Antithrombotic properties of the thromboxane A2/prostaglandin H2 receptor antagonist S18886 on prevention of platelet-dependent cyclic flow reductions in dogs

A potent thromboxane A(2)/PGH(2) (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 I I dogs, S 18886 (300 mu g/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, P-O2, P-CO2, 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, P-O2, P-CO2, 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 I I dogs. PA induced by collagen (4 mu g/mL), collagen (0.25 mu g/mL) plus epinephrine (1 mu g/mL), collagen (I mu g/mL) plus epinephrine (I mu g/mL), ADP (40 mu M) plus epinephrine (I mu g/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, S 18886 is a potent platelet inhibitor that attenuates in vivo platelet-dependent thrombosis in the experimental dog model and reduces ex vivo platelet aggregation.