Modulation of nitric oxide synthesis in inflammation - Relationship to oxygen-derived free radicals and prostaglandin synthesis

The role of nitric oxide (NO) derived from constitutive (cNOS) and inducibl e (iNOS) nitric oxide synthases and its relationship to oxygen-derived free radicals and prostaglandins was investigated in two models of inflammation , namely, carrageenan granuloma air pouch (acute model) and Freund's adjuva nt-induced arthritis (chronic model) in rats. Inflammation was assessed by measurement of NO and prostaglandin E-2 (PGE(2)) levels and the lysosomal l eakage of the enzyme N-acetyl-B-D-glucosaminidase (NAG) into the exudate of the granuloma pouch 4 h after carrageenan injection. Evaluation of paw vol ume and determination of serum NO, lipid peroxide (LP), and PGE(2) levels w ere used for the assessment of adjuvant-induced arthritis after either 4 da ys (early phase) or 16 days (late phase) of adjuvant injection. Results of the study showed that the administration of either N-G-nitro-L-arginine met hyl ester (L-NAME, non-selective cNOS/iNOS inhibitor) or aminoguanidine (AG , selective iNOS inhibitor), prior to carrageenan injection or during devel opment of adjuvant arthritis, caused a significant reduction in NO and PGE( 2) levels and in the NAG activity of the granuloma inflammatory exudate, wh ereas decreases in paw volume and in serum NO level were noticed in the adj uvant model as related to untreated rats. Similar treatment with L-arginine failed to elaborate a significant change in the parameters measured. Other observations included: no noticeable differences between the results of ea rly and late phases of adjuvant arthritis; no clear correlation between NO, LP and PGE(2) levels in the adjuvant arthritis inflammation and inability of the NOS inhibitors to modify the levels of serum LP that is increased du ring adjuvant-induced arthritis. The data give further evidence that NO is implicated in the development of both acute and chronic inflammation and th at NOS inhibitors have potential antiinflammatory activity. Further studies are required to unravel the mechanisms by which NO interacts with other me diators of inflammation.