Evaluation of the acute hemodynamic effects and pharmacokinetics of coronary thrombolysis produced by intravenous tissue-type plasminogen activator in the anesthetized dog.

The thrombolytic dose-response effectiveness and pharmacokinetics of tissue-type plasminogen activator (rt-PA) was evaluated in anesthetized, open-chest dogs instrumented for the measurement of systemic hemodynamics. Intracoronary thrombi were formed by injecting thrombin (100 U) and CaCl2 (50 microM) into a cannulated, isolated segment of the left anterior descending coronary artery (LAD). Coronary blood flow was measured by placing an electromagnetic flow probe proximal to the LAD thrombus. Thirty minutes after formation of a stable LAD thrombus, intravenous infusion of rt-PA was given at rates of 0.5, 1, 2, 4, or 8 micrograms/kg/min (n = 8/dose) for 60-90 min, and the animals were followed for an additional 30 min. In vehicle-treated animals, residual thrombus wet weight, determined at the end of the experiment, was 30 +/- 4 mg (mean +/- SEM, n = 8) and spontaneous reperfusion did not occur. The rt-PA produced a dose-related increase in the number of animals reperfusing, a decrease in the time to reperfusion, and a decrease in residual thrombus weight, but had no effect on systemic hemodynamics. The increase in infusion rate from 0.5 to 4 micrograms/kg/min resulted in a linear increase in both the steady-state rt-PA plasma concentration and the area under the rt-PA plasma concentration versus time curve (n = 3-5 animals/dose); between the infusion rates of 4 and 8 microgram/kg/min there was a disproportionate increase in both these parameters that was due to a decrease in the total systemic clearance of rt-PA. The postdosing elimination half-life (t1/2 alpha) did not differ significantly at any dose of rt-PA, and the pooled half-life (t1/2 alpha) for all doses of rt-PA was 2.36 +/- 0.12 min (n = 19).(ABSTRACT TRUNCATED AT 250 WORDS)