SUPPRESSION OF ADJUVANT ARTHRITIS AND SYNOVIAL MACROPHAGE INDUCIBLE NITRIC-OXIDE BY N-IMINOETHYL-L-ORNITHINE, A NITRIC-OXIDE SYNTHASE INHIBITOR

Nitric oxide (NO.) is a pro-inflammatory effector molecule in certain inflammatory diseases, including arthritis. We investigated the produc tion of NO. by adjuvant arthritis (AA) synovial macrophages, and studi ed the effects of a NO. synthase inhibitor, N-iminoethyl-L-ornithine ( L-NIO). Compared to control rats, rats treated with L-NIO in vivo exhi bited significantly lower articular index (p < 0.05), paw volume (p < 0.05), and synovial fluid cell count (p < 0.05). No effect on cutaneou s delayed-type hypersensitivity to the disease-initiating antigen was observed. Inducible NO. synthase (iNOS) was detected in AA synovial ma crophages, and cultured AA synovial macrophage iNOS levels were increa sed by a factor of 138 +/- 17% (p < 0.01) by 1 mu g/ml LPS in vitro. C onstitutive NO. production by AA synovial macrophages (43 +/- 1 nmol/1 0(5) cells/24 h) was significantly inhibited by 10 mM L-NIO in vitro ( 32 +/- 0.5, p < 0.01). NO. production induced by 1 mu g/ml LPS (48 +/- 2) was also decreased by L-NIO (39 +/- 2, p < 0.05). In vivo L-NIO tr eatment also inhibited alveolar macrophage NO. production (p < 0.05). The ability of L-NIO to decrease iNOS-mediated synovial macrophage NO. production and inhibit the clinical parameters of AA implicate macrop hage-derived NO. in the pathogenesis of this disease.