endothelin-1 and Stomach-Ulcer

To observe the effect of ranitidine on gastric acid, plasma endothelin, and calcitonin gene-related peptide (CGRP) in patients undergoing the brain operation, and to explore the possible pathogenesis of ranitidine on preventing from gastric mucosal injury under the stress.. Thirty patients who underwent brain surgery were randomly divided into 2 groups: Fifteen patients in the control group did not use ranitidine and the other 15 in the treatment group received ranitidine 150 mg intravenously twice daily besides the routine therapy. We continuously monitored the gastric pH value from 4 hours pre-operatively to 72 hours post-operatively in the 30 patients. We also determined the plasma endothelin and CGRP levels of the patients at the 4th hour pre-operatively and at the 4th, 24th, and 72nd hours post-operatively.. In the control group there was no significant difference between the mean intra-gastric pH values pre-operatively and post-operatively (P> 0.05). In the treatment group the level of intra-gastric pH was much higher than that in the control group (P< 0.05). In the control group, the level of plasma endothelin significantly higher and the level of calcitonin gene-related peptide significantly lower than that pre-operatively (P< 0.01), but the level of plasma endothelin significantly was lower and the level of calcitonin gene-related peptide obviously higher in the post-operative treatment group than that pre-operatively (P< 0.01).. The brain operation obviously influences the endogenous plasma endothelin and CGRP levels, but its influence on the intra-gastric acid is not visible. Ranitidine can obviously decrease the level of intra-gastric acid, and improve the macrocirculation of gastric mucous membrane by decreasing ET and increasing the CGRP level.

Topics: Adult; Anti-Ulcer Agents; Brain; Calcitonin Gene-Related Peptide; Endothelin-1; Female; Gastric Acid; Humans; Infusions, Intravenous; Male; Middle Aged; Postoperative Complications; Ranitidine; Stomach Ulcer

We investigated the relationship between microcirculatory disturbance and the host response to Helicobacter pylori infections in gastric ulcer scars to determine the role of endothelin-1 (ET) in ulcer recurrence. The subjects were divided into three groups. The GuS group consisted of patients who had red scarring (S1 stage) at the gastric angle with H. pylori, the gast+ group who had gastritis with H. pylori, and the gast- group who had gastritis without H. pylori. During endoscopic examination, biopsies were taken from the gastric angle. Mucosal ET, nitric oxide (NO), interleukin-8 (IL-8), and RANTES were measured. ET, inducible NO synthase (iNOS), and endothelial constitutive NOS (ecNOS) were immunostained. Mucosal ET and oxides of nitrogen (NOx) were significantly higher in the GuS group than in the other groups. IL-8 was elevated in the GuS and gast+ groups, and RANTES was elevated in the gast+ group (p < 0.01). There was prominent inflammatory cell infiltration in the GuS group. ET-positive cells were found in vascular smooth muscle, gastric epithelium, and gastric smooth muscle. iNOS-positive cells were found in vascular smooth muscle, gastric epithelium, gastric smooth muscle, and inflammatory cells. In conclusion, local inflammation and microcirculatory disturbance persist at the center of the ulcer scar (S1). Decreased cytokine levels and increased ET and NO (mainly synthesized by iNOS) levels suggested that microcirculatory disturbance is a more important factor than immune response in ulcer recurrence.

Topics: Cytokines; Endothelin-1; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Microcirculation; Nitric Oxide; Recurrence; Stomach Ulcer

Gastric ulcer (GU), a prevalent digestive disease, has a high incidence and is seriously harmful to human health. Finding a natural drug with a gastroprotective effect is needed. Ocotillol, the derivate of ocotillol-type saponins in the

Topics: Acetic Acid; Animals; Anti-Inflammatory Agents; Anti-Ulcer Agents; Endothelin-1; Ginsenosides; Male; Metabolomics; Nitric Oxide; Rats; Rats, Wistar; Stomach Ulcer

To assess whether Veronicastrum axillare (V. axillare) can ameliorate ethanol-induced gastric mucosal lesions in rats, reduce the production of pro-inflammatory cytokines, suppress apoptosis and improve local microcirculation disturbances.. Totally 48 male Sprague-Dawley rats were randomly divided into six groups, eight rats in each group. Rats in the normal group and the model group were administered with 0.9% normal saline respectively. Rats in the positive group and ranitidine group were administered with 0.18% ranitidine suspension by intragastric administration respectively. Those in the high dose V. axillare group, the medium dose V. axillare group and the low dose V. axillare group were administrated with V. axillare at the daily dose of 2.8 g/kg, 1.4 g/kg and 0.7 g/kg by intragastric administration. Gastric mucosal lesions were produced by intragastric administration of absolute ethanol. Water extract of V. axillare was successively injected for 14 d and last day was injected 1 h before ethanol administration. Gastric mucosal ulcer index and ulcer inhibitory rate were counted by improved Guth methods. The tissue sections were made for pathological histology analysis. Also, we measured the concentrations of tumor necrosis factor-α (TNF-α) and endothelin-1 (ET-1) in gastric mucosal, as an index of the pro-inflammatory cytokines, apoptosis and local microcirculation. Besides, the mRNA contents of TNF-α and ET-1 were measured to verify effects on gene expression by real-time fluorescent quantitative PCR.. Water extract of V. axillare significantly ameliorated the gastric mucosal lesions induced by ethanol administration (P<0.01). Pro-inflammatory cytokines, TNF-α and ET-1 were increased after ethanol administration and significantly reduced by water extract of V. axillare. The expressions of TNF-α and ET-1 mRNA were also be inhibited by water extract of V. axillare.. Current evidences show water extract of V. axillare is effective for defending against ethanol-induced gastric mucosal lesions, significantly inhibiting the production of pro-inflammatory cytokines and the expressions of TNF-α and ET-1 mRNA, which may be useful for inhibiting apoptosis and improving local microcirculation.

Topics: Animals; Anti-Ulcer Agents; Apoptosis; Disease Models, Animal; Endothelin-1; Ethanol; Gastric Mucosa; Gene Expression Profiling; Male; Plant Extracts; Plantago; Ranitidine; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Treatment Outcome; Tumor Necrosis Factor-alpha

To select the optimal combination of five active component of Banxia Xiexin Decoction on gastric ulcer rat, and observe its effect on Leptin and ET-1.. Eighty-seven SD rats were randomly divided into normal group, sham-operated group and acetic acid-induced gastric ulcer group, omeprazole group as a positive control, five active components (glycyrrhetic acid, beta-sitosterol, berberine, baicalin and ginsenoside) of Banxia Xiexin Decoction were divided into groups by L16 orthogonal design. The ulcer area, and the content of Leptin and ET-1, and the mRNA expression level of both were detected.. Among the sixteen orthogonal design groups, the ulcer area of these groups using both beta-sitosterol and berberine was the smallest (P < 0.05), the content of Leptin of these groups using both glycyrrhetic acid and ginsenoside was the highest in blood serum (P < 0.05), the group using glycyrrhetic acid had the minimum concentration of ET-1 in blood plasma. Compared with model group, berberine could raise the mRNA expression level of Leptin (P < 0.01), and beta-sitosterol could lower the mRNA expression level of ET-1 (P < 0.01).. The pathogenesis of gastric ulcer may be related with the down-regulation of concentration and mRNA expression level of Leptin, and upregulation of concentration and mRNA expression level of ET-1, the active components in Banxia Xiexin Decoction may upregulated Leptin and inhibit ET-1 to accelerate the healing of gastric ulcer.

Topics: Acetates; Animals; Berberine; Disease Models, Animal; Drugs, Chinese Herbal; Endothelin-1; Flavonoids; Gastric Mucosa; Leptin; Male; Plants, Medicinal; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sitosterols; Stomach Ulcer

To establish a rat ethanol gastritis model, we evaluated the effects of ethanol on gastric mucosa and studied the preventive effects of geranylgeranylacetone on ethanol-induced chronic gastritis.. One hundred male Sprague-Dawley rats were randomly divided into 4 equal groups: normal control group, undergoing gastric perfusion of normal saline (NS) by gastrogavage; model control group and 2 model therapy groups that underwent gastric perfusion with ethanol (distillate spirits with 56% ethanol content) by gastrogavage for 4 wk. Low or high doses of geranylgeranylacetone were added 1 h before ethanol perfusion in the 2 model therapy groups, while the same amount of NS, instead of geranylgeranylacetone was used in that model control group. The rats were then sacrificed and stomachs were removed. The injury level of the gastric mucosa was observed by light and electron microscopy, and the levels of prostaglandin 2 (PGE₂), endothelin-1 (ET-1) and nitric oxide (NO) were measured by radioimmunoassay and the Griess method.. The gastric mucosal epidermal damage score (EDS; 4.5) and ulcer index (UI; 12.0) of the model control group were significantly higher than that of the normal control group (0 and 0 respectively, all P = 0.000). The gastric mucosal EDS and UI of the 2 model therapy groups (EDS: 2.5 and 2.0; UI: 3.5 and 3.0) were significantly lower than that of the model control group (all P < 0.01). There was no statistically significant difference between the low-dose and high-dose model therapy groups. The expression value of plasma ET-1 of the model control group was higher than that of the normal control group (P < 0.01) and the 2 model therapy groups (all P < 0.01). The expression values of gastric mucosal PGE₂ and serum NO of the model control group were lower than those of the normal control group (all P < 0.05) and the 2 model therapy groups (all P < 0.05). The thickness of the gastric mucous layerand the hexosamine content in the model control group were significantly lower than that in the normal control group (all P < 0.01) and the 2 model therapy groups (all P < 0.05). Scanning and transmission electron microscopy observation showed that in the model control group, the epithelial junctions were vague, the intercellular joints disappeared and damage of the intracellular organelles were significantly worse than those in the normal control group. However, in the 2 model therapy groups, damage to the intercellular joints and organelles was ameliorate relative to the model control group.. Administration of geranylgeranylacetone was correlated with a more favorable pattern of gastric mucosa damage after ethanol perfusion. The mechanism could be related to regulation of ET-1, NO and PGE₂.

Topics: Animals; Anti-Ulcer Agents; Cytoprotection; Dinoprostone; Disease Models, Animal; Diterpenes; Endothelin-1; Ethanol; Gastric Mucosa; Gastritis; Male; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Nitric Oxide; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Stomach Ulcer

To investigate the mechanism of gastric mucosal demage induced by water immersion restraint stress (WRS) and its prevention by growth hormone releasing peptide-6 (GHRP-6).. Male Wistar rats were subjected to conscious or unconscious (anesthetized) WRS, simple restraint (SR), free swimming (FS), non-water fluid immersion, immersion without water contact, or rats were placed in a cage surrounded by sand. To explore the sensitivity structures that influence the stress reaction besides skin stimuli, a group the rats had their eyes occluded. Cervical bilateral trunk vagotomy or atropine injection was performed in some rats to assess the parasympathetic role in mucosal damage. Gastric mucosal lesions, acid output and heart rate variability were measured. Plasma renin, endothelin-1 and thromboxane B2 and gastric heat shock protein 70 were also assayed. GHRP-6 was injected [intraperitoneal (IP) or intracerebroventricular (ICV)] 2 h before the onset of stress to observe its potential prevention of the mucosal lesion.. WRS for 6 h induced serious gastric mucosal lesion [lesion area, WRS 81.8 ± 6.4 mm² vs normal control 0.0 ± 0.0 mm², P < 0.01], decreased the heart rate, and increased the heart rate variability and gastric acid secretion, suggesting an increase in vagal nerve-carrying stimuli. The mucosal injury was inversely correlated with water temperature (lesion area, WRS at 35 °C 56.4 ± 5.2 mm² vs WRS at 23 °C 81.8 ± 6.4 mm², P < 0.01) and was consciousness-dependent. The injury could not be prevented by eye occlusion, but could be prevented by avoiding contact of the rat body with the water by dressing it in an impermeable plastic suit. When water was replaced by vegetable oil or liquid paraffin, there were gastric lesions in the same grade of water immersion. When rat were placed in a cage surrounded by sand, there were no gastric lesions. All these data point to a remarkable importance of cutenuous information transmitted to the high neural center that by vagal nerves reaching the gastric mucosa. FS alone also induced serious gastric injury, but SR could not induce gastric injury. Bilateral vagotomy or atropine prevented the WRS-induced mucosal lesion, indicating that increased outflow from the vagal center is a decisive factor in WRS-induced gastric injury. The mucosal lesions were prevented by prior injection of GHRP-6 via IP did, but not via ICV, suggesting that the protection is peripheral, although a sudden injection is not equivalent to a physiological release and uptake, which eventually may affect the vagal center.. From the central nervous system, vagal nerves carry the cutaneous stimuli brought about by the immersion restraint, an experimental model for inducing acute gastric erosions. GHRP-6 prevents the occurrence of these lesions.

Topics: Animals; Anti-Ulcer Agents; Biomarkers; Disease Models, Animal; Endothelin-1; Gastric Acid; Gastric Mucosa; Heart Rate; HSP70 Heat-Shock Proteins; Immersion; Injections, Intraperitoneal; Injections, Intraventricular; Male; Oligopeptides; Parasympatholytics; Photic Stimulation; Rats; Rats, Wistar; Renin; Restraint, Physical; Skin; Stomach Ulcer; Stress, Psychological; Thromboxane B2; Time Factors; Touch; Vagotomy; Vagus Nerve; Water

To investigate the role of endothelin on nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX2) enzyme inhibitors-induced effects on the gastric mucosa.. This study was carried out in the Department of Pharmacology Laboratory, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey during the period January to December 2002. In the first group a cyclooxygenase-1 (COX1) and COX2 enzyme inhibitor, indomethacin (25 mg/kg, subcutaneous injection (s.c), n=7), a selective COX2 enzyme inhibitor, NS398 (10 mg/kg, s.c) and normal saline were administered. In the second group, endothelin-1 (ET1) was administered (200 pmol/kg) alone, in the presence of an endothelin receptor antagonist bosentan, (100 mg/kg) and PGE1 [40 microg/kg, orally] with submucosal injection. In the third group, NS398 and indomethacin were applied in the presence of bosentan. In the fourth group, NS398 were applied in the presence of N (G)-nitro-l-arginine methyl ester (L-NAME) (10 mg/kg, s.c).. Indomethacin caused gastric mucosal injury. The effect of NS398 on gastric mucosa did not differ considerably from that of the control group. Submucosal injection of ET1 caused a gastric damage, which could not be prevented by intragastric administration of bosentan, while pretreatment with PGE1 prevented ET1-induced ulcer. Pretreatment with bosentan did not attenuate indomethacin-induced gastric mucosal damage but it increased NS398-induced damage by 1.5 fold. Pretreatment with L-NAME increased NS398-induced gastric mucosal damage as bosentan did.. These results suggest that neither endothelin-induced nor indomethacin-induced ulcer is completely receptor dependent. Cyclooxygenase-2 inhibitors caused ulcer in the presence of bosentan. Protective effects of gastric mucosal injury of COX2 inhibitors may be via endothelin receptor related nitric oxide release.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Gastric Mucosa; Indomethacin; Rats; Rats, Wistar; Regional Blood Flow; Stomach Ulcer; Sulfonamides

Endothelin (ET)-1 is a potent inducer of peptic ulcers. The roles of ET-1 in ulcer healing, however, have remained unclear, and these were investigated in mice. Gastric ulcers were induced in mice by serosal application of acetic acid. Three days later, mice were given a neutralizing ET-1 antibody or nonimmunized serum. The ulcer size, amount of fibrosis and myofibroblasts, and localization of ET-1 and ET(A/B) receptors were analyzed. To elucidate the mechanisms underlying the effects of ET-1, we examined the proliferation, migration, and release of growth and angiogenic factors in gastric myofibroblasts with or without ET-1. The expression of prepro-ET-1 (an ET-1 precursor) and ET-converting enzyme-1 was examined in gastric myofibroblasts using RT-PCR. Immunoneutralization of ET-1 delayed gastric ulcer healing. The areas of fibrosis and myofibroblasts were smaller in the anti-ET-1 antibody group than in the control. ET-1 was expressed in the gastric epithelium, myofibroblasts, and other cell types. ET(A) receptors, but not ET(B) receptors, were present in myofibroblasts. ET-1 increased proliferation and migration of gastric myofibroblasts. ET-1 stimulated the release of hepatocyte growth factor, VEGF, PGE(2), and IL-6 from gastric myofibroblasts. mRNA for prepro-ET-1 and ET-converting enzyme-1 was also expressed. ET-1 promotes the accumulation of gastric myofibroblasts and collagen fibrils at gastric ulcers. ET-1 also stimulates migration and proliferation of gastric myofibroblasts and enhances the release of growth factors, angiogenic factors, and PGE(2). Thus ET-1 has important roles not only in ulcer formation but also in ulcer healing via mobilizing myofibroblasts and inducing production of stroma-derived factors.

Topics: Angiogenesis Inducing Agents; Animals; Antibodies; Cell Movement; Cell Proliferation; Cytokines; Dose-Response Relationship, Drug; Endothelin-1; Fibroblasts; Gastric Mucosa; Growth Substances; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Peptides, Cyclic; Placebos; Receptor, Endothelin A; Receptor, Endothelin B; Stomach; Stomach Ulcer; Time Factors; Ulcer

To prospectively identify histologically and endoscopically the effect of omeprazole on the expression of endothelin-1 (ET-1), inducible nitric oxide synthase (iNOS) and macrophage inflammatory protein-1alpha (MIP-1alpha) in the gastric mucosa of neurosurgical patients with stress ulcer.. Twenty-five patients with severe acute intracranial lesions caused by trauma were enrolled in this study. A 40 mg intravenous bolus of omeprazole (OME) was given daily for 7 days. The intragastric pH was continuously recorded for 24 hours on day 1 and 8. Endoscopic evaluation of the gastric corpus, antrum, and duodenal bulb was performed in the ICU, within 24 hours after brain injury, and at follow-up on the 7th day after admission. Paired biopsies were obtained for histologic examinations and immunohistochemical analysis was performed using a LSAB method for MIP-1alpha, ET-1, and iNOS.. There were 72% and 70% of gastroduodenal mucosal lesions at the initial and follow-up endoscopies, respectively. However, the severity of mucosal lesions showed significant improvement in most patients at follow-up (p < 0.05). Mean percentages of time intragastric pH were greater than or equal to 4.0 were 20 +/- 11% and 70 +/- 17% on day 1 and 8, respectively (p < 0.05). The incidences of ET-1, iNOS and MIP-1alpha expression were not significantly different between the patients before and after OME prophylaxis.. Prophylactic OME is effective in reducing the severity of stress ulcerations in severe neurotraumatic patients. High incidence of tissue ET-1 expression combined with increased activity of iNOS and MIP-1alpha may be responsible for the gastric mucosal injury. We also show that OME fails to counter the enhancement in the mucosal expression of ET-1, iNOS, and MIP-1alpha caused by severe brain damage.

Topics: Adult; Aged; Anti-Ulcer Agents; Brain Injuries; Chemokine CCL3; Chemokine CCL4; Endothelin-1; Female; Gastric Mucosa; Humans; Hydrogen-Ion Concentration; Macrophage Inflammatory Proteins; Male; Middle Aged; Nitric Oxide Synthase Type II; Omeprazole; Stomach Ulcer; Wounds and Injuries

To investigate in rats the role of endothelin (ET)-1 gene expression in the development and progression of acute gastric mucosal lesions (AGML) induced by stress, and the effect of BQ-123 (a special ETA receptor antagonist) on the AGML.. A rat model of gastric ulcer induced by cold-restraint-stress (CRS) was used. ET-1 concentrations in the plasma and gastric mucosa were determined by radioimmunoassay (RIA), gastric mucosa blood flow (GMBF) was measured with a laser Doppler flow meter, the ulcer index (UI) was used to estimate the degree of gastric mucosa damage and the expression levels of ET-1 mRNA in the gastric mucosa were measured using dot blot and reverse transcription polymerase chain reaction (RT-PCR). Different doses of BQ-123 were administered via the left femoral vein prior to the stress in order to observe the effects of BQ-123 on the ET-1 concentrations in the plasma and gastric mucosa, the GMBF and the UI.. Compared with the normal controls, the ET-1 concentrations in the plasma and gastric mucosa of the stressed rats were increased significantly (P < 0.05), the GMBF was decreased markedly (P < 0.01), and the UI increased dramatically (P < 0.01). There was a significant positive correlation between the gastric mucosal EF-1 concentration and the UI (r = 0.98, P < 0.01), and a significant negative correlation between the gastric mucosal ET-1 concentration and GMBF (r = -0.89, P < 0.01) and also between the UI and GMBF (r = -0.98, P < 0.01). The expression level of ET-1 mRNA in the gastric mucosa of the stressed rats increased significantly compared with that of the normal controls (P < 0.01), and there was a positive correlation between the expression of ET-1 mRNA and the ET-1 concentration in the gastric mucosa (r = 0.93, P < 0.01). Compared with the untreated animals, the GMBF was increased (P < 0.01) and the UI decreased significantly (P < 0.01) in the BQ-123-treated rats, and the dose of BQ-123 correlated with the degree of change in the GMBF and UI; however, the ET-1 concentrations of either the plasma or the gastric mucosa did not change markedly in the BQ-123-treated animals (P > 0.05).. The present study showed that the level of expression of ET-1 mRNA and the synthesis of ET-1 in the gastric mucosa both increased significantly, which suggests that the increased concentration of endogenous ET-1 may be involved in the development and progression of stress ulcer (acute gastric mucosa lesion). The mechanism of action may be associated with a reduction of GMBF induced by ETAR-mediated vasoconstriction. BQ-123 can dose-dependently attenuate significantly the degree of damage to the gastric mucosa induced by stress, and may have therapeutic benefits for stress ulcer.

Topics: Acute Disease; Animals; Cold Temperature; Endothelin Receptor Antagonists; Endothelin-1; Gastric Mucosa; Gene Expression; Male; Peptides, Cyclic; Rats; Rats, Sprague-Dawley; Restraint, Physical; RNA, Messenger; Stomach Ulcer; Stress, Physiological

We studied the relation of hypoxia-inducible factor-1alpha (HIF-1alpha) to vascular endothelial growth factor and vasoactive factors during the healing of gastric ulcers. The gastric ulcers were divided into three stages (active stage, healing stage and scar stage). The expression of HIF-1alpha, endothelin-1, inducible nitric oxide synthase, and vascular endothelial growth factor mRNA was highest during the active stage of ulcer healing, and endothelin-1, vascular endothelial growth factor protein levels and nitric oxide were higher during the healing stage. Thus, levels of HIF-1alpha mRNA tend to increase during the active stage of gastric ulcer healing, suggesting that this factor participates in the induction of endothelin-1, inducible nitric oxide synthase, and vascular endothelial growth factor. Also, the HIF-1alpha mRNA level did not differ significantly among the various stages of ulcer healing, and detectable levels of HIF-1alpha protein were not found during any stage. This suggests that these angiogenic factors and vasoactive substances may be induced by HIF-1alpha. During the active stage on endoscopic examination, considered the initial phase of ulcer healing, the process of ulcer healing has begun, and the tissue at the ulcer margin has already been reoxygenated.

Topics: Case-Control Studies; Endothelin-1; Gastric Mucosa; Gastroscopy; Gene Expression Regulation, Enzymologic; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Nitric Oxide; Nitric Oxide Synthase Type II; RNA, Messenger; Stomach Ulcer; Up-Regulation; Vascular Endothelial Growth Factor A; Wound Healing

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

Gastric microcirculatory disturbances are involved in the ethanol-induced gastric mucosal damage. In this study in humans we evaluated the time course of plasma and gastric mucosal endothelin-1 (ET-1) concentrations after intragastric ethanol administration; furthermore we determined the correlation among changes in gastric tissue endothelin-1 and microscopic and gross gastric hemorrhagic damage. ET-1 concentrations in plasma and gastric mucosa were measured by radioimmunoassay. The endoscopic appearance of the gastric mucosa was evaluated and scored on a scale of 0-5, and gastric biopsies for histological evaluation were obtained from the antral and the corpus mucosa just before and 30 min after 40% ethanol administration in seven healthy volunteers. Plasma ET-1 concentration increased as soon as 20 min after ethanol administration, reached a significant peak at 30 min (P < 0.01), and returned to near basal level within 120 min. Gastric mucosal ET-1 concentration significantly increased 30 min after ethanol administration in both the body (P < 0.05) and the antrum (P < 0.05) of the stomach; however the ET-1 increase was significantly higher in the body. Moreover, data obtained 30 min after ethanol administration showed a significant correlation between gastric mucosal ET-1 levels and gross hemorrhagic damage (r = 0.84). A significant correlation was also observed between antral gastric mucosal ET-1 and microscopic lesions (r = 0.70). We conclude that 40% ethanol, given orally, stimulates the release of gastric mucosal endothelin-1 and causes a rapid and time-dependent increase of ET-1 plasma level in humans. The increased plasma and gastric tissue endothelin-1 concentration may play a role in ethanol-induced gastric hemorrhagic injury in humans.

Topics: Adult; Alcohol Drinking; Biopsy; Capillary Permeability; Endothelin-1; Gastric Mucosa; Gastritis; Gastroscopy; Humans; Male; Microcirculation; Peptic Ulcer Hemorrhage; Stomach Ulcer; Vasoconstriction

Endothelins (ETs) participate directly and indirectly in angiogenesis via ET receptors. During early fetal angiogenesis, vascular endothelial growth factor (VEGF) and its receptors kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase-1 (Flt-1) are required for the development of the systemic vasculature. In late angiogenesis, stromal-cell-derived factor (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) act in an organ-specific manner to promote the formation and development of large blood vessels supplying the gastrointestinal tract. We studied the roles of these ligand receptors in angiogenesis during healing of gastric ulcers. We studied the following five groups, each consisting of ten cases of endoscopically confirmed gastric ulcer: active stage (GA), healing stage (GH) and scar stage (GS) of gastric ulcers located in the angulus; Helicobacter pylori (Hp)-positive gastritis (gast+); and Hp-negative gastritis (gast-). All cases in the ulcer groups were Hp-positive. The study materials consisted of frozen biopsy specimens of lesions arising in the angulus. ET-1 was measured by enzyme immunoassay. The other factors were assayed by reverse-transcription-PCR. The distributions of ET-1, ETA receptor (ETAR), SDF-1 and CXCR4 in the gastric mucosa were evaluated by enzyme immunoassay. ET-1 and ETAR reached peak levels during the GH (ET: P<0.05, ETAR: P<0.01). VEGF mRNA increased slightly during the GA, but did not differ significantly among the groups. KDR and Flt-1 levels were high during the GA, the level being significantly higher than those during the GH and GS (P<0.05). SDF-1 levels significantly decreased during the GH and GS compared with levels during the GA, and CXCR4 significantly increased during the GH and GS (P<0.01). On immunostaining, ET-1-positive cells and ETAR-positive cells were found in the endothelium, vascular smooth muscle and gastric epithelium, and CXCR4-positive cells were found in the endothelium and gastric epithelium during the GH and GS. Our results suggest that VEGF receptors are mainly expressed early in ulcer development and participate in the initial stage of angiogenesis. SDF-1 receptors and ETAR are primarily expressed during the GH and GS and are involved in vascular maturation and gastric mucosal regeneration during late angiogenesis.

Topics: Chemokine CXCL12; Chemokines, CXC; Endothelial Growth Factors; Endothelin-1; Extracellular Matrix Proteins; Gastric Mucosa; Growth Substances; Helicobacter Infections; Helicobacter pylori; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Lymphokines; Neovascularization, Physiologic; Receptor, Endothelin A; Receptors, CXCR4; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; Stomach Ulcer; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors

To elucidate the physiological roles of endothelin-1 (ET-1) and endothelin-2 (ET-2)/vasoactive intestinal contractor (VIC) in gastric injury of mice, we measured the gene expression rates of ET-1 and ET-2/VIC in gastric injury induced by ethanol in young (8 weeks) and old (>33 weeks) mice. Mice that were fasted for 24 h were injected with absolute ethanol intragastrically and killed after 1 or 4 h of ethanol exposure. The size of the gastric lesions increased gradually after ethanol exposure and was at its greatest after 4 h, in both young and old mice. The gene expression of ET-1 tended to increase after 1 h and to decrease by 4 h of ethanol exposure in both young and old mice. However, the gene expression of ET-2/VIC in young mice increased significantly after 1 and 4 h of ethanol exposure, whereas the gene expression of ET-2/VIC in the old mice did not change after ethanol exposure. Based on these results, we conclude that aging influences the gene expression of ET-2/VIC but not lesion size or gene expression of ET-1 in ethanol-induced gastric injury in the mouse. We therefore suggest that regulation of gene expression of these two genes differs during the course of aging.

Topics: Aging; Animals; Endothelin-1; Endothelin-2; Ethanol; Gene Expression Regulation; Male; Mice; Mice, Inbred ICR; Models, Animal; Neovascularization, Physiologic; Reverse Transcriptase Polymerase Chain Reaction; Stomach Ulcer

The course of events associaed with healing gastric mucosal injury involves an orderly interplay between the array of signaling molecules that exert their influence on the processes leading to the restoration of the mucosal integrity. In this study, we investigated the effect of antiulcer agent, sucralfate, on the mucosal apoptotic processes during gastric ulcer healing by analyzing the expression of interleukin-4 (IL:4), endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-alpha), and the mucosal activity of capase-3, and constitutive (cNOS) and inducible nitric oxide synthase (NOS-2).. Rats with experimentally induced chronic gastric ulcers were administered twice daily for 14 days either sucralfate at 100 mg/kg or vehicle, and at different stages of treatment their stomachs were used for macroscopic and biochemical assessments.. The ulcer onset was characterized by a massive epithelial apoptosis associated with a 33-fold increase in caspase-3 activity, 5.7-fold increase in TNF-alpha, 17.5-fold increase in NOS-2 and a 3.9-fold increase in ET-1, while the mucosal expression of cNOS activity showed a 7.6-fold drop and IL-4 expression fell by 37.2%. The healing was reflected in a rapid recovery in IL-4, and a decrease in apoptosis, caspase-3, TNF-alpha, ET-1 and NOS-2, and a slow recovery in cNOS activity, and the process was accelerated in the sucralfate-treated group. While in the absence of sucralfate the expression of IL-4 returned to that of the normal mucosa by the 7th day of healing and that of ET-1 and TNF-alpha by the 14th day, an accelerated ulcer healing with sucralfate treatment was associated with IL-4 recovery by the 4th day and that of ET-1 and TNF-alpha by the 10th day when the ulcer heated, while recovery in cNOS activity required 14 days. Yet, in both groups of animals the apoptotic DNA fragmentation rate, caspase-3 and the expression of NOS-2 activity remained significantly elevated even after the ulcer healed.. The results suggest that a decrease in the mucosal expression of the regulatory cytokine IL-4 at the ulcer onset may well be a key factor causing dysregulation of ET-1 production, induction of TNF-alpha, and triggering the apoptotic events that affect the efficiency of mucosal repair process. We also show that accelerated ulcer healing by sucralfate may be the result of a rapid mucosal IL-4 generation that leads to the suppression of the mucosal apoptotic events.

Topics: Animals; Anti-Ulcer Agents; Apoptosis; Caspase 3; Caspases; Down-Regulation; Endothelin-1; Interleukin-4; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Sucralfate; Tumor Necrosis Factor-alpha; Wound Healing

Submucosal injection of endothelin (ET)-1 induces gastric ulcer. We investigated the roles of neutrophils and adhesion molecules (intercellular adhesion molecule (ICAM)-1 and CD18) in the development of ET-1-induced ulcers in rats. Ulcers were induced by submucosal injection of ET-1. Rats were injected with anti-neutrophil serum or F(ab')2 fragments of irrelevant mouse IgG2a (control), anti-ICAM-1 antibody, or anti-CD18 antibody. Ulcer tissues were subjected to measurement of myeloperoxidase (MPO) activity, ulcer size, and immunohistochemical study. Within 3 hr, arterial vasoconstriction and vascular congestion were observed at sites of ET-1 injection. By 6 hr, vascular congestion had disappeared, and ICAM-1 expression had markedly increased in venules in deep portions of the mucosa and submucosa, accompanied by an increase in the number of CD18-positive neutrophils. By 48 hr, ulcers that extended into the submucosa had developed. In controls, MPO activity gradually increased and was maximal by 6 hr. Neutrophil depletion, and immunoneutralizing of ICAM-1 and CD18 inhibited the increase in MPO activity, and decreased ulcer sizes measured at 48 hr. In conclusion, ET-1 causes ischemia-reperfusion injury, and neutrophil accumulation after reperfusion mediated by the ICAM-1-CD18 pathway may be important in the development of ET-1-induced gastric ulcer.

Topics: Animals; CD18 Antigens; Endothelin-1; Gastric Mucosa; Injections; Intercellular Adhesion Molecule-1; Male; Mice; Neutrophils; Peroxidase; Rats; Rats, Wistar; Reperfusion Injury; Stomach Ulcer

In order to study the roles of vasoactive peptides during tissue repair of gastric ulcers, we compared concentrations in tissue surrounding gastric ulcers of endothelin-1(ET-1), adrenomedullin (AM), and transforming growth factor-beta (TGF-beta) among different stages of ulcer development. A total of 82 cases were studied. Ulcers were located in the gastric angulus in 51 cases. All cases were positive for Helicobacter pylori (Hp). Ten cases were in the active stage (GA), 18 were in the healing stage (GH), and 28 were in the scarring stage (GS). As control, 17 cases of Hp-positive gastritis (gast+) and 14 of Hp-negative gastritis (gast-) were studied. The concentrations of endothelin (ET) and TGF-beta were in the order of GH> GA> GS, and those of AM were in the order of GS > GH > GA. On immunostaining, ET stained positively in endothelial cells and vascular smooth muscle cells (VSMCs) during the GH and GS stages, and AM stained positively in histiocytes during GA, GH and GS, and also stained positively in glandular epithelia and smooth muscle fibers during GH and GS. When our results were reviewed with respect to the regulation of vascular tonus and the proliferation of VSMCs, ET and AM were considered to have roles in the regulation of proliferation.

Topics: Adrenomedullin; Endothelin-1; Gastric Mucosa; Humans; Immunoenzyme Techniques; Peptides; Stomach Ulcer; Transforming Growth Factor beta; Wound Healing

Endothelin-1 (ET-1), nitric oxide, and cytokines are recognized mediators of the inflammatory processes associated with gastric mucosal injury. In this study, we investigated mucosal expression of ET-1, interleukin-4 (IL-4), and the activity of constitutive nitric oxide synthase (cNOS) during indomethacin-induced gastric mucosal injury, and evaluated the effect of antiulcer agents on this process. The experiments were conducted with groups of rats pretreated intragastrically with ranitidine (100 mg/kg), ebrotidine (100 mg/kg), sulglycotide (200 mg/kg) or vehicle, followed 30 min later by an intragastric dose of indomethacin (60 mg/kg). The animals were killed 2 h later and their mucosal tissue subjected to macroscopic damage assessment and the measurements of epithelial cell apoptosis, ET-1, IL-4, and cNOS. In the absence of antiulcer agents, indomethacin caused multiple hemorrhagic lesions and extensive epithelial cell apoptosis, accompanied by a 20.7% reduction in IL-4, a 3.1-fold increase in mucosal expression of ET-1 and a 4.2-fold decline in cNOS. Pretreatment with H2-receptor antagonist, ranitidine produced a 15.7% reduction in the mucosal damage caused by indomethacin, 29.5% decrease in epithelial cell apoptosis and a 19.6% reduction in ET-1, while the expression of IL-4 increased by 10.8% and that of cNOS showed a 2-fold increase. The H2-blocker, ebrotidine, also known for its gastroprotective effects, reduced the indomethacin-induced lesions by 90.2%, epithelial cell apoptosis decreased by 61% and ET-1 showed a 58.2% decline, while IL-4 increased by 30.6% and that of cNOS showed a 3.1-fold increase. Pretreatment with gastroprotective agent, sulglycotide, led to a 51.2% reduction in the extent of mucosal damage caused by indomethacin, a 43.9% decrease in apoptosis, and a 63.5% decrease in ET-1, while the expression of cNOS increased by 3.4-fold and the level of IL-4 showed a 32.2% increase. The results suggest that an increase in vasoconstrictive ET-1 level combined with a decrease in regulatory cytokine, IL-4, and a loss of compensatory action by cNOS may be responsible for gastric mucosal injury caused by indomethacin. Our findings also point to a value of ebrotidine and sulglycotide in countering the untoward gastrointestinal side effects of NSAID therapy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Apoptosis; Benzenesulfonates; Endothelin-1; Gastric Mucosa; Indomethacin; Interleukin-4; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Ranitidine; Rats; Rats, Sprague-Dawley; Sialoglycoproteins; Stomach Ulcer; Thiazoles

We investigated the course of events associated with gastric ulcer healing by analyzing mucosal expression of interleukin-4 (IL-4), endothelin-1 (ET-1), tumor necrosis factor-alpha (TNF-alpha), and the activity of constitutive (cNOS) and inducible nitric oxide synthase (NOS-2). Ulcer onset was characterized by a massive epithelial apoptosis associated with a 5.7-fold increase in TNF-alpha, a 17.5-fold increase in NOS-2, and a 3.9-fold increase in ET-1, while mucosal expression of cNOS showed a 7.6-fold drop and IL-4 fell by 37.2%. Healing was accompanied by a rapid raise in IL-4; decrease in apoptosis, TNF-alpha, ET-1, and NOS-2; and a slow recovery in cNOS. The expression of IL-4 returned to control levels by the 7th day of healing and that of ET-1 and TNF-alpha by the 14th day, while apoptotic DNA fragmentation and the activity of NOS-2 remained significantly elevated beyond the 14-day period. The results suggest that a decrease in the mucosal level of IL-4 at ulcer onset may well be a key factor causing dysregulation of ET-1 production, induction of TNF-alpha, and triggering the apoptotic events that affect the efficiency of mucosal repair.

Topics: Animals; Chronic Disease; Down-Regulation; Endothelin-1; Gastric Mucosa; Interleukin-4; Laparotomy; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Stomach; Stomach Ulcer; Tumor Necrosis Factor-alpha; Wound Healing

Ammonia, one of the pathogenic factors in Helicobacter pylori-induced mucosal injury, induces acute mucosal lesions in the rat glandular stomach.. The effect of ammonia administered intragastrically on gastric peptides was investigated in urethane-anesthetized rats.. Gastric mucosal lesions were observed 5 min after 0.3% ammonia (4 ml/kg, intragastrically). Immunoreactive endothelin-1 (ET-1) and immunoreactive thyrotropin-releasing hormone (TRH) concentrations in the gastric wall decreased significantly 2 min and 5 min after ammonia, respectively. A significant increase in gastric juice immunoreactive ET-1 and TRH levels was reciprocally observed. The severity of gastric mucosal injury and changes in gastric immunoreactive ET-1 and TRH concentrations were shown to be concentration-dependent 30 min after ammonia. Atropine (5 mg/kg, intraperitoneally, -20 min) prevented ammonia-induced injury accompanied by a block of changes in gastric immunoreactive ET-1 and TRH concentrations. BQ-485 (ET(A) receptor antagonist; 2 mg/kg, subcutaneously) also abolished ammonia-induced lesions and gastric immunoreactive TRH changes.. These findings suggested that gastric ET-1 and TRH play a role in ammonia-induced gastric mucosal injury mediated via a muscarine and an ET(A) receptor.

Topics: Ammonia; Animals; Anti-Ulcer Agents; Atropine; Azepines; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Gastric Juice; Gastric Mucosa; Male; Muscarinic Antagonists; Oligopeptides; Rats; Rats, Wistar; Somatostatin; Stomach Ulcer; Thyrotropin-Releasing Hormone; Time Factors

Endothelin-1 has been reported to be responsible for gastric mucosal damage in various experimental models. We evaluated the role of endogenous endothelin-1 in the pathogenesis of gastric mucosal damage induced by indomethacin and HCl in the rat. Rats were given indomethacin (25 mg/kg) subcutaneously, and 15 min later, 0.2N HCl intragastrically. Gastric mucosal damage, gastric endogenous endothelin-1, and gastric mucosal hemodynamics were measured. The effects of bosentan, a mixed endothelin receptor antagonist, on gastric mucosal integrity and hemodynamics were assessed. Gastric endogenous endothelin-1 was significantly elevated at 20 min, gastric mucosal blood flow began to decrease significantly at 25 min, and gastric damage occupied 52.2% of the total glandular mucosa at 135 min after injection of indomethacin. Intragastric pretreatment with bosentan (5, 10, 30, and 60 mg/kg) significantly attenuated gastric damage, to 26.1%, 7.7%, 3.6%, and 1.6%, respectively, of the total glandular mucosa. Bosentan (60 mg/kg) prevented the initial decrease of blood flow and, even at 135 min, improved blood flow and hemoglobin oxygen saturation significantly. We suggest that indomethacin-induced endogenous endothelin-1 diminishes gastric mucosal blood flow and tissue oxygenation and ultimately causes gastric damage. Endogenous endothelin-1 may play an important role in the pathogenesis of the acute gastric mucosal lesions induced by indomethacin and HCl.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Bosentan; Endothelin Receptor Antagonists; Endothelin-1; Gastric Mucosa; Hydrochloric Acid; Indomethacin; Male; Rats; Rats, Wistar; Regional Blood Flow; Stomach Ulcer; Sulfonamides; Time Factors

Gastric microcirculatory disturbances are involved in the pathogenesis of stress ulcers; however, vasomodulators causing this process are not fully understood. This study was conducted to investigate the role of endothelin 1 (ET-1), a potent vasoconstrictive peptide, in stress ulcers in critically ill patients.. Using sandwich enzyme immunoassay, we measured ET-1 content in plasma and the gastric mucosa of 16 critically ill patients with traumatic head injury on admission and of 11 healthy subjects. Gastric mucosal samples were obtained endoscopically. When gastric drainage contained occult blood, endoscopic examination was performed again, and ET-1 concentrations in injured and adjacent normal mucosa were compared.. Plasma and mucosal ET-1 concentrations were significantly higher in critically ill patients on admission (6.1 +/- 0.6 pg/ml and 13.8 +/- 1.6 ng/g, respectively) compared with values in control subjects (2.7 +/- 0.4 pg/ml and 8.2 +/- 0.5 ng/g, respectively) (p < 0.01). The mucosal ET-1 concentration tended to be elevated in patients who had experienced hypoxia compared with those who had not (p = 0.07). In five patients who were again examined endoscopically, the ET-1 concentration in the injured mucosa was significantly higher than that in adjacent mucosa (19.2 +/- 3.2 and 10.1 +/- 1.6 ng/g, respectively; p < 0.05).. These results suggest that endogenous ET-1 plays an important role in the local pathogenesis of stress ulcers, especially those caused by hypoxia.

Topics: Adult; Critical Illness; Endothelin-1; Female; Gastric Mucosa; Humans; Hypoxia; Male; Middle Aged; Prospective Studies; Stomach Ulcer; Time Factors

To investigate the cause of decrease of gastric mucosal blood flow (GMBF) in obstructive jaundice under stress.. With common bile duct ligation (CBDL) in Wistar rats under cold restraint stress, GMBF and the content of Endothelin-1, Angiotensin-II, H2, alpha 1 receptor in gastric mucosa were measured. Before stress anti-ET-1 serum, Enalapril, Cimentidine and Phetolamins were administrated, and the change of GMBF was studied.. GMBF was significantly decreased in CBDL in stress than those in control subjects. The content of ET1 and Ang-II was significantly increaced, the density of H2 and alpha 1 receptor was significantly decreased. Before stress antagonist was administrated, and GMBF was significantly increased.. GMBF was decreased by increased ET, Ang-II and decreased H2, alpha 1 receptor in CBDL, under stress. Antagonist improved gastric mucosal blood flow. They had protection from gastric mucosa.

Topics: Angiotensin II; Animals; Cholestasis; Cold Temperature; Endothelin-1; Gastric Mucosa; Male; Rats; Rats, Wistar; Receptors, Histamine H2; Regional Blood Flow; Stomach Ulcer; Stress, Physiological