Dose-dependent effects of linear and cyclic somatostatin on ethanol-induced gastric erosions: the role of mast cells and increased vascular permeability in the rat

Somatostatin prevents hemorrhagic gastric erosions produced by ethanol. In this paper we describe studies with linear (reduced) and cyclic (oxidized) synthetic somatostatin-14 in the rat model of ethanol-induced gastric mucosal injury. The linear form of somatostatin was more potent at concentrations of 10(-9) to 10(-8) mol per rat than the cyclic isomere. However, at a concentration of 10(-7) mol per rat i.p. injection of linear somatostatin significantly (P less than 0.01) enhanced gastric erosions caused by the alcohol. The area of hemorrhagic mucosal lesions correlated significantly (r = -0.846) with mast cell depletion in the gastric mucosa of the animals. Increased vascular permeability and mast cell degranulation were also observed after intradermal injection of linear or cyclic somatostatin. The 'cytoprotective' as well as the aggravating potency of linear somatostatin may be connected to gastric mucosal mast cell activity in the rat.     

The effect of central serotonin administration on the neurogenic damage to the gastric mucosa due to chronic social stress in inbred mice]

A reiterated negative experience of intermale confrontations for 3 and 10 days resulted in aggravation of neurogenic ulceration of gastric mucosa in defeated males from all strains of mice under study, the number of mucosa erosions being 2-3-fold greater than in winners or control animals. Administration of serotonine into the lateral ventricles increased the number of erosions in intact mice of all genotypes. In experimental groups, a considerable diversity was found in respect to the effects of exogenous serotonine on the gastric mucosa. Following 10 days of the stress, both in winners and losers, a decrease of the gastric mucosa sensitivity to central serotonine was revealed.     

Protective effects of several amino acid-nutrients on gastric hemorrhagic erosions in acid-irrigated stomachs of septic rats

Our previous report demonstrates that severe gastric mucosal damage is produced in lipopolysaccharide (LPS)-intoxicated rats. In the present study, we examined protective effects of several amino acids including taurine, phenylalanine and L-Arginine on gastric hemorrhagic erosions in acid-irrigated stomachs of LPS rats. The animals were deprived of food for 24 hr. Intravenous LPS (3 mg/kg) was challenged 12 hr after withdrawal of food. Gastric vagotomy was performed, followed by irrigation the stomachs for 3 hr with a physiological acid solution containing 100 mM HCl and 54 mM NaCl. The ulcerogenic parameters including increased gastric acid back-diffusion, mucosal histamine concentrations, lipid peroxide productions, luminal hemoglobin contents, stomach erosions and the lowered glutathione levels were markedly enhanced in LPS rat stomachs irrigated with acid solution. Both phenylalanine and taurine caused dose-dependent attenuations of these ulcerogenic parameters in LPS rats. L-arginine also was effective in inhibition. The inhibitory effect was restored by pretreatment of nitric oxide synthase inhibitors, such as N(G)-nitro-L-arginine-methyl ester or L-N(G)-(1-iminoethyl)-lysine. Furthermore, marked amelioration of hemorrhagic erosions in LPS rats was observed when a combination of these amino acid nutrients was used. The results provide evidence that these amino acid nutrients may ameliorate gastric hemorrhagic erosion via GSH synthesis stimulation, histamine cell membrane stabilization and antioxidant actions in LPS rat stomachs.     

Effects of dexamethasone and FK506 on Helicobacter pylori-induced gastritis and bacterial viability in Mongolian gerbils.

FK506 and dexamethasone were used to investigate whether or not immunosuppression affects H. pylori colonization and gastric mucosal damage induced by Helicobacter pylori in Mongolian gerbils. Two weeks after H. pylori infection, FK506 and dexamethasone or vehicle alone were subcutaneously administered once daily for the following 2 weeks. FK506 or vehicle alone was administered subcutaneously once daily for 5 weeks (1 week before and 4 weeks after infection). In H. pylori-infected animals for 4 weeks, hemorrhagic erosions and inflammatory responses (neutrophil infiltration and lymphoid follicle formation) were induced in gastric mucosa at an incidence of 100%. Both FK506 and dexamethasone administered for 2 weeks markedly reduced such mucosal changes. In these animals, H. pylori viability in the stomach was significantly elevated. FK506 administered for 5 weeks also significantly inhibited the hemorrhagic erosions, edema and neutrophil infiltration in the stomach. H. pylori viability was slightly elevated as compared with the control. It was concluded that the host immune responses might play dual roles both by deteriorating gastritis induced by H. pylori and by protecting against H. pylori infection in its early stage.     

Aspirin-induced gastric injury in the rat: histologic changes and sucralfate cytoprotection

The effect of pretreatment with intragastric sucralfate on aspirin acid-induced gastric mucosal lesions in the rat was studied. The finding by others that sucralfate is cytoprotective and that this cytoprotective effect probably is mediated, at least in part, by stimulation of endogenous prostaglandin synthesis was confirmed. In addition, a time course study revealed that the maximum cytoprotective effect was present 1 min after sucralfate administration and persisted for at least 6 hr. Microscopic evaluation of histologic sections revealed that sucralfate significantly decreased aspirin-induced deep mucosal erosions (those extending into the parietal cell area) but not superficial mucosal damage. Superficial mucosal damage (surface cell injury and erosions involving the mucous neck cell area) could not be detected grossly. The lesions seen grossly were deeper erosions involving the parietal cell area of the mucosa.     

Effects of dexamethasone and FK506 on Helicobacter pylori-induced gastritis and bacterial viability in Mongolian gerbils

FK506 and dexamethasone were used to investigate whether or not immunosuppression affects H. pylori colonization and gastric mucosal damage induced by Helicobacter pylori in Mongolian gerbils. Two weeks after H. pylori infection, FK506 and dexamethasone or vehicle alone were subcutaneously administered once daily for the following 2 weeks. FK506 or vehicle alone was administered subcutaneously once daily for 5 weeks (1 week before and 4 weeks after infection). In H. pylori-infected animals for 4 weeks, hemorrhagic erosions and inflammatory responses (neutrophil infiltration and lymphoid follicle formation) were induced in gastric mucosa at an incidence of 100%. Both FK506 and dexamethasone administered for 2 weeks markedly reduced such mucosal changes. In these animals, H. pylori viability in the stomach was significantly elevated. FK506 administered for 5 weeks also significantly inhibited the hemorrhagic erosions, edema and neutrophil infiltration in the stomach. H. pylori viability was slightly elevated as compared with the control. It was concluded that the host immune responses might play dual roles both by deteriorating gastritis induced by H. pylori and by protecting against H. pylori infection in its early stage.     

Effect of paracetamol on gastric mucosa.

The effect of paracetamol on the gastric mucosa was examined in seven healthy volunteers. The dose used (2 g instilled in 100 ml isotonic saline) was equivalent to about six tablets taken with water. Biopsy specimens were taken before and 10 and 60 minutes after instillation. The mean incidence of damaged surface cells in the control period was 1.7%. Ten minutes after instillation 3.5% of the surface cells were damaged. This increase was not significant. Light microscopy showed focal cell disruption and infiltration of red blood cells. Scanning electronmicroscopy showed minimal loss of normal cell apices. No erosions were seen on microscopy. Biopsy specimens taken 60 minutes after paracetamol showed similar changes. These findings differ appreciably from the extensive cell damage and microscopic erosions caused by therapeutic doses of 600 mg (two tablets) of aspirin. We conclude that large "analgesic" doses of paracetamol cause minimal ultrastructural changes in normal human gastric mucosa. The continued use of paracetamol in place of aspirin appears to be justified when there is a possibility of gastric mucosal injury.     

Dietary nitrate inhibits stress-induced gastric mucosal injury in the rat

Dietary nitrate is reduced to nitrite by some oral bacteria and the resulting nitrite is converted to nitric oxide (NO) in acidic gastric juice. The aim of this study is to elucidate the pathophysiological role of dietary nitrate in the stomach. Intragastric administration of nitrate rapidly increased nitrate and NO in plasma and the gastric headspace, respectively. Water-immersion-restraint stress (WIRS) increased myeloperoxidase (MPO) activity in gastric mucosa and induced hemorrhagic erosions by a nitrate-inhibitable mechanism. In animals that had received either cardiac ligation or oral treatment with povidone-iodine, a potent bactericidal agent, administration of nitrate failed to increase gastric levels of NO and to inhibit WIRS-induced mucosal injury. WIRS decreased gastric mucosal blood flow by a mechanism which was inhibited by administration of nitrate. These data suggested that the enterosalivary cycle of nitrate and related metabolites consisted of gastrointestinal absorption and salivary secretion of nitrate, its conversion to nitrite by oral bacteria and then to NO in the stomach might play important roles in the protection of gastric mucosa from hazardous stress.     

Effect of taurine on gastric oxidative stress and hemorrhagic erosion in brain ischemic rats

The effect of taurine on gastric hemorrhage and mucosal erosion in the brain ischemia (BI) is unknown. The aim of the research was to study the involvement of gastric oxidative stress in hemorrhagic erosion produced in BI rats. The protective effect of taurine on this erosion model was evaluated. Male Wistar rats were deprived of food for 24 h. Under chloral hydrate -anesthesia, bilateral carotid artery ligation (BCAL) was performed 12, 18 and 21 h after removal of food to obtain 12, 6 and 3 h of BI duration. The pylorus and carotid esophagus of rats also were ligated. The stomachs were then irrigated for 3 h with normal saline or simulated gastric juice containing 100 mM HCl plus 17.4 mM pepsin and 54 mM NaCl. The stomach was dissected. Gastric samples were harvested. The rat brain was dissected for examination of ischemia by using triphenyltetrazolium chloride staining method. Changes in gastric ulcerogenic parameters, such as decreased mucosal GSH level as well as enhanced gastric acid back-diffusion, mucosal lipid peroxide generation, histamine concentration, luminal hemoglobin content and mucosal erosion in gastric samples were measured. The results indicated that BCAL could produce severe BI in rats. Moreover, a BI- duration-dependent exacerbation of various ulcerogenic parameters also was observed in these rats. Intraperitoneal taurine (0-300 mg/kg) dose-dependently ameliorated gastric oxidative stress and hemorrhagic erosion in BI rats. Taken together, BI could produce gastric oxidative stress and hemorrhagic erosions that was ameliorated by taurine through stimulation of GSH biosynthesis and inhibition of oxidative stress.     

The cytoprotective effect of the desamino-D-Trp 7-10 fragment of somatostatin on ethanol-induced erosions in the rat stomach

The concept of cytoprotection was established by Robert. It means that several materials of different structure and in doses which are not antisecretoric ones, can protect the gastric mucosa against exogenous noxous agents. Absolute ethanol causes haemorrhagic erosions on the rat gastric mucosa. Somatostatin (SRIF) and its 7-10 fragment, which is the active centre of the hormone were cytoprotective in the ethanol-induced cytoprotective model. The desamino-D-Trp fragment (a suspected enzyme resistant variant of the active centre of SRIF) is also protective. It decreases significantly the extension of the lesions. Its dose-response curve shows two peaks, which may correspond to the existence of two SRIF receptor types, described in the rat gastric mucosa.     

Histopathology of gastric erosions. Association with etiological factors and chronicity

Background: The histopathologic characteristics of the antral erosions, and a comparison with samples systematically collected from the background antral mucosa, have not been studied previously. Similarly, unknown is the association of these features with suspected etiological factors and chronicity of erosion. Material and Methods: We studied 117 patients with gastric erosions in the absence of peptic ulcer disease. With 28 patients available for a follow‐up 19 years later, sites of erosions and background mucosa were biopsied and histopathology of both independently assessed at both visits. Helicobacter pylori status was examined from the biopsies taken in the initial and follow‐up gastroscopies. Only subjects originally displaying antral erosions were included. The presence of Herpes simplex virus (HSV) antibodies was analyzed and use of nonsteroidal anti‐inflammatory drug (NSAID) was inquired. Results: Initially, the inflammation was more active in the region of erosions than elsewhere in antral mucosa. More active inflammation in the erosion was associated with HSV seropositivity, Helicobacter pylori infection, and the recent use of NSAIDs. In the follow‐up visit, antral erosions were present in 38% (3/8) of Helicobacter pylori negatives and in 35% (7/20) of positives (p = ns). The Helicobacter pylori positive subjects with chronic or recurrent erosions had initially higher scores of neutrophils compared to subjects with nonrecurrent or nonchronic erosions (2.7 ± 0.5 vs 1.2 ± 1.0; p = .002). Conclusions: Focally enhanced inflammation is characteristic for gastric erosions. This focal inflammation was associated with HSV seropositivity or NSAID use suggesting that such inflammation may be important in the pathogenesis of gastric antral erosions. Highly active inflammation in the erosions associates with their chronicity.     

Cytoprotective and antisecretory properties of a non-diarrheogenic and non-uterotonic prostacyclin analog: U-68,215

U-68,215 [15-Cyclohexyl-9-deoxo-13,14-dihydro-2',9 alpha-methano-4,5,6,16,17,18,19,20-octanor-3-oxa-3,7-(1', 3'-interphenylene)-PGE1] is a stable prostacyclin analog. When given orally to rats, it is cytoprotective for the stomach (ED50: 0.8 micrograms/kg) and the intestine (ED50: 22 micrograms/kg), is gastric antisecretory (ED50: 35 micrograms/kg) and antiulcer (aspirin) (ED50: 5 micrograms/kg). The oral antisecretory ED50 in dogs is 50 micrograms/kg. It has a long duration of gastric cytoprotection: 8-10 hours compared to 3 hours for 16,16-dimethyl PGE2. Unlike most prostaglandins of the E type, it is not diarrheogenic (not enteropooling), it does not induce cellular proliferation of the gastrointestinal mucosa, when given twice a day for eight days, it is not uterotonic (in monkeys), and it does not prevent embryo implantation in hamsters. It inhibits ex vivo platelet aggregation (ED50: 300 micrograms/kg), but does not promote bleeding from cut vessels nor from gastric ulcers. U-68,215 lowers blood pressure at an oral dose corresponding to 1-5 times the antisecretory ED50 in rats and dogs, and to 150 times the cytoprotective ED50 in rats. It may be of therapeutic value in the treatment of conditions where inhibition of gastric acid secretion is desirable, e.g., gastric and duodenal ulcer, and in conditions responding to cytoprotection, e.g., stress ulcers, hemorrhagic gastritis and gastric erosions associated with nonsteroidal antiinflammatory drugs.     

失血性休克大鼠模型的改进及胃黏膜血流量的测定

目的探讨失血性休克大鼠模型的建立及胃黏膜血流量的测定。方法16只健康雄性SD大鼠随机分为两组：对照组（n=8）、失血性休克组（n=8）。失血性休克组使用颈动脉失血-颈静脉失血回输的方式制备失血性休克大鼠模型。维持平均动脉压40mmHg 1h后复苏,复苏后2h动物模型制作成功。使用激光多普勒血流仪测定大鼠胃黏膜血流量;采用光镜及透射电镜观察胃黏膜损伤情况。结果失血性休克组胃黏膜血流量较对照组明显降低,差异非常显著（P〈0．01）,胃黏膜细胞坏死、脱落、溶解,局部溃疡形成。结论失血性休克大鼠胃黏膜血流量明显降低,存在广泛的胃黏膜损伤。     

Lysosomal enzyme activity of the gastric mucosa in rats during experimental ulcer formation

Lysosomal membrane stability has been studied in the gastric mucosa in response to mechanical damage caused by lysosomal fractionation and release of lysosomal enzymes from mucous cells into the gastric cavity of alive animals during induction of acetic ulcer or erosive damage of the gastric mucosa resulting from intraperitoneal introduction of histamine and serotonin. It has been found that all types of ulcerogenesis in the gastric mucosa led to the decrease in lysosomal membrane stability to mechanical stress in the course of lysosomal fractionation. In addition there was a substantial release of lysosomal enzymes into the gastric cavity in different types of ulcerogenesis. The decrease in lysosomal membrane stability combined with a subsequent development of ulcers and erosions in the gastric mucosa seems indicative of the fact that lysosomal enzymes take part in the initial formation of ulcers in the gastric mucosa.     

Proliferative activity of the surface foveolar gastric epithelium in acetysalicylic acid injury

The proliferative activity of gastric mucous cells (GMC) was studied in white mice following the administration of acetylsalicylic acid (200 mg/kg). One hour before sacrifice all the animals received intraperitoneal injection of 3H-thymidine. The mitotic index and index of labeling nuclei were calculated by means of radioautographers 3, 10 and 20 days after administering the drug. Following 3-day exposure to acetylsalicylic acid the proliferative activity of GMC remained unchanged as compared to controls. Long-term administration (10 and 20 days) of the drug produced no increase in the number of erosions, but there was a statistically significant rise in the proliferative activity of GMC. This rise was accounted for by increased number of proliferating cells in the foveated and cervical divisions of the glands as well as due to the extension of the zone of distribution of precursor cells in the gastric glands as far as the basal divisions. These changes may be considered as manifestation of the protective-adaptive reaction of the gastric mucosa in response to the damaging effect of acetylsalicylic acid.     

C-reactive protein (CRP) measurement in canine serum following experimentally-induced acute gastric mucosal injury

To establish the diagnostic significance of canine C-reactive protein (CRP) in gastrointestinal disorders, the serum canine CRP concentration was measured in dogs with experimentally-induced acute gastric mucosal injury. Gastric injury was induced in one male and one female beagle by a single dose oral administration of acetylsalicylic acid (200 mg/kg body weight) or indomethacin (60 mg/kg body weight), or sodium chloride (1,000 mg/kg body weight). CRP was measured prior to dose, and 1, 3, 7, and 14 days after the administration of the drugs, together with the total leucocyte counts and serum iron. Changes in the serum CRP in dogs with gastric injury were similar for the three test compounds, and reflected by the endoscopic findings. CRP values increased from 87 to 390 mg/l within 1 to 3 days after the compound administration but returned nearly to the predose levels within 14 days. Endoscopy revealed haemorrhagic erosion of the gastric mucosa in all dogs one day after dosing, with no evidence of the erosions observed after 7 days in many of the dogs. Changes of the total leucocyte and serum iron also occurred following gastric injury, but these changes were not as marked as those observed for CRP. The results of this study suggest that serum CRP level may be a useful indicator of a gastrointestinal mucosal injury in dogs.     

Influence of sex hormones on ethanol-induced gastric haemorrhagic erosions in rats.

The role of sex hormones in the pathogenesis of ethanol-induced gastric erosions was investigated following the recent observation that ethanol generates more severe gastric damage in male rats. Female and male Wistar rats aged 110 +/- 6 days were used. Intact female, ovariectomized female, intact male, orchidectomized male and cyproterone acetate-pretreated (this compound a testosterone antagonist) male rats were investigated. 1 ml of 75% ethanol was used to induce gastric lesions. The extent of the erosions was determined planimetrically 60 min after ethanol administration. The plasma testosterone and 17-beta-oestradiol levels were checked by radioimmunoassay (RIA) in gonadectomized rats. Ethanol generates more severe lesions in male rats. Orchidectomy and cyproterone acetate treatment each reduced the extent of ethanol-induced gastric erosions in male rats. Ovariectomy had no effect in this model. The plasma testosterone and 17-beta-oestradiol levels were significantly reduced after gonadectomy. It is concluded that endogenous testosterone plays an aggressive role in the pathogenesis of ethanol-induced gastric erosions in rats.     

Effect of the brain 5-HT2 receptor blockade on gastric mucosa damage caused by social stress in males of two mouse strains

Mice-losers in social conflicts had an increased number of haemorrhages and erosions in gastric mucosa as compared with the control and winners-mice. Administration of ciproheptadine and/or ketanserin enhanced the neurogenic gastric damage both in the winners and in control mice. The CBA strain mice were more sensitive to the damaging effects of the drugs than the C57-strain winners. The experience of social confrontations seems to change the gastric mucosa condition and to modify the mucosa response to the brain serotonine receptor blockade, depending on the social confrontations outcome and the animals' genotype.     

Role of hypergastrinemia in the antiatrophy effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on oxyntic gland mucosa of the rat stomach

Atrophy of the gastrointestinal mucosa that occurs in pair-fed control rats is not observed in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treated rats (1). Our objective was to determine if the gastrointestinal trophic hormone, gastrin, is involved in the antiatrophy effect of TCDD on the gut mucosa. Adult male Sprague-Dawley rats treated with 100 micrograms/kg of TCDD were slightly hypergastrinemic 7 days after dosing and markedly hypergastrinemic 14 days after treatment whereas pair-fed control rats were normogastrinemic. After 14 days of feed restriction, atrophy of the oxyntic gland and ileum mucosa occurred in pair-fed control rats but only atrophy of the ileum mucosa developed in TCDD-treated animals. The oxyntic gland mucosa of TCDD-treated rats was protected from mucosa atrophy as well as from mucosa erosions. The protection against feed restriction-induced atrophy was demonstrated by measurements of oxyntic gland mucosal height and DNA and protein content. Since hypergastrinemia stimulates growth of oxyntic gland mucosa, but not ileum mucosa, the antiatrophy effect of TCDD on mucosa of the oxyntic gland might in part be due to hypergastrinemia. In support of this interpretation, TCDD treatment exerted an antiatrophy effect on the oxyntic gland mucosa only when TCDD-treated animals were hypergastrinemic. For example, hypergastrinemia does not develop within the first 48 hr after TCDD administration, and TCDD treatment affords no protection against fasting-induced atrophy of the oxyntic gland mucosa during this time. On the other hand, the ability of TCDD treatment to protect against feed restriction-induced erosions of the oxyntic gland mucosa might be mediated by hypergastrinemia since these events occur at a later time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of monochloramine on recovery of gastric mucosal integrity and blood flow response in rat stomachs--relations to capsaicin-sensitive sensory neurons.

Gastric mucosal blood flow (GMBF) response and the recovery of gastric mucosal integrity were investigated in anesthetized rat stomachs after damage by monochloramine (NH2Cl), in comparison with 20 mM taurocholate Na (TC). A rat stomach was mounted in an ex-vivo chamber, and the mucosa was exposed to 50 mM HCl during a test period. Mucosal application of 20 mM TC for 10 min caused a marked reduction of transmucosal potential difference (PD), but the PD recovered rapidly without development of gross lesions 90 min later. In contrast, the exposure of the mucosa to NH2Cl (5 to approximately 20 mM) produced a concentration-dependent decrease in gastric PD, and the values remained lowered even 90 min after removal of the agent, resulting in severe hemorrhagic damage in the stomach. TC caused a considerable H+ back-diffusion, followed by an increase in the GMBF. In the mucosa damaged by NH2Cl, such GMBF responses were not observed, except for the temporal increase during the exposure, although similar degrees of H+ back-diffusion were observed following NH2Cl treatment. In addition, the prior exposure of the mucosa to NH2Cl significantly attenuated gastric hyperemic response induced by capsaicin but not by misoprostol (a PGE1 derivative) or NOR-3 (a NO donor). Chemical ablation of capsaicin-sensitive sensory neurons had no effect on the PD reduction caused by TC but totally attenuated the GMBF response, resulting in hemorrhagic damage in the stomach. These results suggest that NH2Cl delayed the recovery of the mucosal integrity in the stomach after damage, and this effect may be attributable, at least partly, to the impairment of gastric hyperemic response associated with H+ back-diffusion, probably due to dysfunction of capsaicin-sensitive sensory neurons.