Inhibition of thromboxane (TX) A2 with aspirin enhances the response to coronary thrombolysis. However, experimental evidence suggests that platelet activation during coronary thrombolysis is mediated by a number of agonists, in addition to TXA2. As a consequence, greater benefit would be expected with antiplatelet agents that have a broader spectrum of activity. However, a recent clinical trial, combining tissue plasminogen activator (t-PA) with the prostacyclin analog, iloprost, did not detect such a benefit. To address the mechanism of this response, we compared the effect of iloprost, a stable analog of prostacyclin, with GR32191, a TXA2/prostaglandin endoperoxide receptor antagonist, on the response to i.v. t-PA in a closed chest, canine model of coronary thrombosis. GR32191 reduced the time to reperfusion by 47% (n = 6, P less than .05), consistent with a role for TXA2-mediated platelet activation in impairing thrombolysis. In contrast, iloprost increased the time to reperfusion by 50% (n = 5, P = NS) and in four of nine animals reperfusion failed to occur despite inhibition of platelet aggregation. In a separate series of experiments, steady-state plasma t-PA clearance increased by 38% (407 +/- 49 vs. 294 +/- 42 ml/min; n = 8, P less than .02) during infusion of iloprost and recovered after its withdrawal. This appeared to be a specific effect, as infusion of nitroglycerin at a dose which induced a similar fall in blood pressure altered neither the time to reperfusion nor plasma t-PA. Iloprost impairs the thrombolytic response to t-PA via an increase in the clearance of this agent.