Modulation of IL-1 effects on cartilage by NO synthase inhibitors: pharmacological studies in rats.

Objective To compare the ability of L-arginine (L-arg) analog nitric oxide synthase (NOS) inhibitors and isothioureas to restore the interleukin-1 (IL-1) induced inhibition of proteoglycan (PG) synthesis in rat.Methods Chondrocytes beads and patellae were challenged with IL-1betain vitro and monitored for NO production and proteoglycan synthesis. Rats injected with IL-1beta in knee joints were monitored for NO(2)( - )+NO(3)( - )levels in joint tissues and ex-vivo(35)S sulfate incorporation in patellae. NOS inhibitors were either added to culture medium or injected concomittantly to IL-1beta.Results Ability of NOS inhibitors to reduce NO(2)( - )levels decreased from chondrocytes beads to patellae. Partial restoration of PG synthesis was restricted to L-arg analogs in patellae. After IL-1 injection, NO was produced from patella and synovium. L-arg analogs restored partly PG synthesis when decreasing significantly NO(2)( - )+NO(3)( - )levels in synovial fluid. Isothioureas were ineffective.Conclusions NO accounts importantly for IL-1 induced inhibition of cartilage anabolism in rat. L-arg analog NOS inhibitors are more effective than isothioureas in restoring PG synthesis and have chondroprotective potency when administered locally in diseased joint.