Protects Rat Gastric Mucosa Research Articles

Topical nicotine protects rat gastric mucosa against ASA-induced damage a role for mucosal fluid secretion in cytoprotection

Acute intragastric nicotine administration has previously been shown to protect against ethanol-induced gastric mucosal damage. The aim of this study was to examine the effects of acute nicotine exposure on ASA-induced gastric mucosal damage and to determine if nicotine's protective effect is secondary to an increase in mucosal blood flow or in mucosal fluid secretion, as reflected by changes in the juxtamucosal pH gradient and volume of intragastric fluid. Mucosal blood flow, using a laser Doppler flowmeter, juxtamucosal pH gradient (depth, magnitude, and surface pH), using antimony microelectrodes, and changes in volume of luminal bathing solutions were measured in rat ex vivo gastric chamber preparations prior to and after a 10-min exposure to topical nicotine (1 mg in 8 ml of 0.2 M mannitol in 50 mM HCl), or to mannitol-HCl solution (vehicle). This was followed by application of acidified ASA (80 mM in 160 mM HCl) to the chambered mucosae for 10 min. Lesion area, expressed as the percentage of total glandular mucosa which was damaged, was significantly (P < 0.05) reduced by nicotine pretreatment. Blood flow decreased with nicotine exposure by 18.4%, compared to 13.6% in the control group (NS). Both gradient depth and gastric fluid volume increased significantly in the nicotine group (P < 0.05) compared to controls. Yohimbine pretreatment prevented both the increase in juxtamucosal pH gradient depth and the protective effect of nicotine. These results suggest that acute intragastric nicotine exposure protects against ASA-induced gastric damage in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The somatostatin analogue octreotide protects against ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa

Somatostatin 14 and various derivatives protect rat gastric mucosa against ethanol-induced lesions. Their mechanism of action is unknown. We investigated the effect of two somatostatin derivatives, octreotide and 5-( l)-citrullin-octreotide, on ethanol-induced hemorrhagic lesions, microcirculatory stasis and elevated vascular permeability in the rat stomach, with the goal to elucitate the pharmacological and microcirculatory mechanisms behind the gastroprotective effect. Radioligand studies revealed a high affinity of octreotide for the somatostatin receptor (IC 50 = 5 × 10 −10 mol/l), in contrast to 5-( l)-citrullin-octreotide (IC 50 = 3 × 10 −6 mol/l). This was in good agreement with the inhibition of growth hormone release from rat anterior pituitary cells (octreotide: IC 50 = 1.2 × 10 −10 mol/l; 5-( l)-citrullin-octreotide: IC 50 = 3 × 10 −6 mol/l. Intragastric administration of ethanol to rats resulted in lesions of the gastric mucosa affecting 18.9 ± 3.1% of the area of the glandular stomach. Octreotide reduced the area to 6.4 ± 1.7%( P < 0.05). The dose-response curve was bell-shaped. 5-( l)-citrullin-octreotide was totally devoid of any protective activity (dose range: 0.1 ng/kg to 0.1 mg/kg). We further investigated the effect of the two peptides on ethanol-induced mic increase in microvascular permeability, measured by the extravasation of the tracer fluorescein-isothiocyanate-dextran (molecular weight 150 000). Pretreatment with octreotide (0.1 ng/kg s.c.) prevented stasis and reduced capillary permeability significantly. 5-( l)-citrullin-octreotide had no effect on ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa. In summary, very low doses of octreotide have a benefical effect on ethanol-induced hemorrhagic lessions, microcirculatory stasis and increased capillary permeability. This effect is most likely mediated by somatostatin receptors.

Transforming growth factor alpha protection against drug-induced injury to the rat gastric mucosa in vivo.

This study was designed to determine whether transforming growth factor alpha (TGF alpha) protects rat gastric mucosa against ethanol- and aspirin-induced injury. Systemic administration of TGF alpha dose-dependently decreased 100% ethanol-induced gastric mucosal injury; a dose of 50 micrograms/kg delivered intraperitoneally 15 min before ethanol decreased macroscopic mucosal injury by > 90%. At the microscopic level, TGF alpha prevented deep gastric necrotic lesions and reduced disruption of surface epithelium. Pretreatment with orogastric TGF alpha (200 micrograms/kg) only partially (40%) decreased macroscopic ethanol damage. Intraperitoneal administration of TGF alpha at a dose of 10 micrograms/kg, which does not significantly inhibit gastric acid secretion, decreased aspirin-induced macroscopic damage by > 80%. TGF alpha protection does not seem to be mediated by prostaglandin, glutathione, or ornithine decarboxylase-related events, as evidenced by lack of influence of the inhibition of their production. Pretreatment with the sulfhydryl blocking agent N-ethylmaleimide partially abolished (40%) the protective effect of TGF alpha. In addition, systemic administration of TGF alpha resulted in a two-fold increase in tyrosine phosphorylation of phospholipase C-gamma 1 and in a time- and dose-dependent increase in levels of immunoreactive insoluble gastric mucin; these events occurred in a time frame consistent with their participation in the protective effect of TGF alpha.

Preventive actions of N-(3-aminopropionyl)-L-histidinato zinc (Z-103) through increases in the activities of oxygen-derived free radical scavenging enzymes in the gastric mucosa on ethanol-induced gastric mucosal damage in rats.

Z-103 at 1 to 25 mg/kg, p.o. prevented 100% ethanol-induced gastric mucosal lesions in a dose-dependent manner. Z-103 at 3 to 25 mg/kg, p.o. significantly elevated gastric mucosal superoxide dismutase (SOD)-like activity 1 hr after its administration to normal rats. In addition, Z-103 at doses (10 and 25 mg/kg, p.o.) which prevented 100% ethanol-induced gastric lesion further increased gastric mucosal SOD-like and glutathione peroxidase (GSH-px) activities elevated by 60% ethanol. Z-103 (10 and 25 mg/kg) significantly inhibited the increase in thiobarbituric acid-reactive substances in gastric mucosa injured by 60% ethanol. The combination with cycloheximide, a protein synthesis inhibitor, completely abolished the prevention of 60% ethanol-induced gastric mucosal lesions and the elevation of both free radical scavenging enzyme activities in the mucosa by Z-103 (10 mg/kg, p.o.). These results suggest that Z-103 may partly protect rat gastric mucosa against ethanol-induced damage by scavenging oxygen-derived free radicals via increases in the synthesis of SOD-like and GSH-px enzymes in the mucosa.

Preventive Actions of N-(3-Aminopropionyl)-L-Histidinato Zinc (Z-103) through Increases in the Activities of Oxygen-Derived Free Radical Scavenging Enzymes in the Gastric Mucosa on Ethanol-Induced Gastric Mucosal Damage in Rats

Z-103 at 1 to 25 mg/kg, p.o. prevented 100% ethanol-induced gastric mucosal lesions in a dose-dependent manner. Z-103 at 3 to 25 mg/kg, p.o. significantly elevated gastric mucosal superoxide dismutase (SOD)-like activity 1 hr after its administration to normal rats. In addition, Z-103 at doses (10 and 25 mg/kg, p.o.) which prevented 100% ethanol-induced gastric lesion further increased gastric mucosal SOD-like and glutathione peroxidase (GSH-px) activities elevated by 60% ethanol. Z-103 (10 and 25 mg/kg) significantly inhibited the increase in thiobarbituric acid-reactive substances in gastric mucosa injured by 60% ethanol. The combination with cycloheximide, a protein synthesis inhibitor, completely abolished the prevention of 60% ethanol-induced gastric mucosal lesions and the elevation of both free radical scavenging enzyme activities in the mucosa by Z-103 (10 mg/kg, p.o.). These results suggest that Z-103 may partly protect rat gastric mucosa against ethanol-induced damage by scavenging oxygen-derived free radicals via increases in the synthesis of SOD-like and GSH-px enzymes in the mucosa.

Gastric mucosal protection with ?-phenylethylamine (PEA) and other sympathomimetic amines against absolute ethanol in the rat

The purpose of this study was to investigate the potential of beta-phenylethylamine (PEA), an amphetamine-like compound present in the blood during high stress situations, to protect rat gastric mucosa against absolute ethanol. F-344 rats were pretreated with PEA in saline at several dose levels and at various times prior to oral administration of 1 ml absolute ethanol. PEA at dose levels of 50 and 100 mg/kg significantly reduced the severity of alcohol-induced lesions following oral, but not parenteral, treatment. The duration of protection with PEA was approximately 90 min, with maximum protection observed when PEA was administered 15-30 min before alcohol. Pretreatment with indomethacin did not prevent or reduce the protection induced by PEA. Other sympathomimetic amines such as isoproterenol and ephedrin were similarly cytoprotective against absolute ethanol while amphetamine, phenylephrine, and epinephrine proved ineffective. These results add further support to the role of the sympathetic nervous system in regulating gastric mucosal protection in the rat.

Protection of gastric epithelial cell monolayers from a human cell line by omeprazole in vitro.

Omeprazole has an anti-ulcerogenic effect and protects rat gastric mucosa against drug-induced damage in vivo. We have evaluated omeprazole protection against damage induced by sodium taurocholate to gastric epithelial cell monolayers, an experimental model that completely excludes the influence of systemic factors. Furthermore, since our model consists of mucus-producing cells, the acid inhibitory effect of the drug in any protection is negligible. The role of prostaglandin and sulfhydryls in any such protection has also been evaluated. Monolayers of gastric cells from a well-differentiated human cell line were studied. A chromium-51 release assay was used to assess cell damage. Sodium taurocholate damaged cells dose-dependently (r = 0.97, p less than 0.01). Pretreatment with omeprazole significantly reduced the amount of cell damage brought about by sodium taurocholate (p less than 0.001). Indomethacin did not prevent the protection afforded by omeprazole, nor did incubation with omeprazole increase the amount of prostaglandin E2 produced by cultured cells. Omeprazole did not increase the amount of sulfhydryl compounds in cultured cells. These results indicate that omeprazole protects gastric cells independently of systemic factors and of inhibition of gastric acid secretion. This protection is not related to stimulation of prostaglandin synthesis nor is it associated with an increase of endogenous sulfhydryl compounds.

REV 5901 and Ly 171,883 protect rat gastric mucosa against ethanol-induced damage.

The effect of the leukotriene antagonist, Ly 171,883, or the 5-lipoxygenase inhibitor, REV 5901, on ethanol-induced gastric lesion formation in the rat was investigated. Pretreatment with REV 5901 resulted in a dose dependent decrease in lesion length. Doses of 32 and 64 mg/kg induced nearly complete protection against ethanol, while doses of 1 and 8 mg/kg were much less effective. With Ly 171,883, 32 and 64 mg/kg doses less dramatically reduced lesion length. These findings implicate products of the 5-lipoxygenase pathway in the production of ethanol-induced gastric lesions.

Carbenoxolone sodium protects rat gastric mucosa against ethanol-induced necrosis.

AbstractGastric necrosis was induced in the rat by oral administration of absolute ethanol. Carbenoxolone sodium, administered orally, but not intravenously, reduced the severity of ethanol-induced lesions in a dose-responsive manner. Maximum inhibition of lesion formation occurred when carbenoxolone was administered 15 min before ethanol. Our results suggest that carbenoxolone, like prostaglandins, is cytoprotective to the rat gastric mucosa. Similarities in the time response for cytoprotection by these two compounds suggest that they exert their effect by a common mechanism.