Epalrestat prevents the decrease in gastric mucosal blood flow and protects the gastric mucosa in streptozotocin diabetic rats

We have recently reported that steady-state gastric mucosal blood flow (GMBF) is decreased in streptozotocin (STZ) diabetic rats, and that their GMBF response to burn-stress is impaired, probably via a nitric oxide (NO)-mediated mechanism. Accordingly, this study was designed to investigate the relation of aldose reductase (AR) and NO synthase to the regulation of GMBF during chronic hyperglycemia. STZ rats were treated with or without chronic oral administration of an AR inhibitor, epalrestat (EPA) and/or an NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). GMBF was measured by laser-Doppler velocimetry (LDV). In the STZ rats, GMBF after a 24-h fasting period was decreased significantly 4 weeks after the onset of diabetes and this was accompanied by an increase in the gastric ulcer index (UI) (a measure of the length of gastric erosions and ulcers). Chronic oral administration of EPA to the STZ rats dose-dependently inhibited the increased UI and the decreased GMBF after the fasting stress, whereas chronic oral administration of L-NAME further increased the UI and further decreased the GMBF. EPA administered in combination with L-NAME to the STZ rats reduced the effects of L-NAME, but the effects did not reach significance. These results suggest that EPA protects the gastric mucosa of diabetic rats, by preventing the decrease in GMBF that is, at least in part, caused by NO-related mechanisms. (Received Mar. 3, 1998; accepted Aug. 28, 1998)     

Brain ischemia and gastric mucosal damage in spontaneously hypertensive rats

Brain ischemia is often accompanied by acute gastric lesions. To clarify the underlying mechanism, the influence of acute ischemic insult to the brain on gastric hemodynamics and mucosal integrity was examined in spontaneously hypertensive rats. One hour after brain ischemia, gastric mucosal blood flow decreased to 71% of the preischemic levels in the control rats but was preserved significantly better, at 94 and 108%, in the prazosin-treated and guanethidine-treated rats, respectively. Vagotomy almost abolished the decrease in gastric mucosal blood flow during cerebral ischemia. Intragastric 0.6 N hydrochloric acid administered just after reperfusion induced more severe hemorrhagic ulcers in the control than in the prazosin-treated and vagotomized groups. These results suggest that noradrenergic neurons acting through ₁-adrenoceptors contributes to the decrease in gastric mucosal blood flow, and the subsequent disturbed integrity of the gastric mucosa, through the vagal adrenergic pathway during brain ischemia in spontaneously hypertensive rats.     

Modulatory action of adenosine on gastric function and ethanol-induced mucosal damage in rats

This study examines the gastric effects of adenosine and its antagonist, theophylline, on secretory function, mucosal blood flow, and on ethanol-induced glandular mucosal damage in rats that were fasted for 24 hr before experimentation. The animals were anesthetized with sodium pentobarbitone (50 mg/kg intraperitoneal) and their tracheae cannulated. An ex vivo stomach chamber then was prepared. The luminal bathing solution was collected every 15 min and the concentrations of H⁺ and Na⁺ were determined by a pH autotitrator and an ionmeter, respectively. The glandular mucosal blood flow was measured by a laser Doppler flowmeter and the severity of lesions was determined by measuring the hemorrhagic areas. Adenosine administration (2.5 or 7.5 mg/kg, subcutaneous) markedly lowered the H⁺ and Na⁺ output but increased the secretory volume and mucosal blood flow in a dose-dependent manner. The same doses of the nucleoside also prevented ethanol-induced mucosal damage. These effects were prevented by pretreatment with theophylline (30 or 60 mg/kg, subcutaneous). Ethanol given alone significantly depressed the H⁺ and Na⁺ secretion. Both effects were not modified by adenosine treatment. However, the depressive action of ethanol on mucosal blood flow was prevented by adenosine. These findings indicate that adenosine modulates the physiological function of the stomach. It also directly activates the defensive mechanism of the stomach, which is partially mediated by the improvement of the gastric mucosal blood flow and an increase in the nonacid component of gastric secretion.     

Monochloramine impairs mucosal blood flow response and healing of gastric lesions in rats: relation to capsaicin-sensitive sensory neurons

AIMS:We examined the effects of monochloramine (NH2Cl) on the gastric mucosal blood flow (GMBF) response and the healing of ethanol-induced gastric lesions in rats. METHODS: Rats fasted for 18 h were given the 99% ethanol p.o. for induction of gastric lesions, and were fed normally from 1 h later onwards. Monochloramine, at non-ulcerogenic doses (5 to approximately 20 mmol/L), was given p.o. twice daily for 7 days, starting 2 h after ethanol treatment. RESULTS: Gastric lesions caused by ethanol healed almost completely within 7 days with re-epithelialization. The repeated administration of NH2Cl significantly delayed the healing of ethanol-induced gastric lesions in a dose-dependent manner. The damaged mucosa showed a marked rise in H+ permeability, resulting in luminal acid loss, but this process was accompanied by an increase of mucosal blood flow. Monochloramine did not affect the increased mucosal H+ permeability observed in the stomach after damage by ethanol, but significantly inhibited the mucosal hyperemic response associated with luminal acid loss. Prior exposure of the mucosa to NH2Cl (20 mmol/L) did not affect the gastric hyperemic response caused by mucosal application of misoprostol (a prostaglandin E1 derivative) or NOR-3 (a nitric oxide donor), but totally attenuated the increase of GMBF in response to intragastric capsaicin. Impaired healing and GMBF responses were also observed in rats following chemical ablation of capsaicin-sensitive sensory neurons. CONCLUSIONS: These results suggest that NH2Cl impaired the healing of acute gastric mucosal lesions at low concentrations, and this action may be attributable, at least partly, to the impairment of gastric hyperemic response caused by the dysfunction of capsaicin-sensitive sensory neurons.     

Relationship between gastric mucosal hemodynamics and gastric motility

Continuous measurement of gastric mucosal hemodynamics (the index of mucosal hemoglobin concentration, the index of oxygen saturation and blood flow) in rats showed oscillatory changes. The mechanism of the oscillations was investigated using a probe specially designed for simultaneous measurement of hemodynamics and intragastric pressure. A hemodynamics-measuring probe for either reflectance spectrophotometry or laser-Doppler flowmetry was tied to a pressure microtransducer, inserted through an incision in the forestomach, and brought into gentle contact with the corpus mucosa. Synchronous oscillatory changes (4-6 cycles/min) in hemodynamics and motility were observed in the resting state (mean blood pressure: 120 mmHg). During moderate hemorrhagic hypotension (mean: 81 mmHg), oscillations in the hemodynamics increased in both amplitude and frequency, while motility remained constant. Oscillations in the hemodynamics were also affected by fluctuations in blood pressure and by topical application of norepinephrine to the corpus serosa. In water-immersion restraint rats, changes in the oscillations in the hemodynamics and motility were virtually synchronous; frequency decreased and amplitude increased. These findings suggest that oscillatory changes in gastric mucosal hemodynamics are regulated not only by gastric motility but also by arteriolar vasomotion of the gastric wall.     

The role of the vagus nerve in the protective action of acid inhibitors on ethanol-induced gastric mucosal damage in rats

The role of vagus in the actions of different acid inhibitors on ethanol-induced gastric damage and mucosal blood flow (GMBF) changes was studied in anaesthetized rats, using an ex vivo stomach chamber preparation. Subdiaphragmatic bilateral vagotomy decreased the basal gastric acid secretion and GMBF; it also intensified ethanol-evoked lesions in the glandular mucosa. Misoprostol, omeprazole and cimetidine produced a similar degree of reduction in acid output. Misoprostol given subcutaneously (s.c.) (50 micrograms/kg), or added to the incubation solution (12.5 micrograms) for 15 min, markedly prevented ethanol-induced lesion formation and reduction in GMBF. The reversing effect of s.c. injection of misoprostol on either lesion formation or on GMBF reduction was attenuated by vagotomy. Omeprazole protected against lesion formation only when present in the incubation solution (12.5 mg) of ex vivo chamber preparations of both vagus-intact and vagotomized animals, but the effect was significantly less in the latter group. The drug also prevented the depressive action of ethanol in vagus-intact animals. Cimetidine pretreatment (50 mg s.c. or 12.5 mg in incubation solution), however, did not modify the effects of ethanol on lesion formation and the GMBF. The findings indicate that the three different types of acid inhibitors exert different actions on ethanol-induced gastric mucosal damage, although they produced similar inhibition of acid output. Vagotomy lowers the GMBF and attenuates the antiulcer action of misoprostol and omeprazole, especially when the drugs are given by the parenteral route.     

Role of mucosal microcirculation in gastric lesions induced by lateral hypothalamic lesions in rats

To evaluate the pathophysiology underlying gastric mucosal lesions induced by lateral hypothalamic (LH) lesions, we investigated the changes in acid secretion, gastric mucosal blood flow, gastric mucus and mucosal integrity in the corpus during the 4 h period and 48 h after the production of bilateral electrolytic LH lesions in male Sprague-Dawley rats. Gastric mucosal lesions were macroscopically produced 24 h (63%) and 48 h (83%) after LH lesions, although there were no visible lesions at 7 h. Gastric acid secretion was significantly increased 48 h after LH lesions, compared with that in the control group. Gastric mucosal blood flow and transmucosal potential difference (PD) in the LH lesion group immediately decreased after LH lesions and did not recover during 4 h and at 48 h. On the contrary, in the control group, gastric mucosal blood flow decreased after the brain surgery but soon recovered, and there was no significant change in PD. LH lesions resulted in the reduction of intramucosal mucus to 50% 3 h after LH lesions. Moreover, we exposed the stomach to 10 mmol/L taurocholic acid (TCA) 3 h after LH lesions to examine the disruption in gastric mucosal defensive function in rats with LH lesions. The recovery of the reduced PD by TCA was slow and gastric mucosal lesions were easily formed in the LH lesion group. These results suggest that gastric mucosal ischaemia after lesioning of LH immediately results in the disruption of mucosal defensive function before the formation of visible gastric lesions, and predisposes to the formation of gastric mucosal lesions by a delayed increase in acid secretion.     

Effects of a gastric mucosal protecting agent in rats with liver cirrhosis

Male Sprague-Dawley rats were fed a 0.1% ethionine-added choline-deficient diet for 8 weeks to induce liver cirrhosis. At the same time 100 mg/kg/day teprenone was administered orally in order to evaluate its effects on the liver and gastric mucosal blood flow. Blood flow increased not only in gastric mucosa but also in liver tissues in the teprenone group. Serum transaminase levels and histopathologic findings of the liver also improved. These findings suggest that teprenone alleviates hepatocellular injuries. This effect may be partly attributable to cytoprotective effects of the catenoid isoprenoid moiety of teprenone on liver cells.     

Nitric oxide-mediated gastric hyperemia decreases ethanol-induced gastric mucosal injury in uremic rats

We investigated whether the recently described endothelium-derived nitric oxide-mediated gastric hyperemia in the uremic rat protects the gastric mucosa against ethanol injury. Uremia was induced by subtotal nephrectomy. Basal gastric mucosal blood flow, measured by a hydrogen gas clearance technique, was significantly higher in uremic than control rats. Continuous intragastric perfusion with 40% ethanol produced significantly less gross and histological lesions in uremic than in control rats. The administration of 3 mg/kg ofN ^W-nitro-l-arginine methyl ester, a specific inhibitor of nitric oxide biosynthesis, decreased resting gastric mucosal blood flow to control levels in uremic rats, but had no effect on basal gastric blood flow in control rats. This pretreatment with the inhibitor of nitric oxide biosynthesis increased 40% ethanol-induced gastric mucosal lesions in uremic rats to the same level as that observed in control rats, but had no effect on lesions in control rats. In conclusion, this study suggests that in the uremic rat, gastric hyperemia, mediated by increased endothelium-derived nitric oxide, attenuates ethanol-induced gastric mucosal injury.Dr. Enrique Quintero is the recipient of a Fogarty International Fellowship Award (N.I.H.) (1 FO5 TW04443-01) and a Grant from Consejería de Educación, Cultura y Deportes of the Canary Islands Autonomous Government. This work was also supported by Veterans Administration Research Funds.     

Gastric mucosal injury and associated changes in mucosal blood flow and gastric fluid secretion caused by dimethyl sulfoxide (DMSO) in rats

Dimethyl sulfoxide applied intragastrically for 10 min in rats caused extensive mucosal damage. In concentrations of 5%, 10%, or 100%, dimethyl sulfoxide caused superficial damage to 33%, 36%, and 97%, respectively, of the corpus mucosa, and 28%, 44%, and 96%, respectively, of the antral mucosa. Concentrated dimethyl sulfoxide also caused damage to the pits and glands in some areas of the mucosa. The amount of fluid in the stomach increased by 0.24 ml, 0.48 ml, and 2.07 ml during application of 5%, 10%, and 100% dimethyl sulfoxide. The 10% dimethyl sulfoxide increased mucosal blood flow by 0.57 ml/min/g in the antrum, and 100% dimethyl sulfoxide increased mucosal blood flow by 2.21 ml/min/g in the antrum and by 1.17 ml/min/g in the corpus. We conclude that dimethyl sulfoxide is a gastric irritant, which should be considered when it is used as an oxygen radical scavenger, as a drug or carcinogen vehicle, or as oral medication in patients. The protective effect of intragastric dimethyl sulfoxide against stress and various drug-induced gastric injury may be due to adaptive cytoprotection rather than an oxyradical scavenger effect.This work was supported by grants from the Norwegian Cancer Society. Dr. Sørbye is a Research Fellow of the Norwegian Cancer Society.     

Morphological and biochemical changes in gastric mucosa of aging rats

Although previous data from this laboratory have indicated that aging is associated with increased gastric mucosal proliferative activity, no direct assessment of proliferative potential of the tissue has been made during aging. In order to assess this, and to determine whether changes in mucosal proliferative potential would be reflected in growth of the tissue, we have examined the labeling index (LI), height and morphology of the gastric mucosa in young (4-month-old) and aged (24-month-old) Fischer-344 rats. In addition, tyrosine kinase (Tyr-k) activity and the levels of phosphotyrosine proteins were determined to evaluate their relationship to mucosal proliferative activity. Histologic evaluation revealed a marked atrophy of the mucosal glandular component with 32% reduction in height in aged rats when compared with young animals. In aged rats, there was also a decrease in gland density, resulting in a reduction in the number of epithelial cells of all types with evidence of decreased secretory activity. Despite the occurrence of mucosal atrophy in aged rats, LI in these animals was significantly increased by 28%. This was associated with a parallel rise in mucosal Tyr-k activity, and a two-to threefold increase in the relative concentrations of seven phosphotyrosine membrane proteins with M_r of 120, 105, 90, 60, 55, 48 and 32 kDa. We conclude that (1) although aging is associated with increased gastric mucosal proliferative activity, this does not result in mucosal growth and that (2) Tyr-k and tyrosine phosphorylation of certain proteins play a role in the regulation of gastric mucosal cell proliferation during aging.     

胃癌和癌前病变中树突状细胞的免疫组化研究

目的 通过研究胃粘膜中S100+,HLA-DR+,CD4+和CD8+产物的表达情况,以了解DC细胞在胃粘膜免疫中的作用．方法 胃癌(143例)、慢性萎缩性胃炎(41例)、不典型增生(15例)、肠上皮化生(27例)和正常对照组(10例)共236例,都经内镜和病理诊断明确．采用HE染色、SP免疫酶标抗体组化染色法与图象分析技术相结合,观察胃粘膜中S-100+,HLA-DR+,GD4+CD8+细胞数量、平均面积和平均吸光度的变化。结果 胃癌患者胃粘膜中S100+(0．6±0．2)μm2,HLA-DR+(0．9±0．2)细胞数量明显多于正常胃粘膜(P     

Monoamine oxidase B inhibition reduces gastric mucosal blood flow,basal acid secretion,and cold water restraint-induced gastric mucosal injury in rats

Inhibition of monoamine oxidase B (MAO B) by selective inhibitors pargyline and l-deprenyl increases dopamine (DA) and norepinephrine (NE) concentrations in nucleus accumbens (NACB) and is associated with reduction in cold water restraint-induced gastric mucosal injury, inhibition of basal gastric acid output, and regional gastric mucosal blood flow. Similar effects were not observed with administration of MAO A inhibitors. These observations suggest that activation of central dopamine and norepinephrine receptors, particularly in NACB, are involved in the control of gastric mucosal function.Supported by PHS grant DK 38198 (G.K.).     

Effects of Ebrotidine on Aspirin-Induced Gastric Mucosal Damage and Blood Flow in Humans

Nonsteroidal anti-inflammatory agents (NSAIDs) such as aspirin (ASA) damage the gastric mucosa both in normal subjects and in arthritic patients. The aim of this study was to investigate the protective action of a new H₂-receptor antagonist, ebrotidine, in the prevention of ASA-induced acute mucosal injury in the stomach of healthy volunteers. In a double-blind randomized crossover study 10 male volunteers received treatment with either placebo plus ASA (500 mg) or ebrotidine (800 mg) plus ASA twice daily for 3 days with 10 days' washout period between treatments. The mean number of gastric erosions seen at endoscopy after treatment with ebrotidine plus ASA (2.0 ± 0.3) was significantly lower than that after placebo plus ASA (3.7 ± 0.2). This reduction in lesion core by ebrotidine was accompanied by a significant increase in gastric blood flow (by 15% in corpus and 26% in antrum), by a rise in transmucosal potential difference (by 12%), and by a decrease of mucosal microbleeding. Ebrotidine afforded substantial protection from ASA-induced injury to the gastric mucosa, and this was accompanied by increase of the mucosal blood flow. We conclude that ebrotidine provides mucosal protection for patients taking NSAIDs     

Relationship between the gastric myoelectric and mechanical activity in the genesis of ulcers in indomethacin-insulin-treated rats

We have proposed that gastric contractile activity mechanically induces ulcers in the nonsteroid antiinflammatory drug (NSAID)-treated rat. This study examines first the relationship between number (dose) of peristaltic contractions applied to the mucosa and the ulcer score. Second, it examines the relative roles of: altered gastric myoelectrical activity (MEA) resulting from indomethacin (Indo) pretreatment, insulin-induced gastric peristalsis, and a combination of the two in the generation of mucosal lesions. Third, it examines the effect of exogenous prostaglandin on the Indo-altered MEA and relates it to ulcerogenesis. Indo pretreatment increased gastric tone and MEA. In such animals, the dose of peristaltic contractions applied to the gastric wall was related to the ulcer score in a dose-dependent manner. Exogenous prostaglandin (PG) reversed the MEA effect of Indo and reduced ulceration. It is postulated that an altered smooth muscle state secondary to inhibition of prostaglandin synthesis (PG-S) renders the mucosa vulnerable to injury by peristaltic action.This study was supported by the Fast Foundation.     

Reduced gastric acid production in burn shock period and its significance in the prevention and treatment of acute gastric mucosal lesions

AIM To investigate the changes of gastric acid production and its mechanism in shock period of severe burn in rats.METHODS A rat model with 30% TBSA fullthickness burn injury was employed and the gastric acid production, together with gastric mucosal blood flow (GMBF) and energy charge ( EC ) were measured serially within 48h postburn.RESULTS The gastric acid production in the acute shock period was markedly inhibited after severe burn injury. At the 3rd h postburn, the gastric juice volume, total acidity and acid output were already significantly decreased (P＜0.01), and reached the lowest point,0.63mL/L ± 0.20mL/L, 10.81mmol/L ±2.58mmol/L and 2.23 mmol/h ± 0.73mmol/h respectively, at the 12th h postburn. Although restored to some degree 24 h after thermal injury, the variables above were still statistically lower, compared with those of control animals at the 48th h postburn. The GMBF and EC were also significantly reduced after severe burns, consistent with the trend of gastric acid production changes.CONCLUSION Gastric acid production, as well as GMBF and EC was predominantly decreased in the early postburn stage, suggesting that gastric mucosal ischemia and hypoxia with resultant disturbance in energy metabolism, but not gastric acid proper, might be the decisive factor in the pathogenesis of AGML after thermal injury, and that the preventive use of anti-acid drugs during burn shock period was unreasonable in some respects. Therefore,taking effective measures to improve gastric mucosal blood perfusion as early as possible postburn might be more preferable for the AGML prevention and treatment.     

西沙比利对大鼠胃粘膜血流影响的实验研究

目的本文研究了西沙比利对大鼠胃粘膜血流的影响,并进而探讨其可能的作用机制.方法32只Wistar大鼠随机分为对照组,西沙比利0.5mg/kg组,1mg/kg组和2mg/kg组,采用中性红分泌法和grees-reactin方法检测胃粘膜血流及一氧化氮含量.结果西沙比利1mg/kg组大鼠胃粘膜血流量为(0.7±0.13mL/min),显著高于空白对照组(0.45±0.18mL/min)和西沙比利0.5mg/kg组(0.4±0.24mL/min)(P＜0.50),且西沙比利1mg/kg组胃粘膜一氧化氮含量亦显著高于空白对照组(23.32±7.40μmol/L/mg vs16.93±3.87μmol/l/mg)和西沙比利0.5mg/kg组(16.76±1.06μmol/L/mg)(P＜0.05).西沙比利2mg/kg组胃粘膜血流量为(0.3±0.17mL/min),显著低于空白对照组(0.45±0.18mL/min)(P＜0.05),其一氧化氮含量(4.35±1.52μmol/L/mg)亦显著低于空白对照组(P＜0.05).结论西沙比利通过影响胃粘膜内一氧化氮含量从而改变胃粘膜血流,西沙比利1mg/kg对大鼠胃粘膜具有保护作用.     

Effects of ammonia solution on the gastric mucosa in cirrhotic rats and therapeutic effects of geranylgeranylacetone

BACKGROUND: We designed an animal model in order to clarify whether Helicobacter pylori infection causes the gastric mucosal lesion frequently seen in cirrhotic patients. METHODS: Ammonia (NH3) solution was given to rats with carbon tetrachloride-induced cirrhosis. The gastric mucosal hexosamine (Hx) content and histopathological findings in the cirrhotic rats were analysed and compared with those of the intact liver rats. Moreover, the usefulness of geranylgeranylacetone (GGA) was investigated in both rat groups. Both rat groups were subdivided according to the treatment as follows: a control group, an NH3 (0.02% solution) group, and an NH3 + GGA (400 mg/kg per day) group; and fed for 4 weeks. RESULTS: The gastric mucosal Hx content of the control group of the cirrhotic rats (16.7 +/- 5.2 microg/mg) was significantly lower than that of the control group of the intact liver rats (26.6 +/- 4.5 microg/mg, P < 0.05). In the cirrhotic rats, the Hx content of both the NH3 (31.9 +/- 13.1 microg/mg) and the NH3 + GGA group (31.9 +/- 9.8 microg/mg) was significantly higher than the Hx content of the control group (P < 0.05). Microscopically, in the cirrhotic rats, while scattered mucosal erosions were recognized in three of five rats of the NH3 group, there were no erosions in any rats of the NH3 + GGA group. CONCLUSIONS: These data suggest that the gastric mucosal defence mechanism is defective in liver cirrhosis and that NH3 enhances this defensive mechanism by acting as mild irritant; however, in some cirrhotics this results in gastric erosion due to excessive irritation. Geranylgeranylacetone protects the gastric mucosa against NH3 irritation in cirrhotics without enhancing the Hx content. Thus, H. pylori infection may be a possible cause of the gastric mucosal lesion in patients with liver cirrhosis. The mechanism of the therapeutic effect of GGA is not due to an enhancement of the gastric mucosal Hx content.