REGULATORY INTERACTIONS BETWEEN INDUCIBLE NITRIC-OXIDE SYNTHASE AND EICOSANOIDS IN GLOMERULAR IMMUNE INJURY

In a rat model of glomerular immune injury induced by administration o f anti-glomerular basement membrane antibody and resembling human rapi dly progressive glomerulonephritis, we explored whether activation of inducible nitric oxide synthase (iNOS) regulates synthesis of eicosano ids originating from cyclooxygenation or lipoxygenation of arachidonic acid. At early stages (24 hr) of injury, inhibition of iNOS using the selective inhibitor L-N-6-(1-iminoethyl) lysine (L-NIL) at doses suff icient to reduce urinary excretion of nitrate/nitrite, reduced glomeru lar synthesis of the prostaglandins PGE, and PGI(2), but had no effect on that of thromboxane A(2) (TxA(2)). The syntheses of 5-hydroxyeicos atetraenoic acid (HETE), 15-HETE and leukotriene B-4 (LTB4) were also reduced. That of 12-HETE remained unchanged. We also explored the effe ct of arachidonate cyclooxygenation and lipoxygenation eicosanoids on iNOS expression. Administration of the cyclooxygenase (COX) inhibitor, indomethacin, at doses sufficient to inhibit glomerular prostaglandin synthesis, increased iNOS mRNA levels in glomeruli. Administration of the 5-lipoxygenase (5-LO) inhibitor, MK-0591, at doses sufficient to inhibit glomerular LTB4 synthesis also increased iNOS mRNA. The effect of 5-LO inhibition on iNOS expression was more pronounced than that o f COX inhibition. In nephritic animals given the iNOS inhibitor, L-NIL , or indomethacin proteinuria worsened. In those given the 5-lipoxygen ase inhibitor there was no change in urine protein excretion. These ob servations point to regulatory interactions between the arachidonic ac id and the L-arginine:NO pathways in glomerulonephritis. These interac tions are of importance in considering antiinflammatory strategies bas ed on inhibition of iNOS or of specific eicosanoids.