diethyl-maleate and Stomach-Ulcer

This study compares the involvement of ATP-sensitive potassium (K(ATP)) channels and prostaglandins in various forms of gastroprotection in the rat. Instillation of 1 ml of 70% ethanol induced severe gastric mucosal damage (lesion index 39 +/- 0.8), which was substantially but not maximally reduced by oral pretreatment with 16,16-dimethyl-prostaglandin (PG) E(2) (75 ng/kg), 20% ethanol (1 ml), sodium salicylate (15 mg/kg), the metal salt lithium chloride (7 mg/kg), the sulfhydryl-blocking agent diethylmaleate (5 mg/kg), and the thiol dimercaprol (10 mg/kg). Administration of indomethacin (20 mg/kg) increased gastric mucosal damage induced by 70% ethanol (lesion index 45 +/- 0.8) and significantly reduced the protective effect of 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The blocker of K(ATP) channels glibenclamide (5-10 mg/kg) significantly antagonized the protective effect of 16,16-dimethyl-PGE(2), 20% ethanol, sodium salicylate, lithium chloride, diethylmaleate, and dimercaprol. The inhibition of protection induced by glibenclamide was reversed by pretreatment with the K(ATP) channel activator cromakalim (0.3-0.5 mg/kg). In conclusion, our results indicate a role of K(ATP) channels in the gastroprotective effect of 16,16-dimethyl-PGE(2) and of the other agents tested. Since the protection afforded by these agents is additionally indomethacin-sensitive, it is suggested that under these conditions endogenous prostaglandins act as activators of K(ATP) channels, and this mechanism, at least in part, mediates gastroprotection.

Topics: 16,16-Dimethylprostaglandin E2; Adaptation, Physiological; Adenosine Triphosphate; Administration, Oral; Animals; ATP-Binding Cassette Transporters; Dimercaprol; Dose-Response Relationship, Drug; Ethanol; Gastric Mucosa; Glyburide; KATP Channels; Lithium Chloride; Male; Maleates; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Inwardly Rectifying; Prostaglandins; Rats; Rats, Wistar; Sodium Salicylate; Stomach Ulcer

The aim of the present study was to investigate the underlying mechanism of the role of hot water extract of black tea [Camellia sinensis (L). O. Kuntze Theaceae] in normalizing the changes in intestinal transit and gastric emptying induced by various ulcerogenic agents in experimental rats. Intestinal transit as well as gastric emptying were significantly reduced in rats treated with glutathione (GSH) depleting agents, diethyl maleate (DEM), indoacetamide (IDA) and N-ethyl maleimide (NEM). Prior oral administration of black tea extract (BTE) at 20 ml/kg of a 10% solution, i.g. once a day for 7 days significantly increased the intestinal transit and gastric emptying with restoration of serum GSH level. Singular administration of succimer (60 mg/kg, i.g.), the standard sulfhydryl containing antiulcer agent used as a reference drug, was also effective. Increase in intestinal transit caused by BTE was reversed both by N-omega-nitro-L-arginine methyl ester (L-NAME) (25 mg/kg, i.p.) and N-omega-monomethyl-L-arginine (L-NMMA) (25 mg/kg, i.p.), but not with N-omega-nitro-D-arginine methyl ester (D-NAME) (25 mg/kg, i.p.). Furthermore, restoration of intestinal nitric oxide synthase (NOS) activity was found to be associated with BTE treatment. These results provide evidence that nitric oxide may play a role in BTE-mediated improvement of intestinal motility changes and gastric emptying induced by DEM, IDA and NEM.

Topics: Animals; Enzyme Inhibitors; Ethylmaleimide; Female; Gastric Emptying; Gastrointestinal Motility; Glutathione; Male; Maleates; Nitric Oxide; Nitric Oxide Synthase; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Tea

The role of a hot water extract of black tea (Camellia sinensis (L). O. Kuntze Theaceae) in the gastric cytoprotective mechanisms was studied using gastric mucosal lesions produced by various ulcerogens in rats as an experimental model. Prior oral administration of black tea extract (BTE) at 20 ml/kg, i.g. once a day for 7 days significantly reduced the incidence of gastric erosions and severity induced by ethanol, diethyldithiocarbamate (DDC) and diethylmaleate (DEM). This treatment also favorably altered the changes in acid and peptic activity of gastric juice in these ulcerogen-treated animals. Singular administration of succimer (60 mg/kg, i.g.), the standard sulfhydryl containing antiulcer drug used as a reference drug, was also effective. The levels of glutathione and glutathione peroxidase were significantly decreased after treatment with ethanol, DDC and DEM, and this decrease was prevented by BTE pretreatment in the aforesaid manner. Other major features of BTE-induced reversal of ulcerogenic agents include a significant decrease in the protein content and a marked increase in hexosamine and sialic acid content. These results suggest a major role for glutathione, an endogenous antioxidant, in the cytoprotection against ulceration afforded by BTE.

Topics: Animals; Anti-Ulcer Agents; Central Nervous System Depressants; Chelating Agents; Ditiocarb; Ethanol; Female; Gastric Juice; Glutathione; Glutathione Peroxidase; Hexosamines; Hot Temperature; Male; Maleates; N-Acetylneuraminic Acid; Plant Extracts; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Tea; Water

We examined the role of reduced glutathione as a defense mechanism against acid-induced gastric mucosal cell damage in vitro. Cellular stores of reduced glutathione were depleted by reaction with diethyl maleate (DEM) or 1-chloro-2,4-dinitrobenzene (CDNB) and increased by reaction with L-cysteine. Depletion of cellular glutathione by reaction with DEM or CDNB potentiated gastric mucosal cell lysis by acid. Increase of cellular glutathione by L-cysteine decreased cell lysis by acid. Altering the cellular reduced-to-oxidized glutathione ratio by tert-butyl hydroperoxide or diamide increased cellular susceptibility to acid. Reduced glutathione is essential for glutathione peroxidase to catalyze hydrogen peroxide. We further studied whether oxygen free radicals were involved in the pathogenesis of acid-induced gastric mucosal injury in vitro. Neither superoxide dismutase, catalase, nor dimethyl sulfoxide decreased acid-induced gastric mucosal cell damage. We conclude that reduced glutathione plays an important role as a defense mechanism against acid-induced injury in cultured rat gastric mucosal cells. Production of oxygen radical in response to acid exposure may occur intracellularly, since exogenous oxygen radical scavengers, which do not gain access to the interior of cells, had no protective effect. Reduced glutathione might protect gastric mucosal cells by mechanisms other than the elimination of oxygen free radicals.

Topics: Acids; Animals; Animals, Newborn; Catalase; Cells, Cultured; Cysteine; Diamide; Dimethyl Sulfoxide; Dinitrochlorobenzene; Female; Gastric Mucosa; Glutathione; Hydrogen-Ion Concentration; Kinetics; Male; Maleates; Oxidation-Reduction; Peroxides; Rats; Rats, Inbred Strains; Stomach Ulcer; Superoxide Dismutase; tert-Butylhydroperoxide

The role of glutathione status in gastric mucosal cytoprotection has been a subject of controversy. Cysteamine, an exogenous sulfhydryl agent and diethyl maleate (DEM), an endogenous glutathione (GSH) depletor both appear to protect rats from ethanol-induced gastric lesions. In this study, we used various agents to alter gastric mucosal GSH levels and assessed the effects on susceptibility to ethanol injury. We found that DEM and buthionine sulfoximine both depleted gastric GSH but only DEM protected against ethanol-induced gastric lesions. L-Oxothiazolidine-4-carboxylate (OXT) and N-acetyl-L-cysteine (NAC) both potentiated ethanol-induced gastric lesions even though only NAC significantly raised the GSH level. The depletion of GSH by DEM was reversed by supplying cysteine in the form of OXT or NAC so that the net result was a GSH level close to normal control. The potentiation of ethanol injury by NAC and OXT was still apparent. These experiments show no relation between gastric GSH levels and susceptibility to ethanol injury.

Topics: Acetylcysteine; Animals; Cysteamine; Ethanol; Gastric Mucosa; Glutathione; Male; Maleates; Pyrrolidonecarboxylic Acid; Rats; Rats, Inbred Strains; Stomach Ulcer; Thiazoles; Thiazolidines

Intragastric administration of sulfhydryl-containing cysteamine or sulfhydryl-oxidizing diethylmaleate caused a dose-dependent reduction in the mean area of gastric lesions induced by absolute ethanol. The protective effects of these agents are abolished by the sulfhydryl blocker N-ethylmaleimide, while indomethacin, a potent inhibitor of cyclooxygenase, caused only about 50% reduction in this protection. This study indicates that mucosal generation of prostaglandins contributes to the gastric cytoprotection by these agents administered intragastrically, but endogenous sulfhydryls are also involved in the gastric mucosal protection by sulfhydryl-containing or sulfhydryl-oxidizing compounds.

Topics: Animals; Anti-Ulcer Agents; Cysteamine; Dinoprostone; Female; Gastric Mucosa; Indomethacin; Male; Maleates; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Stomach Ulcer; Sulfhydryl Compounds

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Gastric Mucosa; Glutathione; Liver; Male; Maleates; Oxidation-Reduction; Rats; Rats, Inbred Strains; Stomach Ulcer

Topics: Animals; Gastric Mucosa; Glutathione; Injections, Subcutaneous; Liver; Male; Maleates; Rats; Stomach Ulcer; Time Factors