THROMBOXANE SYNTHASE INHIBITORS SUPPRESS MORE EFFECTIVELY THE AGGREGATION OF THROMBOXANE RECEPTOR-DESENSITIZED THAN THAT OF NORMAL PLATELETS - ROLE OF ADENYLYLCYCLASE UP-REGULATION

Exposure of human platelets to U46619, a thromboxane (Tx) A(2) mimetic , desensitizes the TxA(2)/prostaglandin (PG) H-2 receptor and sensitiz es adenylylcyclase to stimuli, such as PGI(2) or PGD(2). This phenomen on may occur in vivo in conditions associated with platelet activation , Tx synthase inhibitors produce a rediversion of arachidonic acid met abolism toward the adenylylcyclase stimulators PGD(2) and PGI(2). We a ssessed whether the desensitization of the platelet TxA(2) receptor af fects the antiplatelet activity of drugs acting on the arachidonic aci d metabolic cascade. A Tx synthase inhibitor (OKY046), a PGH(2)/TxA(2) receptor antagonist (BM13.505), their combination, two dual Tx syntha se inhibitors/receptor antagonists (picotamide and ridogrel) or the cy clooxygenase inhibitor aspirin were studied. OKY046 alone or combined with BM13.505, picotamide and ridogrel, as well as PGD(2), but not BM1 3.505 or aspirin, caused a stronger inhibition of platelet aggregation with desensitized platelets; this effect was potentiated by the phosp hodiesterase inhibitor HL725 and was almost abolished by the adenylylc yclase inhibitor SQ22,536. A larger increase in cAMP synthesis was obs erved in desensitized as compared with control platelets with a Tx syn thase inhibitor or with dual Tx synthase inhibition/receptor antagonis m. No differences were observed in the degree of TxA(2) suppression. O ur observations showed that Tx synthase inhibitors exerted a stronger antiaggregatory effect in TxA(2) receptor-desensitized platelets due t o a stimulation of adenylylcyclase. This can be of relevance in the tr eatment of thrombotic disorders in which an in vivo desensitization of platelet TxA(2) receptors takes place.