COMPARISON OF THE NITRIC-OXIDE SYNTHASE INHIBITORS METHYLARGININE ANDAMINOGUANIDINE AS PROPHYLACTIC AND THERAPEUTIC AGENTS IN RAT ADJUVANTARTHRITIS

Objective. To compare the nitric oxide synthase (NOS) inhibitors N-G-m ethyl-L-arginine (L-NMA) and aminoguanidine (AG) as prophylactic and t herapeutic agents in rat adjuvant induced arthritis (AIA). Methods. Ar thritis was induced in male Lewis rats by the injection of adjuvant in to the base of the tail. L-NMA or AG was administered twice daily by g astric intubation starting at the time of adjuvant injection, just bef ore the onset of clinical symptoms, or after the onset of clinical sym ptoms. Paw swelling, plasma fibrinogen levels and urinary NO2-/-NO3- e xcretion were measured to assess the effect of the inhibitors on the a rthritis response and whole body NO biosynthesis. Selected joints were also evaluated histopathologically. The abilities of L-NMA, AG and an other NOS inhibitor, N-G-nitro-L-arginine methyl ester (L-NAME), to in hibit NO production by chondrocytes and synoviocytes were also compare d. Results. Treatment with L-NMA (400 mg/kg/day) or AG (500 mg/kg/day) reduced the urinary excretion of NO2-/NO3- to the control level. L-NM A suppressed the development of AIA when administered prophylactically ; however, its antiarthritic properties declined with increasing delay of application. It was only weakly effective against established AIA. AG had neither a prophylactic nor a therapeutic antiarthritic effect. AG and L-NAME were much weaker inhibitors of NO production by chondro cytes and synoviocytes than L-NMA. Conclusion. Although L-NMA complete ly suppresses the development of AIA when administered prophylacticall y, it is much less effective when administered therapeutically. Furthe rmore, not all inhibitors of NOS show equal prophylactic activity agai nst AIA. In addition, NOS inhibitors may be only weakly therapeutic, o r even detrimental, in established disease. These findings should be c onsidered when evaluating NOS inhibitors as potential therapeutic agen ts for the treatment of established human arthritis.