Water Immersion Stress-induced Gastric Lesions Research Articles

Effect of cilostazol, a selective type-III phosphodiesterase inhibitor, on water-immersion stress-induced gastric mucosal injury in rats

Cilostazol, a specific type-III phosphodiesterase inhibitor, is widely used for the treatment of ischemic symptoms of peripheral vascular disease. Recent studies have reported that the mechanism of cilostazol is related to the suppression of pro-inflammatory cytokine production and improvement of local microcirculation disturbances. The pathogenesis of stress-induced gastric mucosal lesions is characterized by the activation of inflammatory cells and the production of inflammatory cytokines. The effects of cilostazol on the development of gastric mucosal lesions have not been reported. In the present study, we examined the effect of a cilostazol on water-immersion stress-induced gastric mucosal lesions. Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of the selective type-III phosphodiesterase inhibitor, cilostazol. We measured the gastric mucosal lesion and the concentrations of myeloperoxidase (MPO), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1), as an index of neutrophil accumulation and pro-inflammatory cytokine production. Cilostazol ameliorated the gastric mucosal injury induced by water-immersion stress (P<0.001). The gastric contents of MPO, TNF-alpha, IL-1beta, and CRO/CINC-1 were all increased after water-immersion stress and were reduced to almost normal levels by cilostazol. In this study, we demonstrated that a selective type-III phosphodiesterase inhibitor, cilostazol, inhibited stress-induced gastric inflammation and damage via suppressing the production of pro-inflammatory cytokines. Cilostazol may be useful for preventing gastric mucosal lesions.

Selective adenosine A2A receptor agonist, ATL‐146e, attenuates stress‐induced gastric lesions in rats

Activation of adenosine A(2A) receptors reduces the production of various pro-inflammatory cytokines and suppresses neutrophil activation. Water-immersion restraint is well known to cause gastric mucosal lesions due to stress. The pathogenesis of stress-induced gastric mucosal lesions is characterized by activation of inflammatory cells and production of inflammatory cytokines. Agonists of adenosine A(2A) receptors are known to be anti-inflammatory, but the effects of these compounds on the development of gastric mucosal lesions has not been reported. In the present study, the effect of a potent and selective adenosine A(2A) receptor agonist, ATL-146e, on water-immersion stress-induced gastric mucosal lesions was studied. Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of a potent and selective agonist of the adenosine A(2A) receptor. The gastric concentrations of myeloperoxidase (MPO), as an index of neutrophil accumulation, and the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), were measured. The total length of gastric erosions (ulcer index) in control rats was 21.6 +/- 3.23 mm and was reduced by 86% to 3.1 +/- 0.83 mm by pretreatment with 5.0 microg/kg ATL146e (P < 0.001). The gastric content of MPO, TNF-alpha and IL-1beta were all increased after water-immersion stress and reduced to near normal levels by ATL-146e. A specific adenosine A(2A) agonist inhibits stress-induced gastric inflammation and damage. A(2A) agonist compounds may be useful for preventing ulcers and appear to act by blocking gastric inflammation.

Exacerbatory mechanism responsible for water immersion stress-induced gastric lesions in aged rats compared with young rats.

1. The present study was designed to investigate whether or not ageing affects the development of water immersion stress-induced gastric lesions in rats. Effects of cetraxate, an anti-ulcer drug, were also examined. 2. Gastric lesions were induced by 6 h water immersion stress in rats. Gastric mucosal blood flow was determined by the hydrogen gas clearance technique and nitric oxide synthase (NOS) activity was measured enzymatically. 3. Early development of gastric lesions was observed in aged rats and exacerbation of gastric lesions was also found. Lowering of gastric mucosal blood flow and reduced NOS activity were observed in aged rats. 4. Cetraxate mitigated the development of gastric lesions in young rats and also increased gastric mucosal blood flow and NOS activity. However, these favourable effects were diminished in aged rats. 5. Decreased NOS activity may be an important exacerbatory factor to the development of gastric lesions in aged rats. 6. Effects of cetraxate differed between young rats and aged rats. 7. These results may explain the refractoriness and drug resistance in gastric ulcers encountered by elderly individuals.

P–336 - Effects of three gastric mucosal defensive drugs on ethanol-induced and water immersion stress-induced gastric mucosal lesions in rats.

P–336 - Effects of three gastric mucosal defensive drugs on ethanol-induced and water immersion stress-induced gastric mucosal lesions in rats.

Implication of aging on nitric oxide synthase activity in the genesis of water immersion stress-induced gastric lesions in rats

Implication of aging on nitric oxide synthase activity in the genesis of water immersion stress-induced gastric lesions in rats

Cytoprotective effects of 4,6-bis(1H-pyrazol-1-yl)pyrimidine and related compounds on HCI.ethanol-induced gastric lesions in rats.

Bis(1H-pyrazol-1-yl)- and bis(1H-imidazol-1-yl)pyrimidines were synthesized and evaluated for cytoprotective effects. Among them, 4,6-bis(1H-pyrazol-1-yl)pyrimidine (3) showed a potent inhibitory effect on the HCl.ethanol-, ethanol-, and water immersion stress-induced gastric lesions in rats, and a very low acute toxicity. One of the major factors responsible for the cytoprotective effects of 3 is the increase in the bicarbonate secretion. This compound appears to be a promising cytoprotective drug for the treatment of gastric mucosal ulcers.

The Effects of Hange-shashin-to on Gastric Function in Comparison with Sho-saiko-to.

The effects of "Hange-shashin-to (TJ-14)" on gastric function were examined in comparison with "Sho-saiko-to (TJ-9)". Oral treatment with TJ-14 (125-500 mg/kg) caused dose-dependent suppression of ethanol-induced gastric injury, while it did not suppress gastric lesions induced by water-immersion stress. TJ-9 (125-500 mg/kg, p.o.) suppressed both water-immersion stress-induced gastric lesions and ethanol-induced gastric injury in a dose-dependent manner. Intraduodenal administration of TJ-14 even at 500 mg/kg did not affect gastric juice secretion, while TJ-9 at 125 to 500 mg/kg dose-dependently suppressed gastric juice secretion. TJ-14 (125-500 mg/kg, p.o.) accelerated gastric emptying in normal rats and improved the delayed gastric emptying induced by BaCl2 in a dose-dependent manner, whereas such effect was not noted with TJ-9. Oral treatment with TJ-14 at 500 mg/kg significantly suppressed apomorphine-induced vomiting, but it did not affect copper sulfate-induced vomiting. These results suggest that TJ-14 exhibits an anti-ulcer action (probably based on its ability to protect the gastric mucosa), improvement of gastric emptying and an anti-emetic action. TJ-9 also showed anti-ulcer effects, probably based on its ability to suppress gastric secretion and to protect the gastric mucosa. Thus, the present study demonstrated the effectiveness of TJ-14 and TJ-9 against gastric disease, and provided basic data which explain the differences in clinical application between these two kampo medicines.

Prevention of water immersion stress-induced gastric lesions through the enhancement of nitric oxide synthase activity in rats.

Gastric mucosal microcirculation is an important factor in the protection of gastric mucosa, and nitric oxide (NO) plays a crucial role in the regulation of regional blood flow. This study was designed to evaluate the effect of cetraxate, an anti-ulcer drug, on water immersion stress-induced gastric lesions in relation to the changes in NO synthase activity. Gastric lesions were induced in rats by water immersion stress. The effects of cetraxate on NO synthase activity with or without stress was determined enzymatically. Changes in gastric mucosal prostaglandin (PG) contents with or without stress were also determined using high-performance liquid chromatography. Gastric mucosal blood flow was measured by hydrogen gas clearance technique. Water immersion stress-induced gastric lesions. Cetraxate significantly mitigated the lesions but N(G)-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO synthase, exacerbated the lesions. The favourable effect of cetraxate was remarkably diminished by administration of L-NMMA. NO synthase activity decreased significantly by 6 h after stress. Cetraxate treatment increased NO synthase activity throughout the experiment in rats with or without stress treatment. Water immersion stress decreased all PGs detected, i.e. 6-keto-PGF1alpha, PGF2alpha, PGE2 and PGD2. Cetraxate prevented stress-induced decreases in PG contents. L-NMMA showed no significant effect on PG contents. Cetraxate increased gastric mucosal blood flow significantly and L-NMMA cancelled out cetraxate-induced increase in blood flow. The pharmacological efficacy of anti-ulcer drugs such as cetraxate might be attributable to the enhancement of NO synthase activity resulting in an increase in gastric mucosal blood flow.

Effects of FK506, an immunosuppressive agent, on genesis of water-immersion stress-induced gastric lesions in rats.

We examined the effects of FK506, an immunosuppressive agent, on the genesis of water immersion stress-induced gastric lesions in rats. Using high-performance liquid chromatography, four kinds of prostaglandins, ie, 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, and prostaglandin D2, were detected, and no leukotrienes were detected in gastric mucosa in rats without stress. After 6 hr of stress, gastric lesions developed with decreases in all prostaglandin contents, and the emergence of peptide leukotrienes was observed. Intramuscular administration of FK506 (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) reduced lesion index dose-dependently. Administration of FK506 at doses over 0.25 mg/kg decreased all prostaglandin contents, but did not affect the increase in leukotriene contents. Pretreatment with famotidine or omeprazole reduced lesion index, and the protective effects were equivalent to those of 1.0 mg/kg of FK506, although FK506 did not affect gastric secretion during water-immersion stress. Water-immersion stress did not change the activities of xanthine oxidase in either stomach or serum. Polyoxyethylene-modified superoxide dismutase did not prevent gastric lesions. Water-immersion stress significantly increased myeloperoxidase activity in gastric mucosa, and FK506 reduced the increase in myeloperoxidase activity induced by stress. From our results, other factors besides gastric acid secretion and tissue eicosanoid contents, such as chemoattractant factor, might also be involved in the genesis of water-immersion stress-induced gastric lesions in rats.

Effects of a Polysaccharide Fraction from the Roots of Bupleurum falcatum L. on Experimental Gastric Ulcer Models in Rats and Mice

Effects of an acidic polysaccharide fraction, BR-2, from the roots of Bupleurum falcatum L., on HCl-ethanol, ethanol and water immersion stress-induced gastric lesions in mice and pylorus-ligated ulcers in rats have been studied. Oral administration of BR-2 at doses of 50 to 200 mg kg-1 inhibited the formation of the gastric lesions induced by necrotizing agents such as HCl-ethanol and ethanol, in a dose dependent manner. This protective effect was observed after oral, intraperitoneal, and subcutaneous administration of BR-2 (25-100 mg kg-1). BR-2 also inhibited the formation of gastric ulcers which were induced by water immersion stress or pylorus-ligation. Prostaglandin E2 in gastric juice from rats and in gastric mucosa from mice was not influenced by oral administration of BR-2. The protective action of BR-2 against HCl-ethanol-induced gastric lesions was not abolished by pretreatment with indomethacin (20 mg kg-1, i.p.). The amount of alcian blue binding to mucosa also increased after administration of BR-2 (100 mg kg-1, p.o.); however, the amount of hexosamine and N-acetylneuraminic acid in mucosa did not change significantly.

RELATIONSHIP BETWEEN GASTRIC MUCOSAL PROSTAGLANDIN LEVELS AND HEALING OF GASTRIC LESIONS IN RATS

1. This study was designed to determine whether or not endogenous prostaglandins (PG) contribute to the healing of gastric ulcers induced by high concentrations of ethanol or water immersion stress. 2. Ethanol-induced gastric lesions; rats were divided into four groups: (1) the control group: untreated; (2) the indomethacin group: indomethacin (2 mg/kg) was injected intramuscularly (i.m.) once daily until the end of the experiment; (3) the ethanol group: rats were given 1 mL of 50% ethanol intragastrically; (4) the ethanol + indomethacin group: indomethacin (2 mg/kg) was injected (i.m.) once daily from 1 h after administration of 50% ethanol until the end of the experiment. 3. Water immersion stress-induced gastric lesions; rats were divided into three groups: (1) control group: untreated; (2) stress group: rats were placed in a stress cage and immersed into a water bath (23 degrees C) for 6 h; (3) stress + indomethacin group: indomethacin (2 mg/kg) was injected (i.m.) once daily for 3 consecutive days immediately after stress treatment or from 3 days after stress treatment until the end of the experiment. 4. Immediately after observation of the lesions, the fundic mucosal layer was separated from the muscle layer and mucosal PG levels were measured by high performance liquid chromatography in each group. 5. Indomethacin did not inhibit ulcer healing until 48 h after administration in the ethanol experiment, and until 3 days after administration in the water immersion experiment. In contrast, indomethacin inhibited ulcer healing thereafter in each experiment respectively. 6. Four kinds of PG, that is 6-keto-PGF1 alpha, PGF2 alpha, PGE2 and PGD2 were detected in gastric mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of protective activity of 16,16-dimethyl PGE2 and acetazolamide on gastric and duodenal lesions in rats

16,16-Dimethyl PGE2 (16,16-dmPGE2), given orally at 10-30 micrograms/kg, had no effects on gastric acid secretion, or carbonic anhydrase activity, but did increase HCO3- secretion in both the stomach and duodenum of rats. 16,16-dmPGE2, at nonantisecretory doses, potently inhibited indomethacin- and water-immersion stress-induced gastric lesions and mepirizole-induced duodenal lesions in rats. Acetazolamide, given orally at 50 mg/kg, markedly inhibited carbonic anhydrase activity, but had no effects on gastric acid secretion and the basal and 16,16-dmPGE2-stimulated HCO3- secretion. Acetazolamide, at a nonantisecretory dose, had no effects on indomethacin-induced gastric lesions and mepirizole-induced duodenal lesions, but significantly inhibited water-immersion stress-induced gastric lesions. Combined administration of 16,16-dmPGE2 and acetazolamide did not influence the protective activity of 16,16-dmPGE2 on these lesions. The mechanism of the cytoprotective activity of 16,16-dmPGE2 may involve an increase in HCO3- secretion (nonmediated by carbonic anhydrase), while mechanisms involved in the effects of acetazolamide are apparently different.