Gastric Mucosal Blood Flow Research Articles

Effect of Oral Vitamin E Administration on Acute Gastric Mucosal Lesion Progression in Rats Treated with Compound 48/80, a Mast Cell Degranulator

The effect of oral vitamin E administration on acute gastric mucosal lesion progression was examined in rats treated once with compound 48/80 (C48/80) (0.75 mg/kg, i.p.) in comparison with that of subcutaneously administered superoxide dismutase (SOD) plus catalase (CAT). Vitamin E (50, 100 or 250 mg/kg) administered at 0.5 h after C48/80 treatment reduced progressive gastric mucosal lesions at 3 h after the treatment dose-dependently, like SOD plus CAT administered at the same time point. The gastric mucosa of C48/80-treated rats had decreased Se-glutathione peroxidase activity and vitamin E, ascorbic acid, and hexosamine contents and increased myeloperoxidase and xanthine oxidase activities and thiobarbituric acid reactive substances content at 3 h after the treatment. Administered vitamin E attenuated all these changes found at 3 h after C48/80 treatment dose-dependently, like administered SOD plus CAT. C48/80-treated rats administered with vitamin E (100 or 250 mg/kg) had higher gastric mucosal vitamin E content than C48/80-untreated rats. Neither administered vitamin E nor SOD plus CAT had any effect on the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow found at 3 h after C48/80 treatment. In the gastric mucosa of C48/80-untreated rats administered with vitamin E, thiobarbituric acid reactive substances content decreased with an increase in vitamin E content. These results indicate that orally administered vitamin E prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing oxidative stress, neutrophil infiltration, and mucus depletion in the gastric mucosa like administered SOD plus CAT.

The effect of highly selective vagotomy on the relationship between gastric mucosal blood flow and acid secretion in man.

Previous work has shown that the duodenal ulcer population can be defined by a lower ratio between gastric mucosal blood flow and acid secretion (during pentagastrin stimulation) than is found in normal subjects. The results of the present investigation have shown that the ratio is restored to normality by highly selective vagotomy. This suggests that increased tonic activity of the vagus on the parietal cell is one of the important disorders in duodenal ulceration.

The effect of histamine and histamine antagonists on gastric acid secretion and mucosal blood flow in man.

Histamine has been investigated for its effect on gastric acid secretion and mucosal blood flow in man. Dose-response curves were constructed and analysed in the presence of H1- and H2-antagonists. Mepyramine had no effect on acid secretion or mucosal blood flow. Cimetidine reduced acid secretion but had no effect on blood flow. This suggests that the vasculature is less sensitive to cimetidine than the parietal cell.

Observations of gastric mucosal blood flow using 99Tcm in rat and man.

The 99Tcm clearance technique is shown to be a useful method of assessing gastric function. It is easily carried out and is relatively non-toxic--the dose of isotope could be reduced to 100 muCi or less without sacrificing the accuracy of the investigation. Although the results are preliminary and the number of cases investigated so far is small, they suggest that the measurement of pertechnetate clearance is directly related to gastric mucosal blood flow; it is a useful parameter of gastric function and may well prove to be a more accurate discriminant in cases of peptic ulceration than the conventional measurement of gastric acid secretion.

Effects of Short-Term Fenoldopam Infusion on Gastric Mucosal Blood Flow in Septic Shock

Survey of Anesthesiology: December 2005 - Volume 49 - Issue 6 - p 295-296 doi: 10.1097/01.sa.0000183985.41669.96

Inhibition of Hydrogen Sulfide Generation Contributes to Gastric Injury Caused by Anti-Inflammatory Nonsteroidal Drugs

Hydrogen sulfide (H(2)S), an endogenous gaseous mediator that causes vasodilation, is generated in mammalian tissues by cystathionine beta-synthase (CBS) and cystathionine-gamma-lyase (CSE). Here, we have investigated the role of H(2)S in a rodent model of nonsteroidal anti-inflammatory drug (NSAID) gastropathy. Rats were given acetyl salycilic acid (ASA) or an NSAID alone or in combination with NaHS, an H(2)S donor, and killed 3 hours later. Gastric blood flow was measured by laser-Doppler flowmetry, whereas intravital microscopy was used to quantify adhesion of leukocytes to mesenteric postcapillary endothelium. At a dose of 100 micromol/kg, NaHS attenuated by 60%-70% the gastric mucosal injury, and tumor necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1, and lymphocyte function-associated antigen (LFA)-1 mRNA up-regulation induced by NSAIDs (P < .05) NaHS administration prevented the associated reduction of gastric mucosal blood flow (P < .05) and reduced ASA-induced leukocyte adherence in mesenteric venules. NaHS did not affect suppression of prostaglandin E(2) (PGE(2)) synthesis by NSAIDs. Glibenclamide, a K(ATP) channel inhibitor, and DL-propargylglycine, a CSE inhibitor, exacerbated, whereas pinacidil, a K(ATP) opener, attenuated gastric injury caused by ASA. Exposure to NSAIDs reduced H(2)S formation and CSE expression (mRNA and protein) and activity by 60%-70%. By promoter deletion and mutation analysis, an Sp1 consensus site was identified in the CSE promoter. Exposure to NSAIDs inhibits Sp1 binding to its promoter and abrogates CSE expression in HEK-293 cells transfected with a vector containing the core CSE promoter. Exposure to NSAIDs inhibits Sp1 and ERK phosphorylation. These data establish a physiologic role for H(2)S in regulating the gastric microcirculation and identify CSE as a novel target for ASA/NSAIDs.

Rebamipide Decreases the Susceptibility of Gastric Mucosa to Acid-Induced Injury in Rats by Inhibiting Neutrophil Activation

We previously demonstrated that activated neutrophils increased the susceptibility of gastric mucosa to acid-induced injury in rats. As rebamipide, an anti-ulcer agent, inhibits neutrophil activation, we examined whether the rebamipide reduces stress-induced gastric mucosal injury by decreasing susceptibility to acid-induced gastric mucosal injury in rats. Increase in both gastric mucosal permeability and gastric microvascular permeability evaluated by (51)Cr-EDTA clearance and Evans blue leakage, respectively, at 6 hr after Water-Immersion Restraint Stress (WIR) were significantly lower in animals with leukocytopenia than those in controls. Pretreatment with neutrophil elastase (NE) inhibitors, an anti-P-selectin monoclonal antibody (MAb), and rebamipide significantly inhibited these increases at 6 hr after WIR. These treatments also inhibited decrease in gastric mucosal blood flow observed at 6 hr after WIR. Acid-induced exacerbation of gastric mucosal injury in rats at 6 hr after WIR was inhibited by NE inhibitors, anti-P-selectin MAb, and rebamipide. Rebamipide significantly inhibited WIR-induced increase in gastric MPO activity at 8 hr after WIR. Observations in the present study raised a possibility that rebamipide decreases the susceptibility of gastric mucosa to acid-induced injury by inhibiting neutrophil activation.

Role of central and peripheral ghrelin in the mechanism of gastric mucosal defence

Ghrelin, identified in the gastric mucosa, has been involved in the control of food intake and growth hormone (GH) release, but whether this hormone influences the gastric secretion and gastric mucosal integrity has been little elucidated. We compared the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of ghrelin on gastric secretion and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) with or without suppression of nitric oxide (NO)-synthase or functional ablation of afferent sensory nerves by capsaicin. The number and the area of gastric lesions was measured by planimetry, the GBF was assessed by the H2-gas clearance method and blood was withdrawn for the determination of the plasma ghrelin and gastrin levels. In addition, the gastric mucosal expression of mRNA for CGRP, the most potent neuropeptide released from the sensory afferent nerves, was analyzed in rats exposed to WRS with or without ghrelin pre-treatment. Ghrelin (5-80 microg/kg i.p. or 0.6-5 microg/kg i.c.v.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS. This protective effect was accompanied by a significant rise in the gastric mucosal blood flow (GBF), luminal NO concentration and plasma ghrelin and gastrin levels. Ghrelin-induced protection was abolished by vagotomy and significantly attenuated by L-NNA and deactivation of afferent nerves with neurotoxic dose of capsaicin. The signal for CGRP mRNA was significantly increased in gastric mucosa exposed to WRS as compared to that in the intact gastric mucosa and this was further enhanced in animals treated with ghrelin. We conclude that central and peripheral ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol or WRS, and these effects depend upon vagal activity and hyperemia mediated by the NOS-NO system and CGRP released from sensory afferent nerves.

Famotidine prevents canine gastric blood flow reduction by NSAIDs

To investigate the effect of famotidine on gastric blood flow reduction induced by diclofenac sodium, a common non-steroidal anti-inflammatory drug in Japan, using laser Doppler flowmetry in the canine stomach. The gastric mucosal blood flow was measured by laser Doppler flowmetry in 15 healthy male beagles before and 60 min after the administration of diclofenac suppository (1.0 mg/kg) into the rectum. The examination was done in a crossover, single-blinded fashion. All dogs underwent both famotidine (0.5 mg/kg) and placebo (saline) injection simultaneously with the administration of diclofenac. In addition, the tissue concentration of prostaglandin E2 was measured. The blood flow decreased by 18.3 +/- 9.1% in the gastric body, by 26.3 +/- 8.1% in the antrum in the placebo group after the administration of diclofenac sodium, while the decreases seen were significantly smaller in the famotidine group: 3.2 +/- 12.6% in the gastric body and 7.9 +/- 16.5% in the antrum (P = 0.001 for the gastric body, P = 0.0034 for the antrum). Conversely, the percentage of mucosal prostaglandin E2 concentration decrease in each group did not show a significant difference. Famotidine alleviates the reduction of gastric blood flow induced by diclofenac sodium. Further, not only mucosal prostaglandins but also gastric acid may play an important role in non-steroidal anti-inflammatory drugs-induced gastric microcirculatory disturbance.

Dual COX-Inhibitors: The Answer is NO?

Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) are a new class of anti-inflammatory agents obtained by adding an NO releasing moiety to existing NSAIDs. They have also christened as COX inhibiting NO-donating drugs (CINOD). Preclinical and clinical studies suggest that CINOD inhibit COX-1 and COX-2 activities while cause less adverse effects on gastrointestinal tract in comparison to conventional NSAIDs and coxibs and reduce systemic blood pressure. A different class of NO-donating drugs has been obtained by coupling NO to aspirin. These NO-releasing aspirins are new chemical entities that maintain and possibly expands the pharmacological properties of aspirin, but spare the gastrointestinal mucosa. Animal studies have shown that CINOD and NO-aspirins maintain gastric mucosal blood flow and reduce leukocyte-endothelial cell adherence.

An in vivo model for gastric physiological and pathophysiological studies in the mouse

In vivo models for studying gastrointestinal physiology and pathophysiology are well established in rats. Since a number of genetically modified mice are available there is a need for reliable mouse models. The aim of this project was to develop an in vivo mouse model for gastrointestinal studies. C57bl/6, NMRI and transgenic FVB/N (expressing human alpha-1,3/4-fucosyltransferase) mice were anaesthetized with isoflurane and the gastric mucosa exteriorized for intravital microscopy. Acid-base status and acid secretion were measured and blood pressure was continuously monitored. Gastric mucosal blood flow was recorded by laser-Doppler flowmetry. Mucus thickness and accumulation rate were measured with micropipettes. We have developed an in vivo mouse model for studies of the gastric mucosa. With isoflurane anaesthesia the preparation can be studied for up to 5 h with stable blood pressure and mucosal blood flow. Acid-base status agrees with results from other laboratories. Blood flow increased in both C57bl/6 and alpha1.3/4-FT mice in response to luminal HCl, and the mucus gel could be divided into a firmly and a loosely adherent layer, all comparable with results in the rat. However, the firmly adherent mucus layer was thinner (45 +/- 2 microm), and the mucus accumulation rate lower, than in the rat. Furthermore, both basal and stimulated acid secretion showed lower outputs than in the rat. This model has great potential for investigations of gastrointestinal physiology and pathophysiology and can be applied for Helicobacter pylori infection studies.

Effects of acupoint-injection of huangqi and danggui injection on gastric mucosal blood flow in chronic atrophic gastritis rats

Effects of acupoint-injection of huangqi and danggui injection on gastric mucosal blood flow in chronic atrophic gastritis rats

Role of gastric mast cells in the regulation of central TRH analog-induced hyperemia in rats

RX 77368 (RX) increases gastric mucosal blood flow by a vagal cholinergic mechanism. The relative roles of mucosal and connective tissue mast cells (MMC and CTMC) were investigated in RX-injected rats. Blood flow and mast cell degranulation were measured after intracisternal RX. RX significantly increased gastric mucosal blood flow, and sequentially degranulated CTMC and MMC. Ketotifen or doxantrazole inhibited the hyperemic response. Ondansetron, RS-039604-90, or famotidine, but not ketanserin or pyrilamine, reduced hyperemia. Mast cells mediate RX-induced gastric hyperemia via 5-HT 3, 5-HT 4, and H 2 receptors; initial increase depends upon CTMC whereas MMC contributes to the later response.

Calcitonin gene‐related peptide released by capsaicin suppresses myoelectrical activity of gastric smooth muscle

It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not capsaicin, which can protect the stomach from noxious stimuli, affects gastric motor activity. Male Sprague-Dawley rats were anesthetized with urethane, and the stomach was cannulated by two catheters from esophageal and duodenal sides. A biopolar electrode was fixed to the serosal surface of the antrum and myoelectrical activity was recorded during the instillation of a small volume of solutions. The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of >2 cmH(2)O. Replacement of intragastric physiological saline with 1.6 mmol/L capsaicin solution significantly suppressed this myoelectrical activity by 50%. Intragastric capsaicin administration caused a significant release of substance P (SP) and calcitonin gene-related peptide (CGRP). The maximum released levels of CGRP in the gastric perfusates were 100-fold those of SP. The myoelectrical activity observed at an intragastric pressure of 2 cmH(2)O was avoided by continuous infusion of CGRP (0.1-3.0 nmol/kg per min) into the gastric artery in a dose-dependent manner, but not by that of SP (1.0 nmol/kg per min). Continuous CGRP-(8-37) infusion into the gastric artery completely blocked the reduction by intragastric capsaicin of myoelectrical activity. These results suggest that the suppression of the myoelectrical activity of gastric smooth muscle by capsaicin is attributable to the endogenous CGRP released.

Partial sleep deprivation compromises gastric mucosal integrity in rats

The gastric mucosa is most susceptible to stress that has been shown to induce mucosal damage in humans and animals. This study aims to explore the underlying mechanisms of partial sleep deprivation, as a source of psychophysiological stress, on gastric functions and its effect on mucosal integrity. Sprague-Dawley rats were partially sleep deprived (PSD) for 7 or 14 days by housing inside slowly rotating drums. Gastric tissues and plasma were sampled at the end of the sleep deprivation periods and mucosal lesion scores were evaluated. Morphological examination was performed after Hematoxylin and Eosin staining. Plasma levels of noradrenaline, adrenaline, gastrin, histamine and somatostatin were determined with enzyme immunoassays. Gastric acidity was measured with acid-base titration in pylorus ligated rats. Gastric mucosal blood flow was evaluated with Laser Doppler Flowmetry. It was found that gastric lesions were induced in about 30%–50% of the PSD rats. Gastric acidity as well as plasma levels of noradrenaline, gastrin and histamine were elevated. Gastric mucosal blood flow and plasma somatostatin level were on the contrary reduced, especially in rats with PSD for 14 days. It is concluded that partial sleep deprivation compromises gastric mucosal integrity by increasing gastric acidity, plasma levels of noradrenaline, gastrin, histamine, and decreasing gastric mucosal blood flow. These results provided experimental evidence on the gastric damaging effects of PSD and it could be one of the risk factors contributing to gastric ulcer formation.

Bombesin-Induced Gastroprotection

Bombesin is an endogenous gut peptide that is prominent in the stomach. In addition to its effects on modulating acid and gut peptide secretion, recent evidence indicates that bombesin is a potent gastroprotective agent. This review article examines the ability of bombesin to prevent gastric injury. Its protective actions appear to be mediated primarily via the release of endogenous gastrin, as gastroprotection is negated by blockade of gastrin receptors. Bombesin-induced gastroprotection and gastrin release are modified by somatostatin. Immunoneutralization of endogenous somatostatin increases the ability of bombesin to prevent gastric injury by increasing gastrin release. In mechanistic studies, ablation of capsaicin-sensitive afferent neurons abolishes bombesin-induced gastroprotection while cyclo-oxygenase inhibition partially reverses this effect. Nitric oxide synthase inhibition also negates bombesin-induced gastroprotection as well as the ability of bombesin to increase gastric mucosal blood flow. Taken together, the available evidence indicates that bombesin causes release of endogenous gastrin that activates sensory neurons located in the gastric mucosa. Activation of sensory neurons causes increased production of nitric oxide through activation of constitutive nitric oxide synthase, which leads to a resultant increase in gastric mucosal blood flow and renders the stomach less susceptible to damage from luminal irritants.

Effect of Gefarnate on Acute Gastric Mucosal Lesion Progression in Rats Treated with Compound 48/80, a Mast Cell Degranulator, in Comparison with That of Teprenone

We have reported that teprenone (geranylgeranylacetone), an anti-ulcer drug, prevents acute gastric mucosal lesion progression in rats treated once with compound 48/80 (C48/80), a mast cell degranulator, possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa. Herein, we examined the preventive effect of gefarnate (geranyl farnesylacetate), an anti-ulcer drug, on acute gastric mucosal lesion progression in rats treated once with C48/80 (0.75 mg/kg, i.p.) in comparison with that of teprenone, because the chemical structure and anti-ulcer action of gefarnate are similar to those of teprenone. Gefarnate (50, 100 or 200 mg/kg) administered orally at 0.5 h after C48/80 treatment, at which time gastric mucosal lesions appeared, reduced progressive gastric mucosal lesions at 3 h dose-dependently. At 3 h after C48/80 treatment, the gastric mucosa had decreased adherent mucus and hexosamine contents and increased myeloperoxdiase (an index of neutrophil infiltration) and xanthine oxidase activities and thiobarbituric acid reactive substances (an index of lipid peroxidation) content. Post-administered gefarnate attenuated all these changes dose-dependently. These preventive effects of gefarnate were similar to those of teprenone at a dose of 200 mg/kg. Post-administered gefarnate did not affect the increases in serum serotonin and histamine concentrations and the decrease in gastric mucosal blood flow at 3 h after C48/80 treatment like teprenone. These results indicate that orally administered gefarnate prevents acute gastric mucosal lesion progression in C48/80-treated rats possibly by suppressing mucus depletion, neutrophil infiltration, and oxidative stress in the gastric mucosa like teprenone.

Effects of sleep deprivation on gastric mucosal blood flow and gastric mucosal lesions in rats

Effects of sleep deprivation on gastric mucosal blood flow and gastric mucosal lesions in rats

A critical role of gastric mucosal ascorbic acid in the progression of acute gastric mucosal lesions induced by compound 48/80 in rats

To study the role of gastric mucosal ascorbic acid (AA) in the progression of acute gastric mucosal lesions induced by compound 48/80 (C48/80), a mast cell degranulator, in rats. C48/80 (0.75 mg/kg) was intraperitoneally injected to fasted Wistar rats. Oral administration of AA (10, 50 or 100 mg/kg) was performed 0.5 h after C48/80 treatment. Determinations for gastric mucosal lesion severity and blood flow, and assays for gastric mucosal total AA, reduced AA, oxidized AA, vitamin E, thiobarbituric acid reactive substances (TBARS), adherent mucus, nitrite/nitrate (NOx), non-protein SH (NPSH), and myeloperoxidase (MPO), and serum total AA, reduced AA, oxidized AA, and NOx were conducted 0.5 and 3 h after C48/80 treatment. Gastric mucosal lesions occurred 0.5 h after C48/80 treatment and progressed at 3 h. Gastric mucosal blood flow decreased 0.5 h after C48/80 treatment but the decrease was recovered at 3 h. Gastric mucosal total AA, reduced AA, vitamin E, and adherent mucus concentrations decreased 3 h after C48/80 treatment. Gastric mucosal oxidized AA concentration remained unchanged after C48/80 treatment. Gastric mucosal NPSH concentration decreased 0.5 h after C48/80 treatment, but the decrease was recovered at 3 h. Gastric mucosal TBARS concentration and MPO activity increased 0.5 h after C48/80 treatment and further increased at 3 h. Serum total AA and reduced AA concentrations increased 0.5 h after C48/80 treatment and further increased at 3 h, while serum oxidized AA concentration increased at 0.5 h. Serum and gastric mucosal NOx concentrations increased 3 h after C48/80 treatment. AA administration to C48/80-treated rats at 0.5 h after the treatment prevented the gastric mucosal lesion progression and the changes in gastric mucosal total AA, reduced AA, vitamin E, adherent mucus, NOx, and TBARS concentrations and MPO activity and serum NOx concentration found at 3 h after the treatment dose-dependently. The AA administration to C48/80-treated rats caused further increases in serum total AA and reduced AA concentrations at 3 h after the treatment dose-dependently. Gastric mucosal AA plays a critical role in the progression of C48/80-induced acute gastric mucosal lesions in rats.

PAR2 as a target for gastric mucosal protection

Protease-activated receptors (PARs), especially PAR2, are abundantly expressed throughout the gastrointestinal tract, including the stomach. PAR2 plays multiple roles in the modulation of gastric functions. Exogenously applied PAR2 agonists stimulate the secretion of gastric mucus and pepsinogen, suppress gastric acid output, enhance gastric mucosal blood flow and modulate the motility of gastric smooth muscle. Most of these gastric functions of PAR2, except for the stimulation of pepsinogen secretion, are thus protective in the stomach. Indeed, PAR2 agonists protect against gastric mucosal lesions induced by ethanol/HCI or indomethacin in laboratory animals. The PAR2-mediated protective mechanisms appear to primarily involve activation of capsaicin-sensitive sensory nerves in the gastric mucosa, although PAR2 stimulation would also trigger activation of other multiple pathways. PAR2 would thus appear to be a novel target for the development of drugs for the treatment of gastric mucosal diseases.