endothelin-1 and Duodenal-Ulcer

Stress is a major etiologic factor in the pathogenesis of gastric and duodenal ulceration, as first described in rats by Hans Selye. In patients with "peptic ulcers" duodenal ulcers are more frequent than gastric ulcers (except in Japan). Thus, our research during the last three decades focused on the molecular mechanisms of duodenal ulcer in rodent models of chemically induced duodenal ulceration, and here we review our three recent findings: Endothelins (ET-1), the immediate early gene egr-1 and imbalance of angiogenic/antiangiogenic molecules. Namely, we found an enhanced expression and release of ET-1 within 15-30 min after the administration of duodenal ulcerogen cysteamine, resulting in local ischemia that triggers the expression of hypoxia-inducible factors (HIF-1alpha). Our gene expression studies also revealed an early (0.5-2 h) increase in the expression of egr-1 that is followed (12-24 h) by upregulation of angiogenic growth factors (e.g., VEGF, bFGF, PDGF). Surprisingly, this event is also associated with an enhanced production of angiostatin and endostatin that probably counteract the beneficial effect of angiogenic molecules. Thus, the initial injury to endothelial and epithelial cells in duodenal ulceration seems to be aggravated (and not initiated) by HCl and proteolytic enzymes. The resulting mucosal necrosis does not rapidly heal because of the imbalance of VEGF and angiostatin/endostatin, hence duodenal ulcers develop. The experimental ulcers Selye described morphologically are now characterized at the molecular and genome level, involving unexpected mediators like ET-1, egr-1 and angiogenesis-related molecules.

Topics: Angiogenesis Inhibitors; Angiogenic Proteins; Animals; Duodenal Ulcer; Early Growth Response Protein 1; Endothelin-1; Humans

To investigate the effect of Helicobacter pylori eradication on endothelin-1 (ET-1) and nitric oxide (NO) in duodenal ulcer (DU) patients.. Sixty-six H pylori-infected active DU patients were consecutively enrolled to receive one-week triple therapy (rabeprazole, amoxicillin and metronidazole) and then one-month rabeprazole therapy. They were asked back to determine ulcer and H pylori status using endoscopy one month later. Thirty-seven healthy controls (H pylori +/-: 17/20) were enrolled for comparison. Blood samples were collected in each visit to measure plasma ET-1 and nitrate/nitrite levels using an enzyme immunoassay kit.. Sixty DU patients finished trial per protocol. The ulcer healing and H pylori-eradication rates were 86.7% and 83.3%, respectively. Plasma ET-1 level in DU patients was higher than that of H pylori-negative and positive controls (3.59+/-0.96 vs 0.89+/-0.54 vs 0.3+/-0.2 pg/mL, P<0.01), while nitrate/nitrite levels among them were also significantly different (8.55+/-0.71 vs 5.27+/-0.68 vs 6.39+/-0.92 mumol/L, P<0.05). H pylori eradication diminished ET-1 levels (3.64+/-0.55 vs 2.64+/-0.55 pg/mL, P<0.01) but elevated nitrate/nitrite level (8.16+/-0.84 vs 11.41+/-1.42 mumol/L, P<0.05).. Both plasma ET-1 and nitrate/nitrite levels increase in active DU patients. After an effective H pylori eradication, DU healing is associated with diminished blood ET-1 level and elevated nitrate/nitrite level.

Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Aged, 80 and over; Amoxicillin; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Ulcer Agents; Benzimidazoles; Biomarkers; Drug Therapy, Combination; Duodenal Ulcer; Endothelin-1; Female; Follow-Up Studies; Helicobacter Infections; Helicobacter pylori; Humans; Male; Metronidazole; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Omeprazole; Rabeprazole

The study included 100 patients with duodenal ulcer (DU), 30 with chronic non-atrophic gastritis (CNAG), 30 with chronic atrophic gastritis (CAG) and 12 practically healthy subjects. All patients with DU and CNAG had morphologically confirmed H. pylori infection. The patients with DU were divided into 2 groups each including age-matched subjects with endoscopically, morphologically, immunohistochemically identical characteristics. Those of group 1 underwent eradication of H. pylori by a traditional 7-day procedure including the use of omeprazole (20 mg BID), claritromycin (500 mg BID) and amoxicillin (1000 mg BID). In group 2 this scheme was supplemented by melatonin (3 mg before bedtime). Patients of group 1 continued to use omeprazole and those in group 2 omeprazole + melatonin till the end of the second month. Healthy subjects and patients with CAG served as controls. All patients underwent FGDS on weeks 2 and 4, immunohistochemical study was conducted to detect endothelin-1 and melatonin-positive cells, apoptotic activity of mucosal epitheliocytes from gastric antrum was determined before and 6 weeks after the onset of therapy. It was shown that introduction of melatonin in the scheme of eradication therapy increases efficacy of H. pylori elimination and accelerates DU cicatrization. Two-month therapy with omeprazole + melatonin more effectively normalizes immunohistochemical parameters (endothelin-1 and melatonin-positive cells) and epitheliocyte apoptotic activity, than omeprazole alone.

Topics: Adult; Antioxidants; Apoptosis; Drug Therapy, Combination; Duodenal Ulcer; Endothelin-1; Epithelial Cells; Female; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Male; Melatonin; Middle Aged; Young Adult

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Duodenal Ulcer; Endothelin-1; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Melatonin; Middle Aged; Nitric Oxide Synthase; Young Adult

Endothelins have been implicated in gastric mucosal damage in a variety of animal models. Furthermore, clinical reports also show elevated gastric mucosal endothelin-1 levels in patients suffering from peptic ulcer diseases. We have demonstrated, first, the presence of immunoreactive endothelin (IR-ET) in human saliva. We also show that endothelins are rather stable in human saliva. The present study was undertaken to determine whether patients with endoscopically proven upper gastrointestinal diseases have a salivary excess of IR-ET, compared with patients with a normal esophagogastroduodenoscopy. Saliva was collected from fasting subjects prior to esophagogastroduodenoscopy. The levels of IR-ET were measured by the radioimmunoassay method. The salivary concentrations of IR-ET in the studied subjects were as follows: 8.9 +/- 1.0 fmol/mL (mean +/- standard error of the mean) for patients with gastric ulcers (n = 18); 7.3 +/- 1.0 fmol/mL for patients with duodenal ulcers (n = 22); and 6.8 +/- 0.6 fmol/mL for patients with gastritis (n = 28). These values are all higher than that of normal subjects (4.4 +/- 0.5 fmol/mL, n = 20; P < 0.001, P < 0.01, and P < 0.05, respectively). No significant differences in salivary IR-ET were noted between patients with a normal esophagogastroduodenoscopy and patients with esophagitis (3.8 +/- 0.7 fmol/mL, n = 4) or gastric cancer (5.3 +/- 1.4 fmol/mL, n = 4). There were no significant differences in the salivary IR-ET levels between males and females. However, the salivary IR-ET levels in the smokers (8.0 +/- 0.6 fmol/mL, n = 38) were significantly higher (P < 0.01) than those of the non-smokers (6.0 +/- 0.4 fmol/mL, n = 58). There was no correlation of IR-ET levels with age. Our findings suggest that salivary endothelin may have a contributing role in certain gastroduodenal diseases.

Topics: Asian People; Duodenal Ulcer; Endoscopy, Digestive System; Endothelin-1; Endothelin-2; Endothelin-3; Esophagitis; Female; Gastritis; Gastrointestinal Diseases; Humans; Male; Radioimmunoassay; Saliva; Smoking; Stomach Neoplasms; Stomach Ulcer; Taiwan; Up-Regulation; Upper Gastrointestinal Tract

Effects of endothelin-1 on gastric acid secretion, duodenal HCO3- secretion, and duodenal mucosal integrity were investigated in anesthetized rats, in comparison with those of TY-10957, a stable analogue of prostacyclin. A rat stomach mounted on an ex-vivo chamber or a proximal duodenal loop was perfused with saline, and gastric acid or duodenal HCO3- secretion was measured using a pH-stat method and by adding 100 mM NaOH or 10 mM HCl, respectively. Duodenal lesions were induced by mepirizole (200 mg/kg) given subcutaneously. Intravenous administration of endothelin-1 (0.6 and 1 nmol/kg) caused an increase of duodenal HCO3- secretion with concomitant elevation of blood pressure; this effect was antagonized by co-administrahon of BQ-123 (ET(A) antagonist; 3 mg/kg, i.v.) and significantly mitigated by vagotomy. Likewise, endothelin-1 caused a significant decrease in histamine-stimulated acid secretion, and this effect was also significantly antagonized by BQ-123. Although TY-10957 (10 and 30 mg/kg, i.v.) produced a temporal decrease of blood pressure, this agent caused not only an increase of duodenal HCO3- secretion, independent of vagal nerves, but also a decrease of acid secretion as well. In addition, both endothelin-1 and TY-10957 significantly prevented mepirizole-induced duodenal lesions at the doses that caused an increase of duodenal HCO3- secretion and a decrease of gastric acid secretion. These results suggest that endothelin-1 affects the duodenal mucosal integrity by modifying both gastric acid and duodenal HCO3- secretions, the effects being mediated by ET(A) receptors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Antihypertensive Agents; Bicarbonates; Duodenal Ulcer; Duodenum; Endothelin-1; Epirizole; Epoprostenol; Gastric Acid; Hydrogen-Ion Concentration; Intestinal Mucosa; Male; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Vagotomy