Antithrombotic Properties of the Thromboxane A2/Prostaglandin H2 Receptor Antagonist S18886 on Prevention of Platelet-Dependent Cyclic Flow Reductions in Dogs

A potent thromboxane A2/PGH2 (TP)-receptor antagonist, S18886, was evaluated for its antithrombotic property in a dog model of acute periodic platelet-mediated thrombosis in stenosed coronary arteries with endothelial damage. After thrombosis had been obtained in 11 dogs, S18886 (300 microg/kg bolus) was administered IV. Heart rate, systemic blood pressure, and coronary blood flow were continuously recorded. Ex vivo whole blood platelet aggregation (PA), blood pH, hematocrit, platelet count, PO2, PCO2, and bleeding times were measured before and 30 minutes after administration of S18886. S18886 completely inhibited thrombosis in all dogs in approximately 5-10 minutes. No change in heart rate, blood pressure, pH, PO2, PCO2, platelet count, or bleeding time and a slight but significant elevation in hematocrit occurred. Infusion of epinephrine IV after complete inhibition of thrombosis by S18886 partially restored thrombosis in 3 of the 11 dogs. PA induced by collagen (4 microg/mL), collagen (0.25 microg/mL) plus epinephrine (1 microg/mL), collagen (1 microg/mL) plus epinephrine (1 microg/mL), ADP (40 microM) plus epinephrine (1 microg/mL), and phorbol 12-myristate 13-acetate (0.5 nM) were attenuated by 90 +/- 8% (P < 0.005), 98 +/- 2% (P < 0.05), 78 +/- 6% (P < 0.005), 70 +/- 10% (P < 0.005), and 28 +/- 8% (P < 0.05), respectively. In conclusion, S18886 is a potent platelet inhibitor that attenuates in vivo platelet-dependent thrombosis in the experimental dog model and reduces ex vivo platelet aggregation.