We investigated the effects of nexopamil, a combined Ca2+/5-HT2 antagonist on thrombus formation in vivo and on platelet aggregation in vitro. In anesthetized mongrel dogs, cyclic flow reductions (CFRs) in the left anterior descending coronary artery (LAD) were induced by implanting a constrictor after the endothelium was injured mechanically. The CFRs were due to intracoronary thrombus formation. After CFRs were recorded for 1 h, the test compounds were injected intravenously (i.v.) for 2 min. Measurements were made for another hour. Nexopamil (0.05 mg/kg) completely abolished CFRs during the first 30 min after application without significantly altering hemodynamics. The same effect was noted with 0.02 mg/kg ketanserin (5-HT2/α1, antagonist). The Ca2+ antagonist gallopamil reduced CFRs only in the highest hemodynamically tolerable dose by 40%. Serotonin-induced platelet aggregation in dog platelet-rich plasma (PRP) in vitro was most potently inhibited by ketanserin (IC50 0.55 x 10-8M), followed by nexopamil (IC50) 0.81 x 10 -7M) and gallopamil (IC50 1.76 x 10 -6M). Because serotonin is an important pathophysiologic mediator in unstable angina, 5-HT2 receptor antagonism should be of considerable benefit by preventing platelet activation and aggregation. The combination with calcium-antagonistic activity leads to an increase in coronary blood flow (CBF) and a decrease in cardiac oxygen demand. Therefore, the effects noted with nexopamil should be of importance in treating patients with coronary artery disease.