We wished to characterize MDL 28,133A (1-(4-fluorophenyl)-2-[4-[(4-methanesulfonamidophenyl)carbonyl]-1- piperidinyl-ethanone HCl), a potent 5-HT2 receptor antagonist, on platelet aggregation and platelet thrombosis and determined its effect on thrombolysis with streptokinase (SK) in dogs with coronary thrombosis. MDL 28,133A and ritanserin, 0.3-1 microM, competitively inhibited 5-HT-induced platelet aggregation in dog platelet-rich plasma (PRP) in vitro. The pA2 values and slopes were 6.29 +/- 0.09, -0.96 +/- 0.14, and 6.58 +/- 0.09, =1.64 +/- 0.34 for MDL 28,133A and ritanserin, respectively, suggesting that both agents are similar in potency to 5-HT2 receptor antagonists. MDL 28,133A (0.01 mg/kg, p.o.) produced inhibition of arachidonic acid-induced platelet aggregation in whole blood from conscious dogs ex vivo for > or = 2 h, indicating oral bioavailability. The magnitude and duration of the effect of MDL 28,133A on platelet aggregation in whole blood was similar to that of ketanserin (2.5 mg/kg, p.o.). MDL 28,133A (0.001-0.03 mg/kg, i.v.) completely abolished cyclic flow reductions (CFRs) in stenosed and partially deendothelialized left anterior descending coronary arteries of anesthetized dogs for at least 120 min without affecting systemic blood pressure (BP) and heart rate, thus indicating that MDL 28,133A is a potent antithrombotic agent. Ketanserin (0.5 mg/kg, i.v.) also abolished CFRs, but produced a significant decrease in systemic BP as well. MDL 28,133A (0.001 mg/kg, i.v.) shortened time to reperfusion (15 +/- 1 vs. 36 +/- 8 min), prolonged time to reocclusion (112 +/- 6 vs. 85 +/- 6 min), and increased total volume reflow (20 +/- 2 vs. 10 +/- 2%) in dogs with coronary artery thrombosis undergoing thrombolysis with SK (1,000 U/min, i.a.). Reocclusion rate was not affected by MDL 28,133A (4 of 5 vs. 4 of 6). Treatment with heparin (150 U/kg, i.v. every hour for 2 h) alone or in combination with MDL 28,133A did not improve time to reperfusion but enhanced total volume reflow and prevented reocclusion. MDL 28,133A is a potent 5-HT2 receptor antagonist that inhibits platelet thrombosis and facilitates thrombolysis in vivo. The impeding effect of MDL 28,133A in coronary thrombosis and the lack of hemodynamic effects suggests that MDL 28,133A may be of benefit in treatment of hyperthrombotic conditions without having hemodynamic side effects.