16-16-dimethylprostaglandin-e2 and Peptic-Ulcer

We examined the effect of lafutidine, a histamine H(2) receptor antagonist with a mucosal protective action mediated by capsaicin-sensitive sensory neurons (CSN), on intestinal lesions produced by loxoprofen administration in rats.. Animals were given loxoprofen (10-100 mg/kg p.o.) and killed 24 h later. Lafutidine (10 and 30 mg/kg), cimetidine (100 mg/kg) or famotidine (30 mg/kg) was given twice p.o. at 0.5 h before and 6 h after loxoprofen. Omeprazole (100 mg/kg) was given p.o. once 0.5 h before. Ampicillin (800 mg/kg) was given p.o. twice at 24 h and 0.5 h before loxoprofen, while 16,16-dimethyl prostaglandin E(2) (dmPGE(2); 0.01 mg/kg) was given i.v. twice at 5 min before and 6 h after.. Loxoprofen dose-dependently produced hemorrhagic lesions in the small intestine, accompanied by invasion of enterobacteria and increased inducible nitric oxide synthase (iNOS) expression as well as myeloperoxidase activity in the mucosa. The ulcerogenic response to loxoprofen (60 mg/kg) was significantly prevented by lafutidine (30 mg/kg), similar to dmPGE(2) and ampicillin, and the effect of lafutidine was totally attenuated by ablation of CSN. Neither cimetidine, famotidine nor omeprazole had a significant effect against these lesions. Lafutidine alone increased mucus secretion and reverted the decreased mucus response to loxoprofen, resulting in suppression of bacterial invasion and iNOS expression. In addition, loxoprofen downregulated Muc2 expression, and this response was totally reversed by lafutidine mediated by CSN.. Lafutidine protects the small intestine against loxoprofen-induced lesions, essentially mediated by the CSN, and this effect may be functionally associated with increased Muc2 expression/mucus secretion, an important factor in the suppression of bacterial invasion.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Ampicillin; Animals; Anti-Bacterial Agents; Anti-Ulcer Agents; Capsaicin; Cimetidine; Disease Models, Animal; Enterobacteriaceae; Famotidine; Histamine H2 Antagonists; Intestinal Mucosa; Intestine, Small; Male; Mucin-2; Nitric Oxide Synthase Type II; Omeprazole; Peptic Ulcer; Peroxidase; Phenylpropionates; Piperidines; Proton Pump Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sensory Receptor Cells

The effects of an EP4 agonist/antagonist on the healing of lesions produced by indomethacin in the small intestine were examined in rats, especially in relation to the expression of vascular endothelial growth factor (VEGF) and angiogenesis.. Animals were given indomethacin (10 mg/kg s.c.) and killed at various time points. To impair the healing of these lesions, a small dose of indomethacin (2 mg/kg p.o.) or AE3-208 (EP4 antagonist: 3 mg/kg i.p.) was given once daily for 6 days after the ulceration was induced, with or without the co-administration of AE1-329 (EP4 agonist: 0.1 mg/kg i.p.).. Indomethacin (10 mg/kg) caused severe damage in the small intestine, but the lesions healed rapidly decreasing to approximately one-fifth of their initial size within 7 days. The healing process was significantly impaired by indomethacin (2 mg/kg) given once daily for 6 days after the ulceration. This effect of indomethacin was mimicked by the EP4 antagonist and reversed by co-administration of the EP4 agonist. Mucosal VEGF expression was upregulated after the ulceration, reaching a peak on day 3 followed by a decrease. The changes in VEGF expression paralleled those in mucosal cyclooxygenase-2 expression, as well as prostaglandin E(2) (PGE(2)) content. Indomethacin (2 mg/kg) downregulated both VEGF expression and angiogenesis in the mucosa during the healing process, and these effects were significantly reversed by co-treatment with the EP4 agonist.. The results suggest that endogenous PGE(2) promotes the healing of small intestinal lesions by stimulating angiogenesis through the upregulation of VEGF expression mediated by the activation of EP4 receptors.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Indomethacin; Intestinal Mucosa; Intestine, Small; Male; Membrane Proteins; Naphthalenes; Neovascularization, Physiologic; Peptic Ulcer; Phenylbutyrates; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP4 Subtype; RNA, Messenger; Severity of Illness Index; Time Factors; Up-Regulation; Vascular Endothelial Growth Factor A; Wound Healing

Mucus and bicarbonate secretions have been widely implicated as an important pre-epithelial protective barrier against autodigestion of the gastric mucosa by acid and pepsin. Evidence from several independent studies shows there is a continuous layer of resilient viscoelastic mucus gel adherent to the surface of the gastroduodenal mucosa. The median thickness of the adherent gastric mucus layer in humans is 180 microns, range 50-450 microns. The epithelial bicarbonate secretion permeates the unstirred matrix of mucus gel neutralizing luminal acid and establishing a pH gradient within the gel. In the duodenum, evidence supports the mucus bicarbonate barrier as a major protective mechanism against acid aggression. The adherent mucus gel, by acting as an effective 'permeability' barrier to pepsin, protects the underlying sensitive mucosa from digestion. However, pepsin slowly digests mucus gel at its luminal surface to produce soluble degraded mucin. In a rat gastric damage model in vivo, pepsin in excess digests the gastric mucus barrier sufficiently rapidly to outweigh new mucus secretion and lead to breaching of the mucus barrier with the formation of small punctate ulcers in the epithelium accompanied by mucosal haemorrhage. The mucus secretagogue 16,16 dimethyl prostaglandin E2 and the muco-adhesive carbopol-polyacrylate both fully protected the mucosa against pepsin damage by enhancing the protective properties of the mucus barrier. Sucralfate and bismuth subsalicylate were partially effective in protection against pepsin damage but this protection was mainly mediated at the level of the mucosa. In peptic ulcer disease, there is increased mucolytic (mucus degrading) activity in gastric juice and this is associated with an impaired mucin polymeric structure and a weaker mucus barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 16,16-Dimethylprostaglandin E2; Acrylic Resins; Animals; Bismuth; Duodenum; Gastric Mucosa; Intestinal Mucosa; Male; Mucus; Organometallic Compounds; Pepsin A; Peptic Ulcer; Rats; Rats, Wistar; Salicylates; Sucralfate

Sucralfate exhibits gastroprotective properties in laboratory animals and enhances the healing of chronic gastroduodenal ulcers, but the mechanisms of these actions have not been entirely elucidated. The present study was designed to determine whether or not epidermal growth factor (EGF), which also has gastroprotective and ulcer-healing properties, contributes to the action of sucralfate in rat stomach. It was confirmed that sucralfate, like 16,16-dimethyl prostaglandin E2, protects the gastric mucosa against ethanol damage and increases mucosal generation of prostaglandins. Removal of the endogenous source of EGF (sialoadenectomy) did not abolish the protective and prostaglandin-stimulating effects of sucralfate. Exogenous EGF and 16,16-dimethyl prostaglandin E2 were also protective in rats with intact and removed salivary glands. Sucralfate, like EGF, enhanced the healing of chronic gastric and duodenal ulcerations induced by serosal application of acetic acid. Sucralfate was found to bind EGF in a pH-dependent manner and to accumulate it in ulcer areas. Thus, the peptide is available locally in high concentrations to accelerate tissue repair and the healing process in ulcerated mucosa. The ulcer-healing effects of sucralfate were reduced with sialoadenectomy and partially restored with oral administration of EGF. It was concluded that EGF is not essential for the gastroprotection induced by sucralfate, but seems to play an important role in the ulcer-healing action of this drug.

Topics: 16,16-Dimethylprostaglandin E2; Acetates; Acetic Acid; Acute Disease; Animals; Chronic Disease; Dinoprostone; Epidermal Growth Factor; Ethanol; Gastric Mucosa; Male; Peptic Ulcer; Rats; Rats, Inbred Strains; Submandibular Gland; Sucralfate; Wound Healing

The time course of gastric mucosal surface epithelial cell damage and macroscopically visible lesions in response to restraint and water-immersion stress (22 degrees C) in rats was examined, and the prophylactic effects on it of 16,16-dimethyl-prostaglandin E2 (dmPGE2) were compared with those of papaverine, timoprazole, and atropine. The stress produced surface epithelial cell damage prior to visible lesion, the former increasing in severity with time and reaching a plateau 60 min later, by which time exfoliation of surface epithelial cells was observable along the mucosal folds. In contrast, macroscopically visible lesions appeared 2 h after stress, and severity continued to increase with time. Pretreatment injections (s.c.) of dmPGE2 (3 and 30 micrograms/kg), papaverine (100 mg/kg), and atropine (1 mg/kg) protected the surface cells against stress-induced (1 h) damage, and inhibited visible lesion formation after 4 h stress. Timoprazole (30 mg/kg s.c.) did not protect the surface cells, but did markedly inhibit visible lesion formation. DmPGE2, papaverine, and atropine, but not timoprazole, inhibited stress-induced increases in gastric contractions. DmPGE2, timoprazole, and atropine, but not papaverine, inhibited acid secretion in stress conditions. These results indicated that stress induced damage to the gastric mucosa within 1 h due to increased gastric contractions, and the surface epithelial cell damage developed into macroscopically visible lesions in the presence of acid, and that dmPGE2 protected the surface epithelium against stress-induced damage probably by inhibiting gastric contractions.

Topics: 16,16-Dimethylprostaglandin E2; 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Atropine; Benzimidazoles; Gastric Acid; Gastric Mucosa; Gastrointestinal Motility; Immersion; Male; Microscopy, Electron, Scanning; Omeprazole; Papaverine; Peptic Ulcer; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Restraint, Physical; Stress, Physiological

Colloidal bismuth subcitrate (CBS; De-Nol) exhibits gastroprotective properties in experimental animals and enhances the healing of chronic gastroduodenal ulcers, but the mechanisms of these actions have not been entirely elucidated. The present study was designed to determine whether epidermal growth factor (EGF), which also has gastroprotective and ulcer healing properties, contributes to the action of De-Nol on the stomach in rats. It was found that De-Nol protects the gastric mucosa against ethanol damage and that this is accompanied by increased mucosal generation of prostaglandins (PG). Removal of the endogenous source of EGF (sialoadenectomy) did not significantly decrease the protective and PG stimulating effects of De-Nol. Pretreatment with exogenous EGF partially protected the stomach against ethanol injury, but did not influence the protective action of De-Nol in sialoadenectomised animals. De-Nol, like EGF given orally, enhanced the healing of chronic gastric and duodenal ulcers induced by serosal acetic acid. De-Nol was found to bind EGF in a pH-dependent manner and to accumulate it in ulcer area. Thus the peptide is available locally in high concentrations to accelerate the re-epithelialisation and tissue repair of the ulcerated mucosa. These ulcer healing effects of De-Nol were reduced by sialoadenectomy and restored in part by oral administration of EGF. We conclude that salivary glands in rats are not essential for the gastroprotection induced by De-Nol, but seem to play an important role in the ulcer healing action of this drug possibly via an EGF mediated mechanism.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Anti-Ulcer Agents; Bismuth; Epidermal Growth Factor; ErbB Receptors; Gastric Mucosa; Male; Organometallic Compounds; Peptic Ulcer; Rats; Rats, Inbred Strains; Submandibular Gland

Stress ulceration can be prevented clinically by prophylaxis with antacids or sucralfate, while hyperosmolar glucose and prostaglandins have prevented gastric mucosal injury in experimental models. We compared these four agents' effectiveness in gastric mucosal protection as well as their interaction with the pathophysiology of hemorrhagic shock. Gastric mucosal injury was produced in a canine model with the insults important in clinical situations: intragastric acid, intragastric bile, and gastric mucosal ischemia. Hypotension was maintained at a constant level for 3 hr, during which one of the prophylactic treatments or vehicle (H2O) was given hourly intragastrically. The stomachs were harvested for quantification of gastric mucosal injury after return of shed blood. The percentage of gastric area damaged was significantly decreased to 1.0 +/- 0.7% by antacids but was increased to 43.5 +/- 4.9% by 16,16-dimethyl prostaglandin E2 (16,16-dmPGE2), in comparison to vehicle treatment which caused 28.4 +/- 4.7% lesioned mucosa. Additionally, hemodynamic function differed between treatment groups after 1 hr of shock. Irrespective of treatment group, parameters reflecting volume status and hemodynamic function correlated significantly with the amount of gastric mucosal injury measured in individual animals. Intragastric treatments did not variably affect systemic pH or systemic glucose, and neither of these parameters was related to gastric mucosal injury. In conclusion, antacids effectively prevent stress ulceration in canine hemorrhagic shock, while the worsening of gastric mucosal injury and hemodynamic function we observed with 16,16-dmPGE2 treatment indicates that this agent could be hazardous in hypotensive patients.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Antacids; Disease Models, Animal; Dogs; Glucose Solution, Hypertonic; Hydrogen-Ion Concentration; Peptic Ulcer; Regional Blood Flow; Shock, Hemorrhagic; Stomach; Stress, Physiological; Sucralfate

While the incidence of duodenal ulcer disease has been documented to be greater in men than in women, this observation has not been previously noted in animal studies of the upper gastrointestinal tract. In this study, we questioned whether the cytoprotective properties of 16, 16-dimethyl PGE2 were sex-related by comparing the degree of ethanol-induced hemorrhagic gastritis in male and female rats pretreated with 16,16-dimethyl PGE2 or lithium chloride. Animals receiving 16,16-dimethyl PGE2 or lithium chloride had significantly less ethanol-induced hemorrhagic gastritis (1.17 +/- 0.15 and 1.24 +/- 0.13, respectively, p less than 0.001) when compared with controls (2.69 +/- 0.10). Female rats treated with 16,16-dimethyl PGE2 had 59% less hemorrhagic gastritis than male rats treated similarly (0.76 +/- 0.14 vs 1.86 +/- 0.19 respectively, p less than 0.001). This sex-related difference in hemorrhagic gastritis was not noted in male and female rats receiving lithium chloride (1.24 +/- 0.15 vs 1.23 +/- 0.27, respectively). However, female rats treated with 16, 16-dimethyl PGE2 had significantly less hemorrhagic gastritis when compared with female rats receiving lithium chloride (0.76 +/- 0.14 vs 1.24 +/- 0.15 respectively, p less than 0.05).

Topics: 16,16-Dimethylprostaglandin E2; Animals; Chlorides; Ethanol; Female; Gastric Mucosa; Gastritis; Gastrointestinal Hemorrhage; Lithium; Lithium Chloride; Male; Peptic Ulcer; Prostaglandins E, Synthetic; Rats; Rats, Inbred Strains; Sex Factors

Topics: 16,16-Dimethylprostaglandin E2; Adult; Electrolytes; Gastric Mucosa; Humans; Hydrogen-Ion Concentration; Male; Middle Aged; Peptic Ulcer; Prostaglandins E, Synthetic