title: Increased nitric oxide synthesis during the development of endotoxin tolerance.
abstract: The role of nitric oxide (NO) synthesis was investigated in endotoxin (LPS) tolerance induced in rats by intraperitoneal injection of a sublethal dose of Salmonella enteritidis LPS (100 micrograms/kg intraperitoneally). Peritoneal macrophages were harvested 6 and 24 h after LPS injection and stimulated in vitro with LPS. LPS significantly stimulated arachidonic acid metabolism, as assessed by 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) levels, and NO production, as assessed by nitrite, in macrophages collected from control rats. In macrophages from tolerant rats LPS-stimulated 6-keto-PGF1 alpha production was significantly reduced, while nitrite production was increased compared to control macrophages (p < .001). In in vivo mortality studies, rats that were pretreated 24 h earlier with sublethal LPS were resistant to the lethal effect of a subsequent dose of LPS (15 mg/kg intravenously) in comparison to control rats (p < .001). NG-Nitro-L-arginine-methyl ester, an inhibitor of NO synthase, decreased mean survival time in control rats and abrogated the resistance to the lethal effect of LPS in tolerant rats. In contrast, molsidomine, a NO donor, improved survival in control rats but did not modify the resistance to the lethal dose of LPS in tolerant rats. The results suggest that sustained NO synthesis may be a beneficial mechanism for the induction of LPS tolerance.
authors.affiliation: Department of Physiology, Medical University of South Carolina, Charleston 29425, USA.
authors.forename: B
authors.initials: B
authors.lastname: Zingarelli
authors.forename: P V
authors.initials: PV
authors.lastname: Halushka
authors.forename: A P
authors.initials: AP
authors.lastname: Caputi
authors.forename: J A
authors.initials: JA
authors.lastname: Cook
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D004361:Drug Tolerance; D004731:Endotoxins / Q000633:toxicity*; D007928:Lethal Dose 50; D008070:Lipopolysaccharides / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D012016:Reference Values; D012477:Salmonella enteritidis; D019323:omega-N-Methylarginine
chemical_list: D001095:Arachidonic Acids; D004731:Endotoxins; D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; C002385:linsidomine; D001120:Arginine; D008981:Molsidomine; D019331:NG-Nitroarginine Methyl Ester