Effect of thromboxane A(2) inhibition and antagonism on prostaglandin and leukotriene synthesis in glomerular immune injury

In glomerulonephritis there is co-activation of the arachidonic acid cycloo xygenase pathway toward synthesis of prostaglandins (PG) and thromboxane (T x) and of lipoxypenase pathways toward synthesis of hydroxyeicosatetraenoic acids (HETEs) and leukotrienes (LTs). Cyclooxygenase inhibition with non-s teroidal antiinflammatory drugs results in enhanced glomerular LT synthesis with potentially adverse effects on the severity of the inflammation. The effect of Tx inhibition or antagonism on LT synthesis is unknown. Because T xA(2) is the most abundant eicosanoid synthesized in nephritic glomeruli, a nd because TxA(2) synthase inhibitors and receptor antagonists are now avai lable for the treatment of glomerulonephritis, it becomes important to addr ess this question. In this study we assessed the effect of a TxA(2) synthas e inhibitor, Dazmegrel, and a TxA(2) receptor antagonist, SQ-29 548, on glo merular PGE(2), LTB4, and 12-HETE synthesis in a model of mesangial nephrit is induced in the rat by the administration of a monoclonal antibody agains t the Thy 1.1 antigen of rat mesangial cells. Dazmegrel, in doses sufficien t to effectively block glomerular TxA(2) synthesis, significantly increased IP-HETE and PGE(2) synthesis without an effect on the synthesis of LTB4. S Q-29 548 had no effect on glomerular PGE(2), LTB4, or 12-HETE production. B ecause PGE(2) preserves kidney function in glomerulonephritis, and because 12-HETE inhibits 5-lipoxygenase, the enhanced PGE(2) and 12-HETE production within nephritic glomeruli after TxA(2) synthase inhibition may be a super ior anti-inflammatory strategy when compared with TxA(2) receptor antagonis m.