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

The aim of the present study was twofold: 1) to assess whether inhibit ion 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 re direction of PG endoperoxides toward the synthesis of antiplatelet PGs , such as PGI2 and PGE2. Thus, cyclic flow variations (CFVs), due to r ecurrent platelet aggregation, were initiated in the stenotic, endothe lially injured carotid arteries of 39 rabbits. After 30 min of CFVs, t he animals received: 1) SQ29548 (up to 0.6 mg/kg bolus + 0.2 mg kg-1 h r-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, dazoxibe n, and picotamide, respectively (P < .01 for picotamide versus SQ29548 and dazoxiben). The animals in which CFVs were not abolished by SQ295 48 or dazoxiben received the other drug at the same dose. CFVs were ab olished by dazoxiben in five of seven rabbits that initially did not r espond to SQ29548 and by SQ29548 in five of six animals that did not r espond 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 CF Vs. Epinephrine restored CFVs in only 2 of 1 0 animals treated with SQ 29548 and dazoxiben and 1 of 12 rabbits treated with picotamide. Howev er, administration of aspirin during epinephrine infusion restored CFV s in 7 of 8 SQ29548 and dazoxiben and 9 of 11 picotamide-treated rabbi ts (P < .01 for both groups). These data demonstrate that: 1) simultan eous inhibition of TxA2 synthase and TxA2/PGH2 receptor blockade is mo re effective in protecting against spontaneous and epinephrine-induced CFVs; 2) these effects are mediated by redirection of PG endoperoxide s toward the synthesis of antiplatelet PGs, as demonstrated by the los s of protective effects after aspirin administration and 3) picotamide , a new compound combining TxA2 synthase and receptor-blocking propert ies, represents a new class of agents of potential interest for the pr evention of arterial thrombosis.