THE IN-VIVO ANTIPLATELET EFFECTS OF THROMBOXANE-A(2) SYNTHASE INHIBITORS ARE POTENTIATED BY SIMULTANEOUS THROMBOXANE A(2)/PROSTAGLANDIN-H-2 RECEPTOR BLOCKADE

The aim of the present study was twofold: 1) to assess whether inhibition of thromboxane A2 (TxA2) synthase exerts more potent antiplatelet effects when applied concomitantly with TxA2 and prostaglandin (PG)H2 receptor blockade and 2) whether these effects are mediated through redirection of PG endoperoxides toward the synthesis of antiplatelet PGs, such as PGI2 and PGE2. Thus, cyclic flow variations (CFVs), due to recurrent platelet aggregation, were initiated in the stenotic, endothelially injured carotid arteries of 39 rabbits. After 30 min of CFVs, the animals received: 1) SQ29548 (up to 0.6 mg/kg bolus + 0.2 mg kg-1 hr-1, n = 13), a TxA2/PGH2 receptor antagonist; 2) dazoxiben (up to 15 mg/kg bolus + 5 mg kg-1 hr-1, n = 13), a TxA2 synthase inhibitor and 3) picotamide (up to 20 mg/kg bolus + 20 mg kg-1 hr-1, n = 13), a drug with simultaneous TxA2 synthase and receptor blocking properties. CFVs were abolished in 6, 7, and 12 animals treated with SQ29548, dazoxiben, and picotamide, respectively (P < .01 for picotamide versus SQ29548 and dazoxiben). The animals in which CFVs were not abolished by SQ29548 or dazoxiben received the other drug at the same dose. CFVs were abolished by dazoxiben in five of seven rabbits that initially did not respond to SQ29548 and by SQ29548 in five of six animals that did not respond to dazoxiben. All animals that responded to the combination of SQ29548 and dazoxiben, as well as those that responded to picotamide, received increasing intravenous infusions of epinephrine to restore CFVs. Epinephrine restored CFVs in only 2 of 1 0 animals treated with SQ29548 and dazoxiben and 1 of 12 rabbits treated with picotamide. However, administration of aspirin during epinephrine infusion restored CFVs in 7 of 8 SQ29548 and dazoxiben and 9 of 11 picotamide-treated rabbits (P < .01 for both groups). These data demonstrate that: 1) simultaneous inhibition of TxA2 synthase and TxA2/PGH2 receptor blockade is more effective in protecting against spontaneous and epinephrine-induced CFVs; 2) these effects are mediated by redirection of PG endoperoxides toward the synthesis of antiplatelet PGs, as demonstrated by the loss of protective effects after aspirin administration and 3) picotamide, a new compound combining TxA2 synthase and receptor-blocking properties, represents a new class of agents of potential interest for the prevention of arterial thrombosis.