SQ 28,668 is a thromboxane receptor antagonist. In whole blood and platelet-rich plasma, micromolar concentrations of SQ 28,668 inhibited aggregation of human and porcine platelets induced by arachidonate and U-46,619, and the secondary phase of epinephrine-induced aggregation of human platelets. SQ 28,668 did not inhibit ADP-induced platelet aggregation and did not influence cAMP concentrations. High concentrations of SQ 28,668 inhibited platelet thromboxane synthase (IC50 = 660 microM), but SQ 28,668 did not inhibit cyclooxygenase or prostacyclin synthetase. In anesthetized pigs with pacing-induced tachycardia, placement of a critical stenosis at a focus of coronary vascular injury initiated a reproducible pattern of coronary blood flow reduction, reflecting thrombus formation at the site of injury. Treatment with SQ 28,668 (1.0 mg/kg, i.v.) abolished reductions in coronary blood flow in five of six pigs for 58 +/- 7 min and slowed the rate of blood flow reduction in the sixth. Before SQ 28,668 treatment, the rate of blood-flow reduction averaged 5.3 +/- 0.7 ml/min per min. Thirty and sixty minutes after treatment, the rates of blood-flow reduction averaged 0.6 +/- 0.6 and 2.1 +/- 1.0 ml/min per min, respectively (P less than 0.05). In control pigs, the rate of blood flow reduction before and 30 min after vehicle treatment averaged 5.7 +/- 2.0 and 5.5 +/- 1.6 ml/min per min, respectively (not significant). These findings indicate that SQ 28,668 is an effective antiplatelet agent in vitro and in vivo.