Dual inhibition of thromboxane A2 synthesis and thromboxane A2/prostaglandin endoperoxide receptors by ridogrel: anti-thrombotic effect in vivo in rat mesenteric arteries.

In rats treated with acetylsalicylic acid (100 mg/kg i.v., -3 h) to block platelet cyclo-oxygenase, a superfusion with tranylcypromine (TCP, 3 x 10(-3) M) plus arachidonic acid (AA; 1 x 10(-4) M) significantly enhances (+70%) the opto-electronically monitored formation of a thrombus, elicited by a superfusion with ADP (4 x 10(-4) M for 45 s) over a de-endothelialized site of a mesenteric artery (200-300 microns diameter). Treatment with ridogrel at doses blocking either singly thromboxane A2 (TxA2) synthetase (0.63 mg/kg i.v., -15 min, n = 6) or additionally TxA2/prostaglandin endoperoxide receptors (5 mg/kg i.v., -15 min, n = 6) reduces (-74%) or abolishes (-100%) respectively the enhancement by TCP + AA of the ADP-induced thrombus formation. These observations demonstrate (1) a transfer of prostaglandin endoperoxides from the vessel wall to the platelets to reinforce thrombus formation in vivo; (2) the antithrombotic potential of combined TxA2 synthetase inhibition plus TxA2/prostaglandin endoperoxide receptor blockade with ridogrel.