This study was designed to compare the efficacy of coronary thrombolysis obtained with i.v. administration of three dose regimens of recombinant tissue plasminogen activator (rtPA). Although many studies have confirmed the efficacy of thrombolytic therapy in treatment of acute myocardial infarction, few prospective studies have been designed to determine which dose regimen optimizes the rate of coronary thrombolysis. A canine model was used. Coronary thrombosis was induced by injection of radioactive, autologous blood clots through a catheter placed in the left anterior descending coronary artery. Subsequently, 15 dogs were randomized into 3 groups of 5 dogs each. In group 1 dogs, 1.25 mg/kg of rtPA was administered i.v. as a bolus; in the group 2 dogs, 1.25 mg/kg of rtPA was administered over 60 min. The administration was "front loaded" so that 15% was administered as a bolus, 60% over 30 min, and 25% over 30 min; in group 3, 1.25 mg/kg of rtPA was divided into two i.v. boluses and administered 15 min apart. Coronary thrombolysis was assessed with a gamma camera. Despite differences in rate of administration of rtPA, at 15, 30, and 90 min after onset of treatment, extent of clot lysis was similar between groups. These results indicate that despite differences in dose regimens, rates of thrombolysis are similar when i.v. rtPA is relatively rapidly administered. Further, the similar rates of clot lysis over time between groups suggest both an effective upper limit to the dose-thrombolytic rate relationship and relatively high, sustained steady-state plasma concentrations of rtPA.