ROLE OF NITRIC-OXIDE SYNTHASE ISOZYMES IN ENDOTOXIN-INDUCED UVEITIS

Purpose, The authors previously reported that in vitro treatment with N-G-nitro L-arginine (L- NNA), an inhibitor of nitric oxide synthase ( NOS), reduces aqueous humor (AH) protein and cellular infiltration in endotoxin-induced uveitis in the rat eye. The objective of the current study was to determine the role(s) of respective major forms (constit utive and inducible) of NOS by comparing the effects of relatively sel ective inhibitors of these NOS isozymes. Methods. NG-nitro L-arginine (L-NNA), a relatively selective inhibitor for constitutive NOS (c-NOS) , and N-iminoethyl L-ornithine (L-NIO), a more selective inhibitor for inducible NOS (i-NOS), were administered in vivo. Male Lewis rats wer e footpad injected with bacterial lipopolysaccharide (LPS, 200 mu g) a nd were injected intraperitoneally at 0 hours, 6 hours, or both, after LPS injection with 10 mg of NIO, NNA, or saline as a control, Nitric oxide synthase activity in the ocular tissue and AH protein and cell c ontent were determined at various times after treatment with LPS. Resu lts. After in vivo treatment, L-NIO was found to be a more potent inhi bitor than L-NNA for ocular i-NOS (87% versus 43% inhibition), and L-N NA was more potent than L-NIO for ocular c-NOS (81% versus 39%). Two i njections of L-NNA, one at time 0 and one 6 hours after LPS injection, inhibited the AH protein increase by 71%, but L-NIO did so by only 30 %. L-NNA inhibited cellular infiltration by 86%, whereas L-NIO had no significant effect on cellular infiltration. A significant inhibition of cellular infiltration and AH protein increase also was observed wit h a single injection of 10 mg of L-NNA but not of L-NIO when the inhib itors were given simultaneously with LPS. Thus, reduction of uveitis s ymptoms correlates with the inhibition of c-NOS. Conclusions, The cons titutive form of NOS in ocular tissue, presumably in vascular endothel ial cells, appears to play a critical role at the onset of the develop ment of endotoxin-induced uveitis.