Acetic Acid-induced Gastric Ulcers Research Articles

Rebamipide, novel prostaglandin-inducer, accelerates healing and reduces relapse of acetic acid-induced rat gastric ulcer comparison with cimetidine

This study was done to elucidate whether rebamipide during the initial period of acetic acid-induced gastric ulcer affected healing and future ulcer relapse. The cumulative healing rate was higher in rats given rebamipide alone or those given rebamipide and cimetidine during and after administration, but not in rats given cimetidine alone, compared to control rats. Cumulative relapse rate was significantly lower in rats initially given rebamipide alone or those given rebamipide and cimetidine than in rats initially given cimetidine alone. These results suggest that rebamipide is beneficial for obtaining a better quality of ulcer healing and reduction of future ulcer relapse.

Effects of free radical scavengers on indomethacin-induced aggravation of gastric ulcer in rats.

Effects of treatment with free radical scavengers in the healing process of acetic acid-induced gastric ulcer on the ulcer aggravation induced by indomethacin were investigated. Gastric ulcers were produced on the anterior wall of the stomach of male Sprague-Dawley rats by submucosal injection of 20% acetic acid. To investigate the role of oxygen radicals, rats with gastric ulcer were treated with scavengers for six weeks and then treated with indomethacin (1 mg/kg/day). While superoxide dismutase (10,000 units/kg/day) did not affect the ulcer area after indomethacin treatment, allopurinol (50 mg/kg/day) slightly inhibited the increase in ulcer area. Dimethyl sulfoxide (1% solution, ad libitum) produced a significant decrease in size of the ulcer after indomethacin treatment. Increased lipid peroxides in the gastric mucosa after indomethacin treatment decreased significantly in the rats of the dimethyl sulfoxide and allopurinol groups. These results indicate that lipid peroxidation mediated by oxygen radicals plays an important role in the mechanism of ulcer aggravation induced by indomethacin.

Wound healing of acetic acid-induced gastric ulcer in rats and the effects of cimetidine and calcitonin, with special reference to prolylhydroxylase and collagenase enzyme activity

The healing of acetic acid-induced gastric ulcer in rats and the effects of cimetidine and calcitonin were investigated with reference to the enzyme activity of both prolylhydroxylase and collagenase as related to histological findings. The rats were observed by endoscopy on the 3rd day after the subserosal injection of acetic acid; rats with ulcers were divided into three groups: non-treated, and cimetidine- and calcitonin-treated. The latter two groups were treated for 7 days. Prolylhydroxylase activity in active ulcers in the non-treated group was slightly higher on the 3rd day and significantly higher on the 10th day than the activity in control rats that had received subserosal injections of physiological saline solution on the respective days. In non-treated rats, the healed ulcer on the 10th day showed lower prolylhydroxylase activity than that in the active ulcer on the same day. Cimetidine did not affect prolylhydroxylase activity, but, with calcitonin, there was higher prolylhydroxylase activity in the healed than in the active ulcer, although the difference was not significant. Interstitial collagenase showed the highest activity on the 3rd day and decreased on the 10th day in non-treated rats. Collagenase activity was higher in the cimetidine-treated group, than that in the non-treated group, and numerous peroxidase-positive granulocytes were seen in the mucosa and submucosa. Calcitonin did not affect collagenase activity. The participation of both enzymes is indispensable in the healing process and the effects of anti-ulcer agents on these enzymes must be considered.

Effect of basic fibroblast growth factor on nitric oxide synthesis during healing process of rat acetic acid-induced gastric ulcers: [formula omitted], M. Nakamura, H. Kimura, S. Miura, M. Oda, M. Tsuchiya, H. Ishii. Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan

Effect of basic fibroblast growth factor on nitric oxide synthesis during healing process of rat acetic acid-induced gastric ulcers: [formula omitted], M. Nakamura, H. Kimura, S. Miura, M. Oda, M. Tsuchiya, H. Ishii. Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan

Increased effector site of platelet-derived growth factor-AA, BB and basic fibroblast growth factor during acetic acid-induced gastric ulcer healing: [formula omitted], Y. Akiba, M. Oda, M. Tsuchiya, H. Ishii. Dept. of Internal Medicine, School of Medicine, Keio University, Tokyo 160, Japan

Increased effector site of platelet-derived growth factor-AA, BB and basic fibroblast growth factor during acetic acid-induced gastric ulcer healing: [formula omitted], Y. Akiba, M. Oda, M. Tsuchiya, H. Ishii. Dept. of Internal Medicine, School of Medicine, Keio University, Tokyo 160, Japan

Involvement of adenosine in the healing of acetic acid-induced gastric ulcer in rats: [formula omitted], K. Czarnobilski, P. Gustaw, R. Sendur, T. Brzozowski, S.J. Konturek. Inst. Physiol., Univ. Med. Sch., Krakow, Poland

Involvement of adenosine in the healing of acetic acid-induced gastric ulcer in rats: [formula omitted], K. Czarnobilski, P. Gustaw, R. Sendur, T. Brzozowski, S.J. Konturek. Inst. Physiol., Univ. Med. Sch., Krakow, Poland

抗潰よう剤レバミピドの開発

A novel series of N-acylamino acid analogues of 2 (1H) -quinolinone was synthesized and evaluated for antiulcer activity against acetic acid-induced gastric ulcer in rats. Out of this investigation, 2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolinon-4-yl] propionic acid (rebamipide, OPC-12759) was identified The structureactivity relationships are discussed.Rebamipide did not only increase the healing rate of a chronic gastric ulcer model, acetic acid-induced gastric ulcer in rats, but also prevented recurrence and/or relapse of the ulcer in long term observation Rebamipide inhibited the formation of gastric mucosal lesions induced by various conditions. Rebamipide did not inhibit gastric acid secretion, although it potentiated gastric mucosal defensive factors such as mucus secretion, alkaline secretion, gastric mucosal blood flow and mucosal barrier. Rebamipide inhibited ethanol-induced gastric mucosal necrosis, which was completely abolished by pretreatment with indomethacin, suggesting the mucosal protective effect is associated with endogenous prostaglandins. Rebamipide inhibited production of superoxide from polymorphonuclear leukocytes and scavenged hydroxyl radical in vitro. Rebamipide showed useful efficacy on Helicobacter pylori-induced cell damage associated with activated neutrophils.The enantiomers of rebamipide were synthesized by using three efficient methods. Both enantiomers showed anti-ulcer activity against acetic acid-induced gastric ulcer and EtOH-induced gastric ulcer. The pair of enantiomers showed a small difference in activity.

Healing-Promoting Action of the Zinc-Cimetidine Complex on Acetic Acid-Induced Gastric Ulcers in Rats

We investigated the effect of the zinc-cimetidine complex on the healing of acetic acid-induced gastric ulcers in rats. When the effects of test drugs were assessed on the 15th day after acetic acid injection, the zinc-cimetidine complex at oral doses of 15.0 (11.4 mg as cimetidine), 30.0 and 60.0 mg/kg twice daily promoted the ulcer healing in a dose-dependent manner. Cimetidine was effective at oral doses of over 45.4 mg/kg twice daily. ZnCl2 was ineffective on all ulcer parameters. The effect of the combination of cimetidine and ZnCl2 was similar to that of cimetidine alone. The zinc-cimetidine complex had already inhibited the increase in thiobarbituric acid reactants in the ulcerated region before the ulcer-healing effect of this compound was recognized. A single oral administration of the complex at 15 and 30 mg/kg to normal rats was ineffective in inhibiting acid secretion and in increasing serum gastrin levels, although cimetidine was markedly effective on both parameters. These results indicate that the zinc-cimetidine complex at about 1 /4 the dose of cimetidine was as effective as cimetidine when the ulcer-healing effects of both compounds were compared with the same dose of cimetidine. In addition, the ulcer-healing effect of this complex may be due, at least in part, to the inhibition of lipid peroxidation but not due to the inhibition of acid secretion or the trophic effect of gastrin.

Tobacco cigarette smoke aggravates gastric ulcer in rats by attenuation of ulcer margin hyperemia

We tested the hypothesis that attenuation of the hyperemia at the margin of acetic acid-induced gastric ulcer in rats by tobacco cigarette smoke will increase the size of the ulcer in the acute and the healing stages. Compared with the adjacent mucosa, blood flow measured by hydrogen gas clearance at the ulcer margin was significantly higher (ulcer margin hyperemia). Tobacco cigarette smoke and subcutaneous nicotine but not nicotine-free smoke from non-tobacco cigarettes significantly attenuated the ulcer margin hyperemia in a dose-related fashion. Repeated exposure of the rats to tobacco cigarette smoke increases ulcer size in the acute and the healing stages. Subcutaneous nicotine but not nicotine-free smoke also increased the size of ulcers in the acute stage. These results indicate that the nicotine in tobacco cigarette smoke may be responsible in part for its adverse effects. We conclude that attenuation of the hyperemia at the ulcer margin is a plausible explanation for the mechanism of the adverse effect of the tobacco cigarette smoke on experimental gastric ulcers in rats.

P2-107 - Effects of IGN-2098, a histamine H2-receptor antagonist, on the healing and relapse of the acetic acid-induced gastric ulcer in rats

P2-107 - Effects of IGN-2098, a histamine H2-receptor antagonist, on the healing and relapse of the acetic acid-induced gastric ulcer in rats

Regeneration of Parietal Cells at the Healing Process of Acetic Acid-induced Gastric Ulcers in Rats. Evaluation of the Quality of Ulcer Healing by the Administration of Various Agents.

Regeneration of Parietal Cells at the Healing Process of Acetic Acid-induced Gastric Ulcers in Rats. Evaluation of the Quality of Ulcer Healing by the Administration of Various Agents.

Cimetidine and omeprazole accelerate gastric ulcer healing by an increase in gastrin secretion.

Daily oral administration of cimetidine or omeprazole markedly accelerated the healing of acetic acid-induced gastric ulcers in rats with a limited food intake time. The increased gastric acid secretion induced by daily treatment with histamine affected neither the spontaneous healing of the ulcers nor the healing-promoting actions of both agents. Pretreatment of rats with ulcers with 6-hydroxydopamine significantly inhibited the increase in the antrum gastrin cells, serum gastrin levels and corpus mucosal thickness elicited by repeated administration of cimetidine or omeprazole. Pretreatment with 6-hydroxydopamine did not affect the inhibitory actions of cimetidine and omeprazole on acid secretion, but completely abolished the ulcer healing-promoting actions of both drugs. Daily intraperitoneal administration of pentagastrin accelerated ulcer healing. These results suggest that cimetidine and omeprazole mainly accelerate the healing of gastric ulcers by the trophic action of gastrin via the increase in gastrin secretion, while the inhibition of acid secretion may play a minor role in ulcer healing.

Anti-ulcer effects of lactic acid bacteria and their cell wall polysaccharides.

The anti-ulcer effects of bifidobacteria, lactobacilli and streptococci were examined using the acetic acid-induced gastric ulcer and ethanol-induced erosion models in rats. Bifidobacterium breve YIT4014 and 4043, and Bifidobacterium bifidum YIT4007 were administered orally, and anti-ulcer effects were confirmed for not only these organisms but also their polysaccharide fractions (PSFs). The major component of these anti-ulcer polysaccharides was rhamnose. In particular, polysaccharides in which the rhamnose content exceeded 60% were more effective in healing gastric ulcers. After administration of the PSF from B. bifidum YIT4007, the levels of epidermal growth factor and basic fibroblast growth factor increased in gastric tissues. Similar results were observed for the culture supernatant of gastric epithelial cells cultured with PSF. Furthermore, the production of 6-ketoprostaglandin F1 alpha by macrophages was also enhanced by PSF. These results indicated that these bacteria and their polysaccharides induced host repair and protective systems in the gastric ulcer model.

硫酸化シクロデキストリンの難水溶性アルミニウム塩による塩基性線維芽細胞増殖因子の安定化および放出制御

Basic fibroblast growth factor(bFGF)is a prototype of heparin-binding growth factor family and could play a crucial role in wound healing processes. Water-insoluble aluminum salts of cyclodextrin sulfates (Al·CyD-Suls) were prepared, and their potential use in oral formulations of bFGF intended for treatment of gastrointestinal ulcers was investigated. Adsorbates of bFGF with Al·CyrD-Suls were prepared by incubating the growth factor with a suspension of Al·CyD-Suls in water. The mitogenic activity of bFGF released from the adsorbate was almost comparable to that of the intact bFGF. Al·CyD-Suls significantly protected bFGF against proteolytic degradation by pepsin, compared with their sodium salts and other sulfated oligosaccharides tested. The in vitro release of bFGF from the Al·β-CyD-Sul adsorbate into isotonic phosphate buffer (pH 7.4) was sustained in proportion to a rise in the ratio of Al·βCyD-Sul to the growth factor. The oral administration of the adsorbate of bFGF with Al·β-CyD-Sul had the most prominent healing effects on acetic acid-induced gastric ulcers. These results suggest that Al·CyD-Suls may potentiate the healing effect of bFGF by both stabilizing and anchoring the growth factor at the site where its action is desired.

P-376 - Effect of zinc-cimetidine complex on healing of acetic acid-induced gastric ulcers in rats with limited food intake time.

P-376 - Effect of zinc-cimetidine complex on healing of acetic acid-induced gastric ulcers in rats with limited food intake time.

Cell proliferation kinetics in acetic acid-induced gastric ulcer evaluated by immunohistochemical staining of proliferating cell nuclear antigen.

A monoclonal antibody to proliferating cell nuclear antigen (PCNA) has been previously shown to be capable of identifying proliferating cells. We investigated proliferative activity in the healing process of acetic acid-induced gastric ulcer by immunohistochemical staining of PCNA and 5-bromo-2-deoxyuridine (BrdU), and the two methods were compared. Cell proliferative activity of regenerated mucosa around ulcers showed continuous acceleration for 42 days, and PCNA-labeled cells had stained nuclei as clearly discernible as those of BrdU-labeled cells. In addition, immunohistochemical staining of PCNA provided reproducible and quantifiable results without the requirement of pretreatment. We conclude that immunohistochemical staining of PCNA may represent a useful technique for analysis of proliferative activity during healing of gastric ulcers.

O-153 - Effect of IGN-2098, H2-blocker, on acetic acid-induced gastric and duodenal ulcers in rats.

O-153 - Effect of IGN-2098, H2-blocker, on acetic acid-induced gastric and duodenal ulcers in rats.

Mechanism by Which Indomethacin Delays Gastric Ulcer Healing in the Rat: Inhibited Contraction of the Ulcer Base

Repeated administration of indomethacin delays the healing of acetic acid-induced gastric ulcers in rats, but the underlying mechanism remains unclear. We examined the effect of indomethacin on the contraction of the connective tissue isolated from the base of 1-week-old ulcers. The tissue samples, suspended in an organ bath, were contracted by serotonin, bradykinin and carbachol and also slightly contracted by prostaglandin (PG) F1α. The effect of serotonin was the most potent. However, 6-keto-PGF1α, PGE2 and histamine had little or no contraction inducing effect. The contractile response to serotonin of the tissue in the indomethacin-treated group was significantly less than that in the control group (without indomethacin treatment). After a 2-week treatment with indomethacin, a histological study of the ulcers showed that the length of rupturing of the muscularis mucosa was significantly greater than that observed in the control group. However, indomethacin had no effect on the length of the regenerated mucosa and the thickness of the ulcer base. We conclude that the connective tissue at the ulcer base has the ability to contract and that the prevention of the contraction of the tissue by indomethacin might be involved in the mechanism underlying delayed ulcer healing.

Effect of NC-1300-0-3 on Healing of Acetic Acid-Induced Gastric Ulcers in Rats

E4177, 3-[(2'-carboxybiphenyl-4-yl)methyl]-2-cyclopropyl-7-methyl-3H- imidazo[4,5-b]pyridine, was characterized by in vitro autoradiography and by examining functional antagonism upon angiotensin II (Ang II)-induced contraction of isolated vessels. In rat adrenal cortex and liver, E4177 competitively inhibited the specific binding of 125I-[Sar1,Ile8]Ang II, with IC50 being (5.2 +/- 1.0) x 10(-8) M for the adrenal cortex and (1.2 +/- 0.3) x 10(-7) M for the liver. These IC50 values were similar to those for losartan, which showed an IC50 of (6.0 +/- 0.9) x 10(-8) M for the adrenal cortex and (1.3 +/- 0.5) x 10(-7) M for the liver. In contrast, E4177 and losartan had little effect on the binding to rat adrenal medulla where AT2-receptors predominate. These results indicate that E4177 is AT1-specific as is losartan. E4177 and losartan competitively antagonized the Ang II-induced contraction of human and rabbit arterial strips without any agonistic action. The obtained IC50 values indicated that E4177 was twice as potent as losartan in human arteries and three times more so in rabbit aortic strips. Responses to norepinephrine, serotonin, histamine or KCl were not affected by E4177. In addition, E4177 (10(-5) M) had no effect on angiotensin-converting enzyme activity. These data indicate that E4177 is a potent AT1 Ang II-receptor antagonist that may be clinically useful for the treatment of cardiovascular diseases such as hypertension.

ラット実験胃潰ようにおける肉芽新生血管の細胞接着因子発現に関する免疫組織化学的研究

Angiogenesis of the experimental-gastric ulcer was investigated by means of immunohistochemical staining using monoclonal antibodies (MoAbs) related to adhesion molecules. In order to study the regulation of the antigen-expression defined by REC16-11, REC4-1 and ICAM-1, which recognize varieties of endothelial cells, we assessed their expression on the microvasculature in the granulation tissues using a model of acetic acid-induced gastric ulcer in rats. Microvasculature in the deep layer of granulation tissues were stained by REC16-11 within 5 days of the ulcer development. In contrast, REC4-1 and/or ICAM-1 were detected in microvasculature only from 10 days, in parallel with the degree of LFA-1-positive lymphocytic infiltration around REC4-1-positive-vessels. In cases of healed ulcer on 40 days, the distribution of the positive reaction with those MoAbs was similar to the normal rats. In cases of unhealed ulcers at the same period, REC16-11-positive-vessels were observed in all vascular endothelial cells of the granulation tissues. However, REC4-1 and/or ICAM-1-positive-vessels had the same pattern as the cases on 15 days. The cell adhesion molecules were expressed temporary on the endothelial cells of these microvasculature during the development of granulation tissues after gastric ulcer. Based on these results, it was suggested that the antigens related to adhesion molecules on the endothelial cells may play an important role in the healing process of gastric ulcer.