title: Regulation of prostaglandin production by nitric oxide; an in vivo analysis.
abstract: 1. Endotoxin E. Coli lipopolysaccharide (LPS)-treatment in conscious, restrained rats increased plasma and urinary prostaglandin (PG) and nitric oxide (NO) production. Inducible cyclo-oxygenase (COX-2) and nitric oxide synthase (iNOS) expression accounted for the LPS-induced PG and NO release since the glucocorticoid, dexamethasone inhibited both effects. Thus, LPS (4 mg kg-1) increased the plasma levels of nitrite/nitrate from 14 +/- 1 to 84 +/- 7 microM within 3 h and this rise was inhibited to 35 +/- 1 microM by dexamethasone. Levels of 6-keto PGF1 alpha 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 inhibitors, that did not affect COX activity in vitro markedly suppressed PG production in the LPS-treated animals. For instance, the LPS-induced increased in plasma nitrite/nitrate and 6-keto PGF1 alpha at 3 h was decreased to 18 +/- 2 microM and 0.5 +/- 0.02 ng ml-1, 23 +/- 1 microM and 0.7 +/- 0.01 ng ml-1, 29 +/- 2 microM and 1 +/- 0.01 ng ml-1 in rats treated with LPS in the presence of the NOS inhibitors NG-monomethyl-L-arginine, NG-nitro arginine methyl ester and aminoguanidine, respectively. 3. The intravenous infusion of the NO donors sodium nitroprusside (SNP) or glyceryl trinitrate (GTN)increased prostaglandin production in normal animals (for instance urinary PGE2 excretion was increased 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 measured in order to evaluate the roles of NO and PG in renal damage associated with the in vivo injection of LPS. Interestingly, dexamethasone and 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 support the potential use of NOS inhibitors in the treatment of renal inflammation.5. This study demonstrates the regulatory contribution of NO on the in vivo production of prostanoids and suggests that in inflammatory diseases that are driven by both NO and the prostaglandins, NOS inhibitors may act to reduce inflammation by the dual inhibition of cytotoxic NO and pro-inflammatory PG.
authors.affiliation: G.D. Searle, Department of Molecular Pharmacology, St. Louis, MO 63167, USA.
authors.forename: D
authors.initials: D
authors.lastname: Salvemini
authors.forename: S L
authors.initials: SL
authors.lastname: Settle
authors.forename: J L
authors.initials: JL
authors.lastname: Masferrer
authors.forename: K
authors.initials: K
authors.lastname: Seibert
authors.forename: M G
authors.initials: MG
authors.lastname: Currie
authors.forename: P
authors.initials: P
authors.lastname: Needleman
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology; D004790:Enzyme Induction; D004926:Escherichia coli; D005069:Evaluation Studies as Topic; D006439:Hemodynamics / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; D008070:Lipopolysaccharides; D011453:Prostaglandins; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; C044101:endotoxin, Escherichia coli; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D000594:Amino Acid Oxidoreductases