Stress-induced Gastric Ulcers In Rats Research Articles

Effect of Bromazepam on stress-induced gastric ulcer in rats and its relation to brain neurotransmitters

The possible antiulcer potential of bromazepam was investigated in relation to its effect on the levels of central neurotransmitters in rats. Peptic ulcer was induced by cold-restraint stress, by immobilizing the animals in open wire restraint cages placed for 2 h at 4 ∘C. Bromazepam (1 and 2 mg kg −1, i.p.) was given as prophylactic regimens, either as a single (2 h before ulcer induction) or repeated (twice daily for 15 days) administration. Results revealed that single (1 mg kg −1) and repeated (1 and 2 mg kg −1) dose regimens of bromazepam succeeded in preventing gastric ulceration, without significant effects on the protein-bound hexose content of gastric mucus. Increases in gamma-aminobutyric acid (GABA) concentrations in almost all tested brain regions were observed in bromazepam-treated groups, as compared to the control stressed group. Cortical dopamine (D) concentrations were reduced following single (2 mg kg −1) as well as repeated administration of bromazepam. Similarly, norepinephrine (NE) concentrations were decreased in the cerebral cortex and thalamus/hypothalamus by repeated doses of bromazepam. Cortical 5-hydroxytryptamine (5-HT) was elevated by single (1 mg kg −1) and repeated (1 mg kg −1) doses of the drug. It could be concluded that bromazepam affords a good gastroprotective potential against cold-restraint stress-induced gastric ulceration and the possible mechanisms might involve an increase in the inhibitory GABA and a suppression of the stimulatory NE and D in central regions, especially the cerebral cortex and/or thalamus/hypothalamus.

Pathogenesis of nicotine treatment and its withdrawal on stress-induced gastric ulceration in rats

Previous studies showed that cigarette smoking was closely associated with gastric ulceration. People usually smoke under stress conditions, and together, these could induce more gastric damage. In the present study, we aimed to study the effects of nicotine administration and its withdrawal on stress-induced gastric ulceration in rats. Male Sprague–Dawley rats were given nicotine (25 or 50 μg/ml) for 10 days and then withdrawn for 2, 4 or 6 days. They were subjected to cold-restraint stress for 2 h after nicotine treatment or after nicotine withdrawal, and then killed. The results indicated that both nicotine treatment and its withdrawal potentiated stress-induced gastric damage. The mucosal glutathione (GSH) and mucus levels were reduced by stress and decreased further by nicotine. The prostaglandin E 2 concentration remained unchanged. To conclude, the adverse effect of nicotine on stress ulceration was prostaglandin E 2-independent but mediated by the depression of glutathione and mucus levels in the gastric mucosa.

Cannabinoid CB1-mediated inhibition of stress-induced gastric ulcers in rats.

The effect of cannabinoid drugs (i.p.) on cold/restraint stress-induced gastric ulcers was studied in rats. The cannabinoid receptor agonist (WIN 55,212-2, 0.1-1 mg/kg), but not the less active isomer WIN 55,212-3 (1 mg/kg), reduced gastric ulceration. The protective effect of WIN 55,212-2 (1 mg/kg) was counteracted by the cannabinoid CB1 receptor antagonist SR141716A, but not by the cannabinoid CB2 receptor antagonist SR144528. These results indicate that the antiulcer effect of the cannabinoid receptor agonist WIN 55,212-2 is mediated by cannabinoid CB1 receptors.

Clonidine Pretreatment Inhibits Stress-Induced Gastric Ulcer in Rats

We studied the effects of clonidine (0.5 mg/kg) on hormonal stress response and antioxidant enzymes cold restraint-induced gastric lesions in rats. Rats in the study group were given 0.5 mg/kg intraperitoneal clonidine (n = 12), whereas the control group received 0.5 mL/kg intraperitoneal isotonic sodium chloride solution (n = 9). Animals were then subjected to immobilization at 4[degree sign]C in restraining devices for 4 h after a starvation period of 24 h. Gastric lesion index, gastric tissue malondialdehyde activity, and plasma cortisol concentrations were assayed. Histopathologic examination demonstrated a stress ulcer index of 3.17 +/- 0.92 mm in the clonidine group and 14.0 +/- 3.22 mm in the control group (P < 0.05). The tissue malondialdehyde concentrations were slightly higher in the control group than in the clonidine group, but the differences were not statistically significant (P > 0.05). Plasma cortisol levels were lower in the clonidine group (P < 0.05). We concluded that clonidine attenuated the tissue damage and stress response in stress-induced gastric ulceration. Implications: Stressful circumstances can cause stomach ulcers, which can bleed, exposing patients to potentially life-threatening complications. In the present animal study, we showed that clonidine, a routinely available medication, may be useful in preventing stress-induced stomach ulcers. (Anesth Analg 1999;89:159-62)

Clonidine pretreatment inhibits stress-induced gastric ulcer in rats.

We studied the effects of clonidine (0.5 mg/kg) on hormonal stress response and antioxidant enzymes cold restraint-induced gastric lesions in rats. Rats in the study group were given 0.5 mg/kg intraperitoneal clonidine (n = 12), whereas the control group received 0.5 mL/kg intraperitoneal isotonic sodium chloride solution (n = 9). Animals were then subjected to immobilization at 4 degrees C in restraining devices for 4 h after a starvation period of 24 h. Gastric lesion index, gastric tissue malondialdehyde activity, and plasma cortisol concentrations were assayed. Histopathologic examination demonstrated a stress ulcer index of 3.17+/-0.92 mm in the clonidine group and 14.0+/-3.22 mm in the control group (P<0.05). The tissue malondialdehyde concentrations were slightly higher in the control group than in the clonidine group, but the differences were not statistically significant (P>0.05). Plasma cortisol levels were lower in the clonidine group (P<0.05). We concluded that clonidine attenuated the tissue damage and stress response in stress-induced gastric ulceration. Stressful circumstances can cause stomach ulcers, which can bleed, exposing patients to potentially life-threatening complications. In the present animal study, we showed that clonidine, a routinely available medication, may be useful in preventing stress-induced stomach ulcers.

Oxidative Inactivation of Gastric Peroxidase by Site-Specific Generation of Hydroxyl Radical and Its Role in Stress-Induced Gastric Ulceration

We have shown earlier that restraint-cold stress-induced gastric ulceration in rats is caused by metal ion dependent generation of hydroxyl radical (OH ̇) and oxidative inactivation of the gastric peroxidase (GPO), an important H 2O 2 scavenging enzyme. To study the mechanism of the oxidative damage of GPO, the purified enzyme was exposed to an OH ̇ generating system containing Cu 2+, ascorbate, and H 2O 2. Kinetic studies indicate that the enzyme is inactivated in a time-dependent process showing saturation with respect to Cu 2+ concentration. The enzyme specifically requires Cu 2+ and is not inactivated by the same concentration of Fe 2+, Mn 2+, or Zn 2+. Sensitivity to catalase indicates the critical role of H 2O 2 in the inactivation. Inactivation is insensitive to superoxide dismutase, suggesting no role of superoxide. The rate of inactivation is not increased in D 2O excluding the involvement of singlet oxygen in the process. However, OH ̇ scavengers such as benzoate or mannitol cannot prevent inactivation. The results indicate a plausible generation of OH ̇ within the enzyme molecule as the cause of inactivation. Fragmentation of peptide linkage or intramolecular crosslinking, gross change of tertiary structure, or change in intrinsic tryptophan fluorescence which occurs in “global” oxidation are not evident. Inactivation is dependent on pH and from a plot of K obs of inactivation against pH, the controlling role of an ionizable group of the enzyme having a pka of 7.8 could be suggested, deprotonation of which favors inactivation. Amino acid analysis shows a specific loss of two lysine residues in the inactivated enzyme. Competitive kinetic studies indicate that pyridoxal phosphate, a specific modifier of the lysine residue, prevents inactivation by competing with Cu 2+ for binding at the GPO. A Cu 2+ binding motif consisting at least of two lysine residues exists in GPO, which specifically binds Cu 2+ and generates OH ̇. The radical oxidizes the lysine residues and perturbs the heme environment to cause inactivation. We suggest that oxidative damage of GPO is mediated by site-specific generation of OH ̇ and not by the OH ̇ generated in the bulk phase.

Central effect of melatonin against stress-induced gastric ulcers in rats.

We investigated the role of melatonin in the induction of gastric lesions induced by water immersion restraint stress or centrally administered thyrotropin-releasing hormone (TRH). Melatonin (0.1-1 ng) injected intracisternally (i.c) 30 min prior to stress dose-dependently inhibited the induction of gastric lesions by water immersion restraint stress, while 100 micrograms/kg, i.p. failed to protect the gastric mucosa. Preadministration of melatonin (1 ng, i.c.) significantly reduced (83%) the severity of gastric lesions induced by a TRH analogue (500 ng, i.c.). Serum melatonin concentrations 30 min after administration of 1 ng melatonin i.c. did not differ from those of rats receiving i.c. vehicle. These results suggest that melatonin plays a protective, anti-stress, role in the gastric mucosa via a mechanism involving the central nervous system.

Reactive Oxygen Species in the Pathogenesis of Stress-Induced Gastric Ulceration in Rats and Protective Effect of Omeprazole

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The influence of peripheral or central administration of ondansetron on stress-induced gastric ulceration in rats.

Ondansetron (0.08, 0.15 or 0.3 mg/kg) injected s.c., every 12 h with the fourth dose given 0.5 h before experiments, dose-dependently lessened gastric glandular mucosal ulceration produced by cold-restraint stress for 2 h. When given intracerebrally (i.c.) (0.1, 0.5 or 1 microgram), using the same treatment regimen, infusion of ondansetron 1 microgram into the nucleus amygdaloideus centralis decreased stress-evoked ulcers; in contrast, injection of the same dose into the nucleus accumbens intensified these lesions. The associated stress-induced stomach wall mast cell degranulation was unaffected by all s.c. or i.c. doses of ondansetron. Pretreatment with disodium cromoglycate i.p. alone, or concurrently with ondansetron s.c., prevented not only ulceration but also mast cell degranulation. 5-Hydroxytryptamine3 receptor antagonism appears to inhibit stress-evoked ulcers mainly by blocking the peripheral effects of the amine after its release from the gastric mucosal mast cells.

Studies on Antiulcer Agents. I. Synthesis and Pharmacological Properties of Ethyl 2-((1H-Benzimidazol-2-yl)sulfinylmethyl)-4-dimethylamino-5-pyrimidinecarboxylate, a New H+/K+-ATPase Inhibitor Possessing Mucosal Protective Activity.

Ethyl 2-[1H-benzimidazol-2-yl)sulfinylmethyl]-4-dimethylamino-5- pyrimidinecarboxylate (2) has been synthesized and evaluated for antiulcer properties. Compound 2 is a H+/K(+)-ATPase inhibitor that affords mucosal protection against absolute ethanol-induced gastric lesions in rats after oral and parenteral administrations. On the other hand, omeprazole, a representative H+/K(+)-ATPase inhibitor, showed mucosal protective action only after oral administration, indicating that it required gastric acid secretion to generate activity. The antiulcer activity of 2 in animal models, such as water-immersion stress-induced gastric ulcer in rats and acidified aspirin-induced gastric ulcer in rats, was three times higher than that of cimetidine.

Effects of 2-(3,4-dimethoxyphenyl)ethylamine derivative (ecabapide, DQ-2511) and its metabolites on water-immersion restraint stress-induced gastric ulcers in rats

Ecabapide (DQ-2511) has been demonstrated to be effective in preventing water-immersion restraint stress ulceration of rats. In the present study, we aimed to define the active molecular features of ecabapide. Seven of 9 degraded materials identified as ecabapide metabolites were synthesized and their antiulcer activities were compared with that of the parent compound. Ecabapide was potent to prevent gastric ulcer formation at the doses of 30-300 mg/kg i.p. Three metabolites (V, VIII and IX) were also active to inhibit ulceration induced by the stress. The antiulcer activity of IX was similar to that of ecabapide, whereas V and VIII had less activities. After the oral administration of ecabapide, the plasma levels of IX reached to less than 15% of that of ecabapide and also IX was largely excreted into the feces. Therefore, the potential implication of the metabolite (IX) as the active component in the antiulcer effect of ecabapide could be excluded. Furthermore, it is also unlikely that the high polar metabolites (IV and VII) are implicated in significant contribution for antiulcer action. In conclusion, we have shown that ecabapide prevents water-immersion restraint stress-induced gastric ulcers, and that this activity is probably mediated by the action of the parent compound.

Gastric lipid peroxidation, gluathione and calcium channel blockers in the stress-induced ulcer model in rats

The antiulcer activity of verapamil and its analogues devapamil and gallopamil was studied. All three drugs reduced cold-restraint stress-induced ulcer development. Gallopamil almost abolished gastric ulcers. Verapamil prevented the increase in gastric lipid peroxidation (LP) due to stress. On the other hand, devapamil and gallopamil increased gastric lipid peroxidation and decreased glutathione levels. This effect may be attributed to the increase in oxygen supply due to possible effective vasodilation at gastric mucosa. The second part of this study revealed that stress-induced gastric ulcers in rats rapidly and spontaneously heal and disappear within 24 h. During recovery, gastric LP decreased and glutathione levels increased within 12 h after the withdrawal of stress, preceded by an initial reduction in glutathione. After 72 h, an unexplained increase in gastric LP and a decrease in glutathione were observed. Treatment with verapamil, devapamil and gallopamil promoted healing, gallopamil being again the most effective. Their effects on gastric LP and glutathione levels are in accordance with the results of pretreatment experiments. In conclusion, devapamil and gallopamil are effective antiulcer agents against stress-induced ulcers, but unlike verapamil, antioxidant activity does not seem likely to be among their mechanisms of action.

Role of endogenous vasopressin in development of gastric ulcer induced by restraint and water immersion

To elucidate the role of arginine vasopressin (AVP) in the development of stress-induced gastric ulcer, the mucosal lesions after restraint and water immersion were examined in Brattleboro strain rats with hereditary hypothalamic diabetes insipidus (DI) and in Long-Evans rats (LE) used as controls. Restrained animals were immersed in water for 2 h, and the size of lesion was expressed as percentage of the lesion area to the total glandular mucosal area, which were defined as ulcer index (UI). In DI rats, UI was significantly higher than in control LE rats, despite the attenuated responses of plasma adrenocorticotropic hormone (ACTH) to stress. Although subcutaneous injection of selective antidiuretic analogue 1-desamino-8-D-AVP did not affect UI, intracerebroventricular (icv) administration of AVP reduced UI in DI rats, and icv administration of V1 antagonist [d(CH2)5Tyr(Me)]AVP elevated UI in LE rats. These results indicate that endogenous AVP plays a role in preventing the formation of gastric ulcers induced by stress via a central V1 receptor. Furthermore, we suggest that elevation of ACTH in plasma is not essential in the development of stress-induced gastric ulcer in rats.

Effects of nicotine on activity and stress-induced gastric ulcers in rats

Nicotine is known to influence locomotor activity. The alkaloid also intensifies gastric ulcer formation in stressed rats. The effects of nicotine on locomotor activity in relation to gastric lesions induced by restraint at 4°C for 2 h (stress) were, therefore, studied. Ten-day treatment with nicotine 25 or 50 μg/ml drinking water potentiated stress-evoked ulceration and mast cell degranulation. These same doses of nicotine increased vertical motor activity; only the higher dose of the alkaloid enhanced horizontal movements. Phenobarbitone (12.5, 25, or 50 mg/kg, SC) dose dependently reduced vertical activity, as well as stress-induced gastric ulceration and mucosal mast cell degranulation. The drug also lessened the potentiating effects of nicotine on motor activity and stress-evoked gastric lesion formation. It is concluded that the ability of chronic nicotine treatment to intensify stress-induced gastric ulceration most likely owes part of its action to a mechanism evoking increased activity, which possibly reflects an influence on the CNS, as well as to enhancement of mast cell degranulation in the stomach glandular mucosa.

N-ethylmaleimide antagonizes stress-induced gastric ulcers in rats

N-ethylmaleimide (NEM) 10 or 25 mg/kg b.wt, given s.c. 20 min beforehand, dose-dependently and significantly antagonizes the severity of gastric glandular ulcers produced by restraint at 4 degrees C (stress) for 2 h. These findings suggest that reduced activity of endogenous nonprotein sulfhydryl substances in gastric tissue does not worsen stress-induced ulceration in rat stomachs, unlike the deleterious effect its depletion is claimed to have on ethanol-evoked gastric mucosal damage. Thus, decreased SH activity appears not to play a role in the aetiology of mucosal ulcers due to stress.

Dimethyl-.BETA.-Propiothetin, New Potent Resistive-Agent against Stress-Induced Gastric Ulcers in Rats.

The preventive effect of dimethyl-beta-propiothetin (DMPT) and methylmethionine at 5 mM each on stress-induced gastric ulcers in rats was compared. Gastric ulcer-diseased rats were induced by the water immersion method. The ulcer index of test rats in the DMPT group was noticeably lower, compared with those in the methylmethionine and the control groups. A comparison of the activities of serum transaminases and amylase, and the amounts of various blood components in test rats claimed that the DMPT group rats were most resistive to such strain compared with the control and the methylmethionine group rats. These results indicate that DMPT is a potent preventive-agent against the stress-induced gastric ulcers in rats without any side effects.

The membrane-stabilizing action of zinc carnosine (Z-103) in stress-induced gastric ulceration in rats

Zinc compounds have been shown to antagonize various types of gastric ulceration in rats. Zinc carnosine (Z-103), a newly developed agent was, therefore, examined for its antiulcer effect in stress-induced ulceration and also its membrane stabilizing action in rat stomachs. Cold-restraint (restrained at 4 ° C for 2 h) stress induced severe hemorrhagic lesions together with increased mast cell degranulation and β-glucuronidase release in the gastric glandular mucosa. Z-103 pretreatment with a single oral dose (3, 10 or 30 mg/kg) reversed these actions in a dose-dependent manner. When the compound was incubated in concentrations of 10 −7, 10 −6, 10 −5 or 10 −4 M, with isolated hepatic lysosomes, it significantly reduced the spontaneous release of β-glucuronidase in the medium. The present study not only demonstrates the antiulcer effect of Z-103 but also indicates that the protective action is likely to be mediated by its membrane-stabilizing action on mast cells and lysosomes in the gastric glandular mucosa.

Nifedipine versus cimetidine in prevention of stress-induced gastric ulcers in rats

The effects of nifedipine and cimetidine on cold/restraint stress-induced gastric ulcers and glandular wall mast cell count were studied in rats. Two hours of restraint at 4°C resulted in 90% ulceration rate in the glandular stomach with a decrease in glandular wall mast cell count in the mucosa, submucosa and muscle layer. Nifedipine in three doses (1, 5 and 10 mg/kg) administered i.p. 30 min before stress significantly and dose dependently prevented gastric ulceration and mast cell degranulation. Cimetidine, in doses of 50, 100 and 150 mg/kg, again administered 30 min before stress prevented only gastric ulceration dose dependently without a significant change in mast cell count. The results indicate that both nifedipine and cimetidine are equally effective to reduce gastric mucosal ulceration in response to stress. However, the unique effect of nifedipine to inhibit mast cell degranulation which was now clearly demonstrated may favour the potential value of this drug in the management of peptic ulcer disease in humans.

Evidence for a modulation of the stress response by the pineal gland

Wistar rats show a circadian variation in their response to stress. Pinealectomy exacerbates stress-induced gastric ulceration in rats. This effect is counteracted by melatonin administration.

Effect of centrally administered β-endorphin on the development of stress-Induced gastric ulcers in rats

Effect of centrally administered β-endorphin on the development of stress-Induced gastric ulcers in rats