CONCOMITANT TREATMENT WITH A 5-LIPOXYGENASE INHIBITOR IMPROVES THE ANTIINFLAMMATORY EFFECT OF THE INHIBITION OF NITRIC-OXIDE SYNTHASE DURING THE EARLY PHASE OF ENDOTOXIN-INDUCED UVEITIS IN THE RABBIT

Nitric oxide (NO) synthase inhibitors, such as N-G-nitro-L-arginine me thyl ester (L-NAME), have been shown to attenuate endotoxin-induced uv eitis (EIU) but they could increase leukocyte adhesion to the vascular endothe lium. We hypothesize that a concomitant treatment with the 5- lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) in 50% dimethy lsulfoxide (DMSO, a hydroxyl radical scavenger) could improve the anti -inflammatory activity of L-NAME. EIU was induced in albino rabbits by intravitreal injection of 100 ng lipopolysaccharide. Animals were tre ated with multiple intraperitoneal injections of 50% DMSO in phosphate -buffered saline (PBS), NDGA (10 mg/kg) in 50% DMSO, L-NAME (50 mg/kg) in PBS, or the combination NDGA+L-NAME. Uveitis was assessed by slit lamp examination, protein levels in aqueous humor, and myeloperoxidase (MPO) activity in the iris/ciliary body 6 h after induction. Nitrite, leukotriene B-4 (LTB4), prostaglandin E-2 (PGE(2)), platelet-activati ng factor (PAF) and interleukin-1 beta (IL-1 beta) levels in aqueous h umor were also determined. NDGA or L-NAME alone did not show a signifi cant reduction of uveitis intensity, although a significant decrease i n MPO or in proteins was found, respectively. The combination NDGA+L-N AME significantly reduced the uveitis intensity, MPO in the iris/cilia ry body, and the levels of nitrites, LTB4, PGE(2), and PAF in aqueous humor. IL-1 beta levels were lower than the detection limit of the rad ioimmunoassay in all treatment groups. We conclude that concomitant tr eatment with NDGA in DMSO improves the anti-inflammatory activity of L -NAME during the early phase of EIU, suggesting that the inhibition of NO synthesis could enhance leukocyte infiltration and the release of oxygen free radicals.