In Vitro And In Vivo Effects Of An Inhibitor Of Thromboxane Synthetase

Abstract

UK-37,248, 4-(2-(lH-imidazol-l-yl)ethoxy)benzoic acid hydrochloride, completely inhibits platelet aggregation in plasma by low concentrations of arachidonic acid at 0.5 uM and thromboxane B2(TXB2) generation in washed platelets at 10 uM. In the latter test system the total amount of cyclooxygenase metabolites is unaltered, the decrease in TXB^ and hydroxyhepatadecatrienoic acid being compensated by an increase in prostaglandins E2 and F2α . Arachidonic acid challenged platelets pretreated with UK-37,248 do not accumulate cyclic AMP ; they however strongly stimulate the production of prostacyclin by aspirin pretreated cultured endothelial cells.In a double blind placebo controlled study ingestion of 200 mg of the compound resulted in a complete inhibition of arachidonic acid induced platelet aggregation, whereas the threshold concentration for irreversible platelet aggregation with ADP was unaltered. Serum TXB2 levels were markedly decreased from the normal pre-values (200-700 pg/ml) to low (60-80 pg/ml). Stimultaneous plasma 6-keto prostaglandin F2α , levels from citrate blood increased from 46 ± 23 pg/ml (mean ± SD) to 409 ± 185 pg/ml).It is concluded that a thromboxane synthetase inhibitor modifies cyclic endoperoxide metabolism in such a way that there is not only a decreased formation of pro-aggregatory thromboxane A2 but also an increased production of antiaggregatory prostacyclin. Thromboxane-synthetase inhibitors may be superior to aspirin as antithrombotic agents. The platelet function defect induced by UK-37,248 is only distinct from that in congenital thromboxane synthetase deficiency in that in the latter condition ADP aggregation always is reversible and arachidonic acid challenged platelets accumulate cyclic AMP (Defreyn et al, 1981). Probably UK-37,248, like imidazole itself, activates phosphodiesterase, thus abolishing part of its anti-aggregating effect.