NITRIC-OXIDE SYNTHASE INHIBITORS EXERT DIFFERENTIAL TIME-DEPENDENT EFFECTS ON LPS-INDUCED UVEITIS

Nitric oxide (NO) is a highly reactive radical which plays an integral role in physiological and pathophysiological processes. NO is produce d endogenously in small amounts by a constitutive NO synthase (cNOS) a s a regulator of vascular tone and neurotransmission. NO can also be p roduced in large amounts by an inducible NOS (iNOS) in response to end otoxin and cytokines, and has been reported to be a mediator of lipopo lysaccharide (LPS)-induced uveitis in rats. The purpose of the present study was to investigate the effects of NOS inhibitors with different NOS isoform specificities in the rabbit model of endotoxin-induced oc ular inflammation. LPS and/or inhibitors of NOS, N-G-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG), were injected intravitr eally and the eyes observed by slit lamp for 24 hr. Coinjection of LPS with L-NAME inhibited anterior inflammation in rabbits. Iridal hypere mia (IH) and aqueous flare (AF) were completely abolished in eight out of nine rabbits in a dose-dependent manner. In addition, total cell c ounts were significantly suppressed (7393 +/- 697 vs, 325 +/- 188 P < 0 . 05) and aqueous protein levels were reduced to near control levels (25 +/- 0 . 75 vs, 1 . 72 +/- 0 . 36 P < 0 . 05). Similar suppression was seen with AG (cell counts = 351 +/- 246 and proteins = 3 . 1 +/- 1 . 2). Administration of L-NAME 0 . 5 hr after LPS injection suppress ed inflammation to a lesser extent than coinjection. In contrast, admi nistration of L-NAME 6 hr after LPS injection was not inhibitory, and in fact significantly increased cellular infiltration. However, AG giv en 6 hr after LPS had a remarkably different effect, since it signific antly decreased both protein extravasation and cellular infiltration i nto the aqueous humor. In fact, our results suggest that cNOS may play a greater role in the earlier stages of this developing inflammatory response, These results extend others' observations that NO is a key m ediator in uveitis, that induction of iNOS plays a critical role in ex perimental uveitis, and suggest that NO has a complex role in the ocul ar inflammatory process. Inhibitors of NOS can abort the LPS-induced i nflammatory response if administered early enough, but could potential ly exacerbate an established inflammatory episode. (C) 1996 Academic P ress Limited