N‐Monomethyl arginine, an inhibitor of nitric oxide synthase, suppresses the development of adjuvant arthritis in rats

Abstract

Objective. To test the hypothesis that nitric oxide (NO) is involved in the pathophysiology of arthritis.Methods. Arthritis was induced in male Lewis rats by the injection of adjuvant into the base of the tail. The NO synthase (NOS) inhibitor, NG-monomethyl-Larginine (L-NMA), was administered daily by the oral route for 19 days. Paw swelling, plasma fibrinogen levels, and urinary NOJNO, levels were measured to assess the effect of L-NMA on the arthritic response and whole-body NO production, respectively. On day 20, the ankle joints were processed for histopathologic evaluation.Results. The onset of clinical symptoms was preceded by elevated biosynthesis of NO. In a dosedependent manner, L-NMA inhibited both NO biosynthesis and paw swelling; histopathologic changes in the ankle joints were also prevented. D-NMA had no effect on the development of arthritis, while L-arginine reversed the effects of L-NMA. Fibrinogen levels in rats with arthritis were unaffected by L-NMA.Conclusion. NO is critical to the development of both the inflammatory and erosive components of adjuvant arthritis in rats. There may be a future clinical role for suitable inhibitors of NO production or activity.Rheumatoid arthritis is a chronic, incurable disease characterized by joint swelling, synovial in- flammation, and cartilage destruction. Antagonism of the mediators which drive these pathophysiologic changes represents one approach to improving the treatment of this condition. Such an endeavor requires the prior identification of the appropriate mediators. In a recent review (I), it was suggested that nitric oxide (NO) should be investigated in this regard; the present paper reports the results of a study that was designed to do so.In vitro studies have demonstrated that both the resident mesenchymal cells of the joints and the leukocytes which enter joints during inflammation have the capacity to synthesize considerable amounts of NO. Thus, cultures of articular chondrocytes (2,3) and synoviocytes (4) produce high levels of NO following activation by interleukin-1, a cytokine present in rheumatoid synovial fluids. Macrophages (9, polymorphonuclear leukocytes (6), mast cells (7), and, possibly, lymphocytes (8) are additional potential sources of NO in inflamed joints. Analysis of synovial fluids (9,lO) from arthritic joints has confirmed the presence of elevated amounts of nitrate and nitrite, the stable end products to which NO spontaneously oxidizes in vivo. Previous animal studies have implicated NO in inflammation (1 I), immunity (12), and tissue destruction (13).NO is synthesized by the enzyme NO synthase (NOS), which exists as several isozymes (14), the main distinction being between constitutive (cNOS) and inducible (iNOS) forms. Cells that contain cNOS quickly and transiently produce small amounts of NO in response to agonists which raise intracellular Ca2' concentrations, while cells with iNOS produce large amounts of NO for a prolonged period following a lag of several hours during which the enzyme is induced.Chondrocytes (2),...

Nitric oxide production during adjuvant‐induced and collagen‐induced arthritis

“…The second phase of AIA is the development of inflammatory arthritis, which is temporally associated with an increase in multiple cytokines (including interleukin-1 [IL-11, IL-2, IL-6, tumor necrosis factor a [TNFa], and interferon-y) (1,12), an increase in NO production (27)(28)(29)(30)(31), and a rise in circulating acute-phase reactants (lJ2). As a composite, these abnormalities are a hallmark of the intense systemic and local inflammatory response seen in AIA; however, the contribution of each component to disease progression is uncertain.…”

“…Other investigators have reduced the severity of AIA (28,32,33) and of streptococcal cell wall-induced arthritis (26) in rats using N-methyl-L-arginine, a NOS inhibitor, which suggests a fundamental role for NO pathways in these experimental models (26,28). However, a recent evaluation of several iNOS inhibitors in AIA showed that aminoguanidine was able to suppress the level of urinary nitrate excretion during AIA without a reduction in arthritis severity (32).…”

“…Moreover, inhibitors of NOS have been shown to suppress arthritis in several animal models (26,28,32,33,35), and increased levels of NO have been found in patients with rheumatoid arthritis (36,37). However, it has not been shown that NO is a requisite component of joint inflammation regardless of the cause of arthritis.…”

“…Recent evaluations of NO synthesis in streptococcal cell wall-induced arthritis (26), A M (27)(28)(29)(30)(31)(32)(33), and MRL-lpdlpr mice (34) showed an association between arthritis, increased N O production, and the induction of NOS (26). Moreover, inhibitors of NOS have been shown to suppress arthritis in several animal models (26,28,32,33,35), and increased levels of NO have been found in patients with rheumatoid arthritis (36,37).…”

Inhibition of nitric oxide synthase (NOS) aggravates Staphylococcus aureus septicaemia and septic arthritis

“…However, the role of NO in arthritis is largely unknown. In contrast, NOS inhibitors were reported to suppress adjuvant and streptococcal cell wall-induced arthritis [15][16][17], yet had no effect on borrelial arthritis [18].…”