Can misoprostol and omeprazole reduce nicotine and ethanol induced gastric mucosal injury? A quantitative macroscopic and microscopic analysis in rats

We compared the effects of misoprostol, omeprazole and methylcellulose (control) on gastric mucosal injury induced by nicotine and/or ethanol. The results demonstrate that misoprostol and omeprazole each significantly reduce macroscopic injury and deep injury at a microscopic level (P < 0.05) induced by nicotine alone, ethanol alone or a combination of ethanol and nicotine. Misoprostol and omeprazole each reduced the leakage of fluorescein isothiocyanate-albumin into the interstitium in the gastric mucosa. Misoprostol and omeprazole are each effective in preventing injury induced by nicotine and ethanol and vascular factors are involved.     

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.     

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.).     

Role of capsaicin sensitive nerves in epidermal growth factor effects on gastric mucosal injury and blood flow

Background—Epidermal growth factor (EGF) andcapsaicin protect against experimental gastric mucosal injury.Capsaicin exerts its gastroprotective effect by stimulating afferentneurones leading to release of calcitonin gene related peptide (CGRP)which causes gastric hyperaemia. EGF also causes gastric hyperaemia butwhether it acts via capsaicin sensitive neurones is unknown.
Aims—To assess the influence of: (1) capsaicindesensitisation on EGF effects on gastric mucosal injury and gastricmucosal blood flow; and (2) close arterial infusion ofhCGRP_8-37, a CGRP antagonist, on EGF effects on gastricmucosal blood flow.
Methods—The absolute ethanol induced gastricmucosal injury model in the rat was used. Gastric mucosal damage wasassessed by planimetry and light microscopy. Gastric mucosal blood flow was measured by laser Doppler flowmetry in a gastric chamber preparation.
Results—Capsaicin desensitisation abolished thegastroprotective and gastric hyperaemic effects of EGF. Close arterialinfusion of hCGRP_8-37 antagonised the hyperaemic effect ofboth capsaicin and EGF.
Conclusion—Results show that EGF may exert itsgastroprotective and gastric hyperaemic effects via capsaicin sensitiveafferent neurones.

Keywords:capsaicin; epidermal growth factor; gastric mucosalinjury; gastric mucosal blood flow; calcitonin gene related peptideantagonist; rat

     

The effects of a prostaglandin E1 analogue, misoprostol, on gastric mucosal blood volume index and haemoglobin oxygenation in humans

A double-blind placebo-controlled parallel design study was conducted in 12 healthy male volunteers to examine the effects of misoprostol, a newly synthesized prostaglandin E₁ analogue, on gastric mucosal haemodynamics in human. The indices of mucosal blood volume (expressed as ΔEr) and mucosal blood haemoglobin oxygenation (Hb-SO₂) were measured at 20 locations in the stomach prior to and after administration of misoprostol or its placebo using reflectance spectrophotometry during endoscopy. It was found that after misoprostol administration, mucosal blood volume was increased by approximately 10–25% throughout the stomach without any significant change in mucosal blood Hb-SO₂. Administration of placebo produced no significant change in these parameters. The results suggest that misoprostol has the potential to accelerate healing of gastric ulcers by increasing the gastric mucosal blood volume and oxygenation in addition to its gastric acid antisecretory activity.     

埃索美拉唑预防氯吡格雷相关性胃黏膜损伤的研究

目的探讨埃索美拉唑是否可以预防氯吡格雷导致的胃黏膜损伤。 方法120只SD大鼠随机分为3组,每组40只,分别给予生理盐水、氯吡格雷、埃索美拉唑联合氯吡格雷灌胃。分别于给药后7 d、14 d、21 d和28 d处死大鼠,使用HE染色对胃黏膜进行组织病理学观察,使用Guth法对胃黏膜损伤进行评分。 结果埃索美拉唑可显著降低胃黏膜损伤的发生率(65.0% vs 42.5%,P＝0.044)。用药后7 d开始,单用氯吡格雷组小鼠胃黏膜出现明显损伤,损伤评分在14 d达到高峰(6.85±0.99),而联合用药组在各时间点胃黏膜损伤的程度均较单用氯吡格雷组更轻微(P<0.01),且损伤程度随用药时间延长无显著变化。 结论氯吡格雷可导致胃黏膜损伤,且损伤程度在14 d达到高峰,而埃索美拉唑可有效预防氯吡格雷相关性胃黏膜损伤。     

Microcirculatory stasis precedes tissue necrosis in ethanol-induced gastric mucosal injury in the rat

The relation of blood flow stasis to the development of unequivocal histologic necrosis (loss of parietal cells from the column of contiguous cells) in ethanol-induced gastric mucosal injury was studied in anesthetized rats. The most rapid vascular change that occurred when the gastric mucosa was exposed to 100% ethanol was a severe segmental constriction of the large submucosal venules. At 22 sec, the average venular diameter was 52.2±6.0% of the original one. This was followed by complete superficial mucosal blood flow stasis at 49±4 sec and appearance of histologic evidence of necrosis in one of seven rats at 2.5 min, four of six rats at 10 min, and seven of seven rats at 60 min. We conclude that in ethanol-induced gastric mucosal injury, submucosal venular constriction occurs first, followed by cessation of mucosal blood flow to be followed later on with histologic evidence of necrosis.     

Mechanism of intragastric nicotine protection against ethanol-induced gastric injury

To elucidate the mechanism of intragastric nicotine protection against ethanol-induced gastric mucosal injury seen in a previous report and in our preliminary study, the following studies were performed. Rats were pretreated with naloxone (8 mg/kg intraperitoneal, 0.5 hr prior to study) to block opiate receptors; or capsaicin (125 mg/kg subcutaneous 10 days prior to study) to denervate the afferent sensory fibers; or indomethacin (2.5 mg/kg intragastric or 5 mg/kg subcutaneous, 1 hr prior to study) to inhibit endogenous prostaglandin synthesis. At 1-hr intervals, nicotine (4 mg/kg) or vehicle and 40% ethanol were then given intragastrically. Total gastric corpus mucosal lesion length was measured unbiasedly. In separate studies, gastric mucosal blood flow (GMBF) was assessed by hydrogen gas clearance before and after intragastric nicotine or vehicle; luminal mucus volume, gastric juice volume, and acid output were measured 1 hr after either intragastric nicotine or vehicle administration. The results showed that the acute protective effect of intragastric nicotine was associated with a significantly larger luminal mucus volume. It was not blocked by naloxone, capsaicin, or indomethacin. There was no increase in GMBF. The larger gastric residual volume did not account for the protection. We conclude that the mechanism mediating nicotine protection is unique and is independent of opiate receptors, capsaicin-sensitife afferent sensory nerve fibers, endogenous prostaglandin generation, or dilution of the injurious agent. The increase in luminal gastric mucus volume may contribute to the protective effect of intragastric nicotine against gastric mucosal injury produced by 40% ethanol.     

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.     

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)     

Effects of leminoprazole, omeprazole and sucralfate on indomethacininduced delayed healing of kissing gastric ulcers in rats

We have examined whether or not repeated treatment with indomethacin delays the healing of kissing gastric ulcers induced in rats. The effects of leminoprazole, omeprazole and sucralfate on any delay in ulcer healing caused by indomethacin were also determined in relation to myeloperoxidase activity. Kissing gastric ulcers were induced by luminal application of an acetic acid solution. Indomethacin significantly delayed ulcer healing in a dose-dependent manner. Leminoprazole and omeprazole decreased the size and depth of ulcers, the healing of which was delayed by indomethacin, while sucralfate only decreased the ulcer depth. Histological studies showed that indomethacin inhibited tissue contraction and regeneration of the ulcerated mucosa. Leminoprazole and omeprazole prevented the inhibition of these parameters. The myeloperoxidase (MPO) activity of the ulcer portion in animals treated with indomethacin was markedly higher than in the control group. Both leminoprazole and omeprazole, but not sucralfate, significantly reduced MPO activity in contrast to the control value (in the presence of indomethacin). There was a significant relationship between the ulcerated area and myeloperoxidase activity. These results suggested that: (i) leminoprazole and omeprazole prevent the indomethacin-induced delay in ulcer healing by promoting tissue contraction and regeneration of the ulcerated mucosa; (ii) sucralfate prevents the indomethacin-induced delay in ulcer healing via the promotion of the formation of granulation tissue; and (iii) MPO activity will be useful to biochemically ensure the healing state of ulcers.     

Fluorographic study on the oxidative stress in the process of gastric mucosal injury: Attenuating effect of Vitamin E

Abstract In vivo oxidative change was visualized in the gastric mucosa of rats and the alteration was analysed by using a fluorescence microscope equipped with a digital imaging processor during the development of mucosal damage. Dichlorofluorescein (DCF)-associated fluorescence increased after the repeated electrical stimulation on the gastric artery (irritation), suggesting the occurrence of lipid peroxidation. The increase was enhanced in the mid-zone of two adjacent collecting venules. Allopurinol attenuated the oxidative stress in mucosa, showing the involvement of xanthine oxidase. Luminol-dependent chemiluminescence value in the blood taken from gastric vein was elevated by the irritation, suggesting that leucocyte-generated oxygen radicals also participate in this oxidative process. α-Tocopherol attenuated both the DCF activation and the increase in chemiluminescence value and prevented gastric mucosal injury. The present results suggest that α-tocopherol may be useful for the prevention of oxidative alteration in gastric mucosa.     

Role of gastric mucosal blood flow in gastroprotective effect of novel xanthine derivative

The effect of 3-ethyl-1-(6-hydroxy-6-methylheptyl)-7-propylxanthine (A90 6119) on 40% ethanol-induced gastric lesions and gastric mucosal blood flow was investigated in rats. Gastric mucosal blood flow was measured by the hydrogen gas clearance technique and the test compounds and vehicle were administered intraduodenally. A90 6119 dose-dependently increased gastric mucosal blood flow and decreased gross and histologic gastric mucosal injury induced by 40% ethanol. Both the gastric mucosal blood flow and protective effects of A90 6119 were completely attenuated by pretreatment with indomethacin. The findings demonstrate that A90 6119 protects against ethanol-induced gastric injury, and this effect involves stimulation of endogenous prostaglandin synthesis and an increase in gastric mucosal blood flow.This work was supported by a grant from Hoechst Japan Ltd., Veterans Administration Research Funds, and the facilities and expertise of the Blood Flow Core of the Center for Ulcer Research and Education.     

Influence of Helicobacter pylori infection and cetraxate on gastric mucosal blood flow during healing of endoscopic mucosal resection-induced ulcers

BACKGROUND AND AIM: Helicobacter pylori (H. pylori) infection is known to affect the gastric microcirculation, and cetraxate is reported to accelerate gastric ulcer healing, possibly by augmenting gastric mucosal blood flow (MBF). The aim of this study is to clarify the effect of H. pylori infection and cetraxate on MBF during gastric ulcer healing. METHODS: Forty-two patients who had undergone endoscopic mucosal resection (EMR) were studied. Mucosal blood flow was measured by the use of a laser Doppler flowmeter in the surrounding mucosa and at the ulcer margin, before, 1 day, 1 week and 4 weeks after EMR. Helicobacter pylori infection was confirmed by the use of bacterial culture and histology. After EMR, patients were randomly assigned to receive 30 mg lansoprazole (u.i.d; L-regimen) or 30 mg lansoprazole (u.i.d.) with 200 mg cetraxate (q.i.d; LC-regimen) for 4 weeks. RESULTS: The MBF ratio (MBF at ulcer margin/MBF in surrounding mucosa) 1 week after EMR was significantly lower than that before or 4 weeks after EMR only in H. pylori-positive patients treated with the L-regimen. No such decrease in MBF was observed after 1 week in H. pylori-positive patients treated with the LC-regimen or in H. pylori-negative patients. CONCLUSION: A transient decrease in MBF was detected at the ulcer margin during healing of EMR-induced ulcers in H. pylori-infected patients. Cetraxate seemed to prevent this decrease in MBF.     

Protective action of omeprazole against gastric mucosal injury induced by hemorrhagic shock in rats

The efficacy of omeprazole in preventing gastric mucosal injury induced by hemorrhagic shock in rats and the putative mechanisms involved in this effect were investigated in the present study. Omeprazole did not affect mean arterial blood pressure under both basal conditions and induction of hemorrhagic shock, but it evoked a marked increase in Alcian blue recovery from gastric preepithelial mucus. The morphometric analysis of histological sections revealed that omeprazole caused a significant reduction of hemorrhagic shock-induced damage of gastric mucosa. Ranitidine, used as the reference drug, failed to affect mean arterial blood pressure, Alcian blue recovery from gastric mucus, or hemorrhagic shock-induced damage of gastric mucosa. Both omeprazole and ranitidine exerted a significant inhibition of gastric acid output from anesthetized pylorus-ligated rats. Overall, the present results indicate that omeprazole is effective in protecting gastric mucosa from necrotic damage induced by hemorrhagic shock and suggest that an enhancement of gastric mucus secretion contributes to this protective action.     

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.     

Reversing gastric mucosal alterations during ethanol-induced chronic gastritis in rats by oral administration of Opuntia ficus-indica mucilage

AIM: To study the effect of mucilage obtained from cladodes of Opuntia ficus-indica (Cactaceae) on the healing of ethanol-induced gastritis in rats. METHODS: Chronic gastric mucosa injury was treated with mucilage (5 mg/kg per day) after it was induced by ethanol. Lipid composition, activity of 5'-nucleotidase (a membrane-associated ectoenzyme) and cytosolic activities of lactate and alcohol dehydrogenases in the plasma membrane of gastric mucosa were determined. Histological studies of gastric samples from the experimental groups were included. RESULTS: Ethanol elicited the histological profile of gastritis characterized by loss of the surface epithelium and infiltration of polymorphonuclear leukocytes. Phosphatidylcholine (PC) decreased and cholesterol content increased in plasma membranes of the gastric mucosa. In addition, cytosolic activity increased while the activity of alcohol dehydrogenases decreased. The administration of mucilage promptly corrected these enzymatic changes. In fact, mucilage readily accelerated restoration of the ethanol-induced histological alterations and the disturbances in plasma membranes of gastric mucosa, showing a univocal anti-inflammatory effect. The activity of 5'-nucleotidase correlated with the changes in lipid composition and the fluidity of gastric mucosal plasma membranes. CONCLUSION: The beneficial action of mucilage seems correlated with stabilization of plasma membranes of damaged gastric mucosa. Molecular interactions between mucilage monosaccharides and membrane phospholipids, mainly PC and phosphatidylethanolamine (PE), may be the relevant features responsible for changing activities of membrane-attached proteins during the healing process after chronic gastric mucosal damage.     

Effects of electroacupuncture on gastric mucosal blood flow and transmucosal potential difference in stress rats

ＥｆｅｃｔｓｏｆｅｌｅｃｔｒｏａｃｕｐｕｎｃｔｕｒｅｏｎｇａｓｔｒｉｃｍｕｃｏｓａｌｂｌｏｏｄｆｌｏｗａｎｄｔｒａｎｓｍｕｃｏｓａｌｐｏｔｅｎｔｉａｌｄｉｆｅｒｅｎｃｅｉｎｓｔｒｅｓｓｒａｔｓＸＵＧｕａｎＳｕｎ１，ＳＵＮＹｏｎｇ１，ＷＡＮＧＺｈｅ...     

Inhibitory effect of misoprostol on gastric acid secretionin vitro

The synthetic PGE₁ analog, misoprostol, was shown to have a marked inhibitory effect on gastric secretion as determined in the isolated gastric fundus from immature rats. It inhibited both the unstimulated and pentagastrin-stimulated acid secretion at 10^–7–10^–4 molar concentrations. Its effect was different from that of PGE₁ and PGE₂, which did not affect basal acid secretion (up to 3×10^{–5 M}), although they inhibited to the same extent as misoprostol the pentagastrin-induced acid secretion. When given by mucosal application, misoprostol (10^–7–10^–5 M) behaved similar to the mast cell stabilizer, compound FPL 52694, but its maximum reduction response was only 50%. The above data suggest that misoprostol has additional antisecretory mechanisms of action not shared by the classical natural prostÃglandins.Supported by a grant from the C.N.R., Rome.