Ketamine suppresses LPS-induced bile reflux and gastric bleeding in the rat.

BACKGROUND: Although ketamine has many beneficial effects in a rat model of noninfectious inflammation with lipopolysaccharide (LPS), its effects on gut ileus are unknown. We hypothesized that ketamine would improve LPS-induced ileus and therefore examined its effects on gastric emptying and intestinal transit as well as duodenogastric bile reflux and associated gastric bleeding. METHODS: Male rats received saline or ketamine (7 mg/kg ip) 1 hour before saline or LPS (20 mg/kg ip) for 5 hours. Thirty minutes before killing, rats received orogastric rhodamine B isothiocyanate-labeled dextran and 5 minutes later fluorescein isothiocyanate-labeled dextran via a duodenal catheter. GI contents were collected for dye, bile acid, and hemoglobin (index of bleeding) determinations. RESULTS: LPS significantly impaired intestinal transit and increased duodenogastric bile reflux and gastric luminal hemoglobin content. Ketamine improved intestinal transit, prevented LPS-induced bile reflux, and diminished gastric bleeding. In mechanistic studies, ketamine also attenuated LPS-induced upregulation of the proinflammatory genes inducible nitric oxide synthase and cyclo-oxygenase-2 in the stomach but preserved expression of the anti-inflammatory gene heme-oxygenase-1 (Western blot). CONCLUSIONS: These data suggest that ketamine may prevent LPS-induced gastric bleeding by decreasing bile reflux through improved intestinal transit or by local changes in nitric oxide, prostaglandin, and carbon monoxide metabolism.

Laparotomy attenuates lipopolysaccharide-induced gastric bleeding in the rat.

Lipopolysaccharide (LPS) increases systemic inflammation and causes duodenogastric reflux of bile and gastric bleeding. Laparotomy prevents gastric injury from the luminal irritant bile, but its effects on LPS-induced gastric injury are unknown. We hypothesized that laparotomy would diminish inflammation and attenuate gastric bleeding caused by LPS. In the rat, laparotomy, done either before or after administration of LPS, attenuated LPS-induced bile reflux, gastric bleeding, and cyclooxygenase-2, but not inducible nitric oxide synthase, expression when compared to controls given LPS. Laparotomy also blunted LPS-induced changes in serum cytokine production. These data suggest that laparotomy has gastroprotective effects by preventing LPS-induced bile reflux and gastric bleeding and by a mechanism mediated, at least in part by cyclooxygenase-2.

Role of serotoninergic system in the development of gastrointestinal diseases.

Experimental gastroduodenal ulcer was simulated after pre-injection of serotonin; gastroesophageal reflux disease and duodenogastral reflux were induced. Activation of the serotoninergic system promoted the development of alteration processes in gastroduodenal ulcer.

Duodenal juice stimulates oesophageal stem cells to induce Barrett's oesophagus and oesophageal adenocarcinoma in rats.

the present study was performed to examine the sequential process of the development of Barrett's oesophagus (BE) and oesophageal adenocarcinoma (ADC) induced by duodeno-oesophageal reflux (DER) in rats. Total gastrectomy was performed in male Wistar rats weighing approximately 250 g followed by reconstruction with oesophago-jejunostomy, which causes unavoidable DER without exposure to exogenous carcinogens. Animals were selected at random and sacrificed every 10 weeks after surgery until 50 weeks. Severe squamous oesophagitis with erosion, regenerative thickening (RT), and basal cell hyperplasia (BCH) were observed on the 10th week after surgery. On the 20th week, glandular structures that stained positively with Galactose oxidase-Schiff (foveolar metaplasia) were observed in the basal layer of the oesophageal squamous epithelium. On the 30th week, the glands developed and formed cysts that stained positively with concanavalin A (pyloric glandular metaplasia) and/or high-iron diamine and Alcian blue (intestinal metaplasia). From the 40th week after surgery, ADC cells surrounded by columnar-lined epithelium were found. Persistent stimulation with DER can alter the stem cells in the squamous epithelial basal layer leading to the formation of columnar-lined cells and subsequent ADC. Foveolar metaplasia was observed as part of the sequence of events leading to the development of columnar-lined epithelium (CLE), followed by the appearance of pyloric glandular metaplasia and intestinal metaplasia, completing the histogenesis of BE.

Therapeutic effect of DA-9601 on chronic reflux gastritis induced by sodium taurocholate in rats.

AIM: To investigate the therapeutic effects of DA-9601 on sodium taurocholate (TCA)-induced chronic reflux gastritis in SD rats. METHODS: In this study, we have investigated the therapeutic effects of DA-9601 on chronic erosive and atrophic gastritis induced by 6 mo of TCA administration (5 mmol/L in drinking water) in SD rats. RESULTS: Four weeks of DA-9601 administration (0.065%, 0.216% in rat chow), following the withdrawal of TCA treatment, resulted in a significant decrease in total length of erosions in rats in a dose-dependent manner. Furthermore, the indicators of atrophic gastritis, such as reduced mucosal thickness and reduction in the number of parietal cells, were improved by the administration of DA-9601 in a dose-related manner. DA-9601 also attenuated inflammatory cell infiltration and the proliferation of collagenous fiber in the gastric mucosa. The improvement in the reduction of the gastric mucus was observed in the rats receiving a high dose of DA-9601 (0.216%). The therapeutic effect of DA-9601 on experimental chronic erosive gastritis was superior to that of rebamipide (1.08% in rat chow). Biochemical analyses showed increased mucosal prostaglandin E2 and reduced glutathione levels by DA-9601 treatment. CONCLUSION: We suggest that DA-9601 is a promising agent for the treatment of chronic erosive and atrophic gastritis with an etiological factor of bile reflux. Increased mucosal prostaglandin E2 and reduced glutathione by DA-9601 treatment may be therapeutic mechanisms for chronic erosive and atrophic gastritis.

Dopamine delays gastric emptying and induces retrograde power contractions with enterogastric reflux.

The purpose of the study was to elucidate the effects of dopamine on gastroduodenal motility and gastric emptying of an acaloric viscous meal. In four conscious dogs, antral, pyloric and duodenal contractions were recorded with extraluminal strain gage force transducers and induction coils. Gastric emptying was assessed radiographically. Dopamine at low dose (5 micrograms/kg x min) significantly diminished gastric emptying. It was mainly caused by a reduction in the contraction force of the antral waves. Dopamine at higher dose (10-15 micrograms/kg x min) induced retrograde power contractions accompanied by enterogastric reflux. When the dopamine infusion was stopped after the occurrence of a reverse power contraction, the antrum exhibited forceful contractions but gastric emptying ceased due to a profound decrease in antral tone. The results suggest that dopamine 1) inhibits gastric emptying of viscous meals, 2) induces reverse power contractions independently from vomiting, and that 3) antral tone is a basic requirement for gastric emptying of viscous meals.

Metformin in the digestive tract.

After ingestion of metformin, a drug of the biguanide class, there are gastrointestinal effects in the form of nausea and vomiting, and about 30% of the drug is recovered in feces. The purpose of this work was to explain these two phenomena. Two sets of experiments were carried out. Study I evaluated the gastroduodenal (GD) absorption in six healthy volunteers by means of an intubation method, employing a twin-lumen tube introduced into the intestine and another into the stomach. Metformin 1 g was introduced into the stomach with a homogenized meal containing a non-absorbable marker, 14C-PEG 4000; another marker, PEG 4000, was perfused continuously into the duodenum at the ampulla of Vater. Samples of GD contents were collected every 15 min during 4 h. Metformin was poorly absorbed from the stomach, about 10% over a 4-h period. It did not modify the gastric emptying of a meal but induced a duodeno-gastric reflux in five out of six subjects. About 20% of the amount of drug emptied from the stomach were absorbed from the duodenum. The delivery process was the rate-limiting factor for metformin absorption from the duodenum. The AUC/24 h increased as the absorption rate from the duodenum increased. Study 2 investigated in six healthy volunteers, using another intestinal perfusion technique, the jejunal and ileal absorption of metformin. Metformin 400 mg in saline solution was perfused, over a 2-h period, below an inflated balloon, directly into either the jejunum or the ileum.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of aspirin and prostaglandin E2 on interdigestive motility complex and duodenogastric reflux in man.

Both increased duodenogastric reflux and chronic aspirin ingestion are associated with the development of gastric ulcers in man. Animal studies suggest aspirin increases duodenogastric reflux. Prostaglandin E2 protects gastric mucosa from the effects of many injurious agents and inhibits gastric motility, but its effect on duodenogastric reflux is unknown. We have studied the effects of aspirin and a synthetic derivative of prostaglandin E2 on duodenogastric reflux during fasting in six normal subjects, while concomitantly monitoring gastrointestinal motility by means of a perfused catheter system. We found that duodenogastric reflux (as measured by bile salt output in gastric aspirates) increased significantly (P less than 0.05) following both the prostaglandin E2 derivative and aspirin. This increase occurred in phases II and III of the interdigestive motility complex. Both drugs were associated with a significant reduction (P less than 0.05) in frequency and amplitude of antral contraction during phase II. Both drugs also induced a significant disruption (P less than 0.01) of phase III, increasing the number of complexes without an antral and duodenal component. These effects of aspirin may be one of the factors predisposing to the gastric mucosal damage associated with aspirin. The prostaglandin E2 derivative protects gastric mucosa by mechanisms other than reducing duodenogastric reflux and ameliorating the motility disturbances caused by aspirin.