L8027 and 1-nonyl-imidazole as non-selective inhibitors of thromboxane synthesis

Abstract

The inhibition of prostaglandin-related actions on the platelets, respiration and hemodynamics of guinea pigs by 1-(isopropyl-2-indolyl)-3-pyridyl-3-ketone (compound L8027) and by 1-nonyl-imidazole (NI) was studied. L8027 (1–10 μg/kg, i.v.) inhibited arachidonic acid (AA)-initiated bronchoconstriction, thrombocytopenia and hypotension in a dose-dependent and reversible manner. NI, however, in doses as high as 8 mg/kg did not inhibit these actions. AA-induced platelet aggregation was antagonized by L8027 (50–500 nM) and NI (25–100 μM), and this action was dose-dependent and competitive. Thromboxane A2 (TxA2) synthesis in blood and platelets, as measured by the rabbit aorta bioassay, was suppressed in a concentration-related manner by L8027 at anti-aggregatory doses. NI did not inhibit TxA2 synthesis in guinea-pig platelet-rich plasma (PRP) at concentrations which blocked platelet aggregation. However, it did block TxA2 synthesis in rabbit and human PRP and in washed guinea-pig platelets, indicating a species or plasma specificity. Both compounds inhibited ATP release from platelets as they inhibited aggregation. The radioimmunoassay revealed that L8027 decreased formation of both TxB2 and PGE2, unlike imidazole which only blocked formation of TxB2 and resulted in an increase of PGE2. These results show that although L8027 does block TxA2 formation, it is not a selective antagonist and it inhibits cyclo-oxygenase as well. NI appears to have the ability to act via mechanisms other than prostaglandin metabolism.