DUAL INHIBITION OF NITRIC-OXIDE AND PROSTAGLANDIN PRODUCTION CONTRIBUTES TO THE ANTIINFLAMMATORY PROPERTIES OF NITRIC-OXIDE SYNTHASE INHIBITORS

We have recently put forward the hypothesis that the dual inhibition o f proinflammatory nitric oxide (NO) and prostaglandins (PG) may contri bute to the antiinflammatory properties of nitric oxide synthase (NOS) inhibitors. This hypothesis was tested in the present study. A rapid inflammatory response characterized by edema, high levels of nitrites (NO2-, a breakdown product of NO), PG, and cellular infiltration into a fluid exudate was induced by the administration of carrageenan into the subcutaneous rat air pouch, The time course of the induction of in ducible nitric oxide synthase (iNOS) protein in the pouch tissue was f ound to coincide with the production of NO2-. Dexamethasone inhibited both iNOS protein expression and NO2- synthesis in the fluid exudate ( IC50 = 0.16 mg/kg). Oral administration of N-iminoethyl-L-lysine (L-NI L) or N-G-nitro-L-arginine methyl ester (NO(2)Arg) not only blocked ni trite accumulation in the pouch fluid in a dose-dependent fashion but also attenuated the elevated release of PG. Finally, carrageenan admin istration produced a time-dependent increase in cellular infiltration into the pouch exudate that was inhibited by dexamethasone and NOS inh ibitors. At early times, i.e., 6 h, the cellular infiltrate is compose d primarily of neutrophils (98%). Pretreatment with colchicine reduced both neutrophil infiltration and leukotriene B-4 accumulation in the air pouch by 98% but did not affect either NO2- or PG levels. In concl usion, the major findings of this paper are that (a) selective inhibit ors of iNOS are clearly antiinflammatory agents by inhibiting not only NO but also PG and cellular infiltration and (b) that neutrophils are not responsible for high levels of NO and PG produced.