ENDOTOXIN-INDUCED UVEITIS IN THE RAT IS ATTENUATED BY INHIBITION OF NITRIC-OXIDE PRODUCTION

Purpose. These experiments were undertaken to assess the role of incre ased nitric oxide production in the pathogenesis of vascular dysfuncti on associated with endotoxin-induced uveitis. Methods. Lipopolysacchar ides (LPS) (100 mu g of Salmonella minnesota) was injected into footpa ds of Lewis rats randomly assigned to an untreated group or to a group treated with subcutaneous injections of aminoguanidine, a selective i nhibitor of the inducible isoform of nitric oxide synthase (iNOS). Con trols included untreated and aminoguanidine-treated rats. Twenty to 24 hours later, blood flow and vascular I-125-albumin permeation were qu antified in ocular tissues. Eyes were graded histologically for leukoc yte infiltration into the anterior uvea and anterior chamber, and leuk ocyte counts were performed on aqueous fluid. Plasma nitrate levels we re measured fluorometrically after enzymatic reduction to nitrite. Res ults. Lipopolysaccharides markedly increased plasma nitrate levels and I-125-albumin permeation in aqueous fluid, retina, anterior uvea, and choroid-sclera. Blood flow was increased only in the anterior uvea. A minoguanidine normalized plasma nitrate levels and prevented or signif icantly ameliorated the I-125-albumin permeation and blood flow change s in ocular tissues. The increased aqueous fluid content of lymphocyte s and neutrophils in LPS-treated rats, as well as the increased histol ogic score of iritis, were significantly reduced by aminoguanidine. Co nclusions. These results suggest that the hemodynamic and vascular per meability changes associated with endotoxin-induced uveitis are mediat ed in large part by increased production of nitric oxide.