s-nitro-n-acetylpenicillamine and Stomach-Ulcer

In a rat model of the ischemia-reperfusion with pylorus ligation, gastric ulcer was formed, although gastric acid secretion was reduced. When the polymorphonuclear leukocytes were inactivated in advance, gastric ulcer was not formed, but acid secretion was increased, indicating that gastric acid is not a cause of the ulcer formation in this model. The mechanism of gastric acid suppression accompanied by ischemia-reperfusion was examined in relation to the role of oxygen-free radicals in this rat model. Prior administration of superoxide dismutase did not modulate acid secretion, but N-nitro-L-arginine methyl ester (L-NAME) increased acid secretion. The action of L-NAME was antagonized specifically by L-arginine, but not by D-arginine. S-nitroso-N-acetylpenicillamine did not inhibit basal acid secretion but antagonized the action of L-NAME. Aminoguanidine increased significantly the gastric acid output that was suppressed by ischemia-reperfusion. When polymorphonuclear leukocytes were inactivated by treatment with their antibody, the gastric acid output recovered to the level in the pylorus-ligated rat without ischemia-reperfusion. These results suggested that nitric oxide (NO) produced by the infiltrated polymorphonuclear leukocytes plays an important role in the suppression of acid secretion induced by ischemia-reperfusion.

Topics: Animals; Arginine; Disease Models, Animal; Enzyme Inhibitors; Free Radical Scavengers; Gastric Acid; Gastric Mucosa; Ligation; Male; Neutrophils; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Penicillamine; Pylorus; Rats; Rats, Inbred Strains; Reperfusion Injury; Stomach; Stomach Ulcer; Superoxide Dismutase; Time Factors

Lipopolysaccharides (LPS) are major components of the outer membrane of gram-negative bacteria playing a central role as potent endotoxins in the pathogenesis of endotoxic shock. Although large amounts of endotoxin may produce hemorrhagic lesions in the stomach, the possible gastroprotective effect of central or peripheral LPS against the acute gastric lesions has not been extensively studied. The aim of the present study was to compare the effect of intracerebroventricular (i.c.v.) and parenteral (i.p.) injection of LPS against gastric lesions induced by 100% ethanol. Male Wistar rats were treated either with a) vehicle (control); b) E-coli-LPS in various concentrations (1-10 microg/kg i.c.v or 0.1-40 mg/kg i.p.) followed 30 min later by 100% ethanol. The effects of pretreatment with nonselective inhibitor of nitric oxide synthase (L-NAME, 20 mg/kg i.g.) or selective inhibitor of inducible nitric oxide synthase, L-NIL (30 mg/kg i.g.) on the gastroprotection induced by LPS was investigated. One hour after ethanol application, the gastric blood flow (GBF) and the area of gastric lesions were determined. In addition, the mucosal expression of iNOS, cNOS and leptin was assessed using RT-PCR. LPS applied i.c.v. or i.p. dose dependently reduced gastric lesions induced by ethanol and this effect was similar to that observed after the administration of NO donor (SNAP). LPS-induced protection was significantly abolished by L-NAME and significantly attenuated by the selective inhibitor of iNOS (L-NIL). The expression of cNOS was detected in vehicle treated gastric mucosa and did not change after LPS administration. iNOS was not detectable in intact mucosa but its expression dose-dependently increased after the LPS administration. The i.c.v. administration of LPS did not upregulate further the iNOS expression, and dose-dependently inhibited the leptin mRNA expression in gastric mucosa. We conclude that LPS applied centrally or peripherally protects gastric mucosa against ethanol-induced damage through an increase in gastric microcirculation mediated by NO due to overexpression of iNOS. Transcriptional downregulation of leptin in gastric mucosa is probably due to the increased leptin release induced by the intracerebroventricular application lipopolysaccharide.

Topics: Animals; Brain; Cytoprotection; Ethanol; Gastric Mucosa; Injections, Intraventricular; Leptin; Lipopolysaccharides; NG-Nitroarginine Methyl Ester; Nitric Oxide; Penicillamine; Rats; Rats, Wistar; Regional Blood Flow; RNA, Messenger; Stomach Ulcer