REGULATION OF PROSTAGLANDIN PRODUCTION BY NITRIC-OXIDE - AN IN-VIVO ANALYSIS

1 Endotoxin E. Coli lipopolysaccharide (LPS)-treatment in conscious, r estrained rats increased plasma and urinary prostaglandin (PG) and nit ric oxide (NO) production. Inducible cyclo-oxygenase (COX-2) and nitri c oxide synthase (iNOS) expression accounted for the LPS-induced PG an d NO release since the glucocorticoid, dexamethasone inhibited both ef fects. Thus, LPS (4 mg kg(-1)) increased the plasma levels of nitrite/ nitrate from 14 +/- 1 to 84 +/- 7 mu M within 3 h and this rise was in hibited to 35 +/- 1 mu M by dexamethasone. Levels of 6-keto PGF(1 alph a) in the plasma were below the detection limit of the assay (< 0.2 ng ml(-1)). However, 3 h after the injection of LPS these levels rose to 2.6 +/- 0.2 ng ml(-1) and to 0.7 +/- 0.01 ng ml(-1) after LPS in rats that received dexamethasone. 2 The induced enzymes were inhibited in vivo with selective COX and NOS inhibitors. Furthermore, NOS inhibitor s, that did not affect COX activity in vitro markedly suppressed PG pr oduction in the LPS-treated animals. For instance, the LPS-induced inc reased in plasma nitrite/nitrate and 6-keto PGF(1 alpha) at 3 h was de creased to 18 +/- 2 mu M and 0.5 +/- 0.02 ng ml(-1), 23 +/- 1 mu M and 0.7 +/- 0.01 ng ml(-1), 29 +/- 2 mu M and 1 +/- 0.01 ng ml(-1) in rat s treated with LPS in the presence of the NOS inhibitors N-G-monomethy l-L-arginine, N-G-nitro arginine methyl ester and aminoguanidine, resp ectively. 3 The intravenous infusion of the NO donors sodium nitroprus side (SNP) or glyceryl trinitrate (GTN) increased prostaglandin produc tion in normal animals (for instance urinary PGE(2) excretion was incr eased from 96 +/- 10 to 576 +/- 12 pg min(-1) and 400 +/- 24 pg min(-1 ) in the presence of GTN or SNP respectively). 4 Proteinuria was measu red in order to evaluate the roles of NO and PG in renal damage associ ated with the in vivo injection of LPS. Interestingly, dexamethasone a nd the NOS inhibitors attenuated proteinuria in the LPS-treated rats. The COX inhibitors had no effect. It therefore appears that NO and not PG contributes to the LPS-induced renal damage; these findings suppor t the potential use of NOS inhibitors in the treatment of renal inflam mation. 5 This study demonstrates the regulatory contribution of NO on the in vivo production of prostanoids and suggests that in inflammato ry diseases that are driven by both NO and the prostaglandins, NOS inh ibitors may act to reduce inflammation by the dual inhibition of cytot oxic NO and pro-inflammatory PC.