/kg rt-PA was infused over 15 (rt-PA15) or 90 (rt-PA90) minutes (47% and 42%, respectively), rate of lysis during infusion was markedly increased with rt-PA15 (56% vs. 27%/hr, p less than 0.001). Corresponding to the increased rate of thrombolysis with rt-PA15, relative PAP decrease was greater at 15 and 30 minutes. At 4 hours, PAP decreased most with rt-PA90. However, two of the six dogs given rt-PA15 had an increase in PAP and lung radioactivity 1 hour after rt-PA. This was associated with dislodgment of a previously trapped clot. These results suggest that rt-PA may be appropriate therapy for pulmonary embolism and support further studies designed to optimize dosing regimes.