title: Effect of inhibition of inducible nitric oxide synthase and guanylyl cyclase on endotoxin-induced delay in gastric emptying and intestinal transit in mice.
abstract: Nitric oxide (NO) is postulated to play a role in endotoxin-induced ileus. We investigated the effect of selective blockade of inducible NO synthase (iNOS) and guanylyl cyclase on endotoxin-induced ileus in mice. Thirty minutes before injection of lipopolysaccharides (LPS), mice were pretreated with L-NAME (N omega-nitro-L-arginine methyl ester, non-selective NOS inhibitor), 1400W (N-(3-(aminomethyl)benzyl)acetamide, selective iNOS inhibitor), ODQ (1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, guanylyl cyclase inhibitor), dimethyl sulfoxide (DMSO, vehicle), or dexamethasone. After 18 h, general well being deteriorated and the mice developed hypothermia and a significant delay in gastric emptying and intestinal transit as measured by Evans blue. 1400W completely reversed the endotoxin-induced delay in gastric emptying, while L-NAME did not have these beneficial effects. On the contrary, even in control mice, L-NAME delayed gastric emptying. Dexamethasone, DMSO, and ODQ mimicked the effect of 1400W on endotoxin-induced delay in gastric emptying. The endotoxin-induced delay in transit was significantly improved only by 1400W. None of the drugs reversed the hypothermia. In LPS mice treated with L-NAME, the behavior scale increased even further, while it decreased after treatment with 1400W. In conclusion, selective inhibition of iNOS reverses the endotoxin-induced delay in gastric emptying and transit and improves general well being. The pathway used by NO, derived from iNOS, may involve inhibition of guanylyl cyclase or radical scavenging.
authors.affiliation: Division of Gastroenterology, Faculty of Medical and Pharmaceutical Sciences, University of Antwerp, Belgium.
authors.forename: Benedicte Y
authors.initials: BY
authors.lastname: De Winter
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Bredenoord
authors.forename: Joris G
authors.initials: JG
authors.lastname: De Man
authors.forename: Tom G
authors.initials: TG
authors.lastname: Moreels
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Herman
authors.forename: Paul A
authors.initials: PA
authors.lastname: Pelckmans
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004731:Endotoxins; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects* / Q000502:physiology; D005772:Gastrointestinal Transit / Q000187:drug effects* / Q000502:physiology; D006162:Guanylate Cyclase / Q000187:drug effects* / Q000378:metabolism; D007415:Intestinal Obstruction / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D012016:Reference Values; D012680:Sensitivity and Specificity
chemical_list: D004731:Endotoxins; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D019331:NG-Nitroarginine Methyl Ester