title: A comparative evaluation of thromboxane receptor blockade, thromboxane synthase inhibition and both in animal models of arterial thrombosis.
abstract: The combination of thromboxane (TX) synthase inhibition and prostaglandin (PG) H2/TXA2 receptor antagonism yields enhanced antithrombotic effects as compared with either intervention alone. However, it is not known whether the enhancing effect of TX synthase inhibition is expressed also in the presence of complete blockade of PGH2/TXA2 receptors. Thus we evaluated the antithrombotic effects of increasing doses of the PGH2/TXA2 receptor antagonist L 670596 alone and in combination with a dose of the TX synthase inhibitor FCE 22178 causing > 95% inhibition of platelet TXB2 production. In the dog model of electrically induced coronary thrombosis, occlusion time in control animals (n = 14) averaged 72 +/- 29 min. L 670596 alone dose-dependently antagonized platelet PGH2/TXA2 receptors and prolonged occlusion time. The addition of FCE 22178 displaced the dose-occlusion time relation of L 670596 in a parallel fashion without modifying receptor occupancy. In the rabbit model of copper coil-induced carotid artery thrombosis, occlusion was very rapid (14 +/- 4 min) in control animals (n = 17) and was not modified by either aspirin or FCE 22178. L 670596 caused a dose-related receptor blockade and prolongation of occlusion time. The association with FCE 22178 enhanced significantly the antithrombotic effect of L 670596 at all doses. We conclude that the full therapeutic potential of PGH2/TXA2 receptor antagonism is expressed at > 90% platelet receptor occupancy. The additive effect of TX synthase inhibition suggests that conversion of PGH2 to platelet-inhibitor and vasodilator prostaglandins might be of therapeutic importance, irrespective of the extent of PGH2/TXA2 receptor blockade.
authors.affiliation: Farmitalia Carlo Erba Research Laboratories, Nerviano, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Salvati
authors.forename: L
authors.initials: L
authors.lastname: Dho
authors.forename: G
authors.initials: G
authors.lastname: Ukmar
authors.forename: L
authors.initials: L
authors.lastname: Vaga
authors.forename: O
authors.initials: O
authors.lastname: Rimoldi
authors.forename: C
authors.initials: C
authors.lastname: Patrono
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D003300:Copper; D003328:Coronary Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004285:Dogs; D005069:Evaluation Studies as Topic; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000378:metabolism; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000037:antagonists & inhibitors
chemical_list: D002227:Carbazoles; D007093:Imidazoles; D009281:Naphthalenes; D011463:Prostaglandins H; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013931:Thromboxanes; C061299:L 670596; D044262:Prostaglandin H2; D013929:Thromboxane B2; D003300:Copper; D013930:Thromboxane-A Synthase; C066217:rolafagrel