In animal models of postoperative ileus (POI), inflammation of the intestine plays an important role in the pathogenesis of POI. Changes in α2-adrenoceptors and nitrergic regulation have been proposed to be implicated. The aim of our study was to investigate the presynaptic α2-receptor–mediated control of cholinergic nerve activity, the nitrergic nerve activity, and the possible role of soluble guanylate cyclase (sGC) during the inflammatory phase of POI.
Ileus was induced by anesthesia and manipulation of the rat jejunum. Rats were treated with the sGC inhibitors methylene blue or ODQ; nonoperated animals served as controls. After 24 h, plasma and jejunal tissue were collected for biochemical assays, nitric oxide synthase-1 (NOS-1)-immunohistochemistry, acetylcholine (Ach)-release experiments, and muscle tension experiments.
In all operated animal groups, myeloperoxidase activity was significantly increased, which indicates initiation of an inflammatory response. The α2-adrenoceptor agonist UK14,304 reduced electrically induced Ach-release similarly in operated and nonoperated animals. In strips of operated animals, electrically induced nitrergic relaxations were decreased, whereas relaxations induced by exogenous nitric oxide (NO) remained unchanged compared with control. The number of myenteric neurons and the percentage of NOS-1-positive neurons were not influenced. Plasmatic cyclic guanosine monophosphate (cGMP) levels were decreased in all operated groups, whereas jejunal cGMP levels were unchanged compared with nonoperated controls; treatment with sGC inhibitors did not reduce plasmatic cGMP levels.
This study demonstrates that presynaptic α2-receptor mediated control of intestinal cholinergic nerve activity is unchanged during manipulation-induced inflammation. However, this inflammation induces impaired nitrergic neurotransmission related to decreased NOS-1 activity in the nitrergic nerves.
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- The management of postoperative ileus.Curr Probl Surg. 2006; 43: 6-65
- Mechanisms of postoperative ileus.Neurogastroenterol Motil. 2004; 16: 54-60
- Activation of an adrenergic and vagally-mediated NANC pathway in surgery-induced fundic relaxation in the rat.Neurogastroenterol Motil. 1999; 11: 467-474
- Surgically induced leukocytic infiltrates within the rat intestinal muscularis mediate postoperative ileus.Gastroenterology. 1999; 117: 378-387
- Inhibition of sympathetic pathways restores postoperative ileus in the upper and lower gastrointestinal tract.J Gastroenterol Hepatol. 2007; 22: 1293-1299
- Alpha2-adrenergic regulation of NO production alters postoperative intestinal smooth muscle dysfunction in rodents.Am J Physiol Gastrointest Liver Physiol. 2004; 287: G658-G666
- Products of cyclooxygenase-2 catalysis regulate postoperative bowel motility.J Surg Res. 1999; 86: 50-54
- Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents.Gastroenterology. 2000; 118: 316-327
- Impaired nitrergic innervation in rat colitis induced by dextran sulfate sodium.Gastroenterology. 2000; 118: 714-723
- Neural mechanisms of early postinflammatory dysmotility in rat small intestine.Neurogastroenterol Motil. 2006; 18: 1102-1111
- Novel effects of nitric oxide.Annu Rev Pharmacol Toxicol. 2001; 41: 203-236
- Protection against TNF-induced lethal shock by soluble guanylate cyclase inhibition requires functional inducible nitric oxide synthase.Immunity. 2000; 13: 223-231
- Effect of inhibition of inducible nitric oxide synthase and guanylyl cyclase on endotoxin-induced delay in gastric emptying and intestinal transit in mice.Shock. 2002; 18: 125-131
- Control of coronary vascular tone by nitric oxide.Circ Res. 1990; 66: 1561-1575
- Light and electron microscopic immunocytochemistry of the same nerves from whole mount preparations.J Histochem Cytochem. 1985; 33: 857-866
- Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models.Gastroenterology. 1984; 87: 1344-1350
- Neurochemical identification of enteric neurons expressing P2X(3) receptors in the guinea-pig ileum.Histochem Cell Biol. 2002; 118: 193-203
- Quantification of neurons in the myenteric plexus: an evaluation of putative pan-neuronal markers.J Neurosci Methods. 2004; 133: 99-107
- Role of reactive nitrogen species in neuronal cell damage during intestinal schistosomiasis.Cell Tissue Res. 2001; 303: 329-336
- Postoperative ileus is maintained by intestinal immune infiltrates that activate inhibitory neural pathways in mice.Gastroenterology. 2003; 125: 1137-1147
- Mast cell degranulation during abdominal surgery initiates postoperative ileus in mice.Gastroenterology. 2004; 127: 535-545
- Selective jejunal manipulation causes postoperative pan-enteric inflammation and dysmotility.Gastroenterology. 2004; 126: 159-169
- Ethyl pyruvate ameliorates ileus induced by bowel manipulation in mice.Surgery. 2005; 138: 530-537
- The adrenergic innervation of the gastrointestinal tract.Ergeb Physiol. 1974; 69: 2-51
- Review article: adrenergic control of motor and secretory function in the gastrointestinal tract.Aliment Pharmacol Ther. 1992; 6: 125-142
- Altered prejunctional modulation of intestinal cholinergic and noradrenergic pathways by alpha2-adrenoceptors in the presence of experimental colitis.Br J Pharmacol. 2003; 139: 309-320
- Influence of nitric oxide donors and of the alpha(2)-agonist UK-14,304 on acetylcholine release in the pig gastric fundus.Neuropharmacology. 2001; 40: 270-278
- Presynaptic modulation of cholinergic neurotransmission in the human proximal stomach.Br J Pharmacol. 2002; 135: 135-142
- Subclassification of presynaptic alpha 2-adrenoceptors: alpha 2D-autoreceptors and alpha 2D-adrenoceptors modulating release of acetylcholine in guinea-pig ileum.Naunyn Schmiedebergs Arch Pharmacol. 1995; 352: 58-66
- Expression and function of genes encoding cholinergic components in murine immune cells.Life Sci. 2007; 80: 2314-2319
- Leukocyte-derived inducible nitric oxide synthase mediates murine postoperative ileus.Ann Surg. 2006; 244: 220-229
- Inhibitory pathways in the circular muscle of rat jejunum.Br J Pharmacol. 2004; 143: 107-118
- Evidence for a feedback inhibition of NO synthesis in enteric synaptosomes via nitrosothiol intermediate.Am J Physiol. 1999; 277: G875-G884
- Effect of adrenergic and nitrergic blockade on experimental ileus in rats.Br J Pharmacol. 1997; 120: 464-468
- Nitric oxide synthase inhibition results in immediate postoperative recovery of gastric, small intestinal and colonic motility in awake rats.Int J Colorectal Dis. 2006; 21: 121-129
- Endogenous nitric oxide modulates small intestinal nutrient transit and activity in healthy adult humans.Scand J Gastroenterol. 2005; 40: 1290-1295
- Nitric oxide and vasoactive intestinal polypeptide mediate non-adrenergic, non-cholinergic inhibitory transmission to smooth muscle of the rat gastric fundus.Eur J Pharmacol. 1990; 191: 303-309
- Release of nitric oxide upon stimulation of nonadrenergic noncholinergic nerves in the rat gastric fundus.J Pharmacol Exp Ther. 1991; 256: 441-447
- Small intestine as possible source of increased plasma cGMP after administration of alpha-hANP to dogs.Am J Physiol Gastrointest Liver Physiol. 1988; 254: G814-G818
- Endogenous endotoxin participates in causing a panenteric inflammatory ileus after colonic surgery.Ann Surg. 2007; 245: 734-744
- Influence of soluble guanylate cyclase inhibition on inflammation and motility disturbances in DSS-induced colitis.Eur J Pharmacol. 2007;
- Downregulation of nitrovasodilator-induced cyclic GMP accumulation in cells exposed to endotoxin or interleukin-1 beta.Br J Pharmacol. 1996; 118: 1359-1366
- Effects of a novel guanylyl cyclase inhibitor on the vascular actions of nitric oxide and peroxynitrite in immunostimulated smooth muscle cells and in endotoxic shock.Crit Care Med. 1999; 27: 1701-1707
- Methylene blue inhibits the increase of inducible nitric oxide synthase activity induced by stress and lipopolysaccharide in the medial basal hypothalamus of rats.Neuroimmunomodulation. 2000; 8: 122-127
- Carbon monoxide protects against cardiac ischemia-reperfusion injury in vivo via MAPK and Akt–eNOS pathways.Arterioscler Thromb Vasc Biol. 2004; 24: 1448-1853
- GW274150, a potent and highly selective inhibitor of iNOS, reduces experimental renal ischemia/reperfusion injury.Kidney International. 2003; 63: 853-865
Accepted: May 17, 2008
Supported by Grant G.0053.02 from the Fund of Scientific Research Flanders, and by Interuniversity Attraction Poles Programme P5/20 (Federal Public Planning Service Science Policy).
© 2008 Mosby, Inc. Published by Elsevier Inc. All rights reserved.