title: Protective effect of exogenous nitrite in postoperative ileus.
abstract: OBJECTIVE
  As the pathogenesis of postoperative ileus (POI) involves inflammation and oxidative stress, comparable to ischaemia/reperfusion injury which can be ameliorated with nitrite, we investigated whether nitrite can protect against POI and explored the mechanisms involved.
  
  
  METHODS
  We used intestinal manipulation (IM) of the small intestine to induce POI in C57BL/6J mice. Sodium nitrite (48 nmol) was administered intravenously just before IM. Intestinal transit was assessed using fluorescent imaging. Bethanechol-stimulated jejunal circular muscle contractions were measured in organ baths. Inflammatory parameters, neutrophil infiltration, inducible NOS (iNOS) activity, reactive oxygen species (ROS) levels, mitochondrial complex I activity and cGMP were measured in the intestinal muscularis.
  
  
  RESULTS
  Pre-treatment with nitrite markedly improved the delay in intestinal transit and restored the reduced intestinal contractility observed 24 h following IM. This was accompanied by reduced protein levels of TNF-α, IL-6 and the chemokine CCL2, along with reduced iNOS activity and ROS levels. The associated neutrophil influx at 24 h was not influenced by nitrite. IM reduced mitochondrial complex I activity and cGMP levels; treatment with nitrite increased cGMP levels. Pre-treatment with the NO scavenger carboxy-PTIO or the soluble guanylyl cyclase inhibitor ODQ abolished nitrite-induced protective effects.
  
  
  CONCLUSIONS
  Exogenous nitrite deserves further investigation as a possible treatment for POI. Nitrite-induced protection of POI in mice was dependent on NO and this effect was not related to inhibition of mitochondrial complex I, but did involve activation of soluble guanylyl cyclase.
authors.affiliation: Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
authors.forename: S M R
authors.initials: SM
authors.lastname: Cosyns
authors.affiliation: Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.|Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shiva
authors.affiliation: Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.
authors.forename: R A
authors.initials: RA
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D005772:Gastrointestinal Transit / Q000187:drug effects; D045823:Ileus / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D015850:Interleukin-6 / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D009504:Neutrophils / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011183:Postoperative Complications / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012977:Sodium Nitrite / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006152:Cyclic GMP; D012977:Sodium Nitrite