SQ-27986 inhibition of platelet aggregation is mediated through activation of platelet prostaglandin D 2 receptors

Abstract

SQ-27986, a oxabicycloheptane derivative, potently inhibits ADP-, collagen- adn arachidonic acid-induced platelet aggregation in human platelet-rich plasma. Human platelet aggregation induced by ADP is inhibited by SQ-27986 (EC 50 = 22nM), and the inhibitory action of SQ-27986 can be prevented with N-0164, a PGD 2 antagonist. By comparison, ADP-induced rat platelet aggreation is unaffected by SQ-27986 (IC 50 > 80 μM). Washed human platelets treated with SQ-27986 exhibit elevated cAMP leves and activated cAMP-dependent protein kinase. Elevation of platelet cAMP levels (greater than 4 fold basal) and activation of the cAMP-dependent protein kinase (greater than 4 fold) are observed with SQ-27986 concentrations above 100 nM. The SQ-27986-induced elevation of cAMP cna be prevented by N-0164. Lysed platelets treated with SQ-27986 showed stimulated adenylate cyclase activity. SQ-27986 competes with [ 3H]prostaglandin D 2 binding to isolated platelet membranes (EC 50 for SQ-27986 is 20 nM, which was more potent than cold PGD 2 itself). Radiolabeled Iloprost binding is virtually unaffected by SQ-27986 (EC 50 > 100 μM), indicating that SQ-27986 does not interact with platelet prostacylin receptors. These studies indicate that SQ-27986 inhibits platelet aggregation by activating platelet adenylate cyclase via stimulation of platelet PGD 2 receptors.