The present investigation was undertaken to produce and to validate a canine model of experimental coronary artery thrombosis. In anesthetized, open-chest dogs, thrombin (150-200 U) was injected through an intracoronary catheter proximal to a brief (1 min) left anterior descending coronary artery occlusion. After 1 min, the mechanical occlusion was released, but no reperfusion occurred. Intracoronary thrombus was limited to the large coronary artery proximal to the site of mechanical occlusion. In two groups of dogs (n = 8), 15 min following thrombosis, vehicle (saline) or streptokinase (20,000 IU) was administered as an intracoronary bolus followed by an intracoronary infusion for 1 hr. None of the vehicle-treated dogs demonstrated antegrade coronary flow for up to 4 hr following intracoronary thrombin, whereas seven of eight had return of antegrade flow among streptokinase-treated dogs. Following streptokinase, thrombus size was reduced from control (25.1 +/- 5.3 mg versus 1.8 +/- 1.3 mg), perfusion to the subepicardium, midmyocardium, and subendocardium was increased, and infarct size was reduced. The results of the present study indicate the usefulness and reproducibility of this model in evaluating the beneficial actions of thrombolytic therapy.