Studies on the pharmacological properties of a novel animal model for gastric antral ulcer and on its application to drug evaluation for antiulcer drugs

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9-1 Aim of the project :We previously reported an original method inducing gastric antral ulcer in rats, which was very unique from the pharmacological point of view. Thus we aimed to improve this method to make it more useful for the pharmacological researches and to clarifiy the etiology of the gastric ulceration, as well as the nervous control mechanism of gastric functions.9-2 Establishment of the gastric antral ulcer model in rats :Previously reported method by us was somewhat complicated in which three pharmacological agents were used in combination. We deviced again a novel method for inducing gastric antral ulcer in rats by loading the limited food intake schedule and oral administration of 0.6-1.0 N HCl. By this simple treatment, very extensive ulceration restricted in the antral region was induced in 4 days after the treatment. Through pharmacological reseaches on the etiology of the ulceration, it was found that free radicals production, blood flow reduction as well as endog … More enous gastric acid production were deeply implicated in the ulceration processes, and the direct necrotizing effect of hydrochloric acid was found to be a rather minor factor.9-3 Role of Helicobacter pylori in gastric ulcerationRecent interest on the etiology of gastric ulceration has been focussed on the role of H.pylori in the stomach. We previously studied ammonia production in the stomach and noticed the urease enzyme contained in this bacteria which produce ammonia by hydrolysing the urea. We found the ingesting of dilute ammonia solusion significantly delayd the healing of gastric antral ulcer. Several kinds of antiulcer drugs were found to have the urease inhibitory effects, and to have bacteriocidal effects, especially under low pH condition mimicking the gastric mucosal environment. Among them, sucralfate was found very effective, and showed competitive urease inhibition with the substrate urea only under the low pH condition.9-4 Involvement of capsaicin sensitive afferent nerve in the gastric mucosal defensive systemWe found gastric antral ulcer was remarkably aggravated after the denervation of primary afferent nerve by repeated treatment with capsaicin. This means the involvement of sensory afferent nervous system in the defense mechanisms of gastric mucosa in the antral area.9-5 Non-adrenergic, Non-cholinergic (NANC) nervous system in the gastric functionsWe previously deviced a method to measure gastric motor function and acid secretion in the isolated mouse whole stomach preparation. By using this method, we found that relaxation of the stomach by vagal stimulation was mediated by NANC nerve, and also found that the mediator involved in this relaxation must be nitric oxide. Thus the importance of NO in the gastric functions was noticed. Nitric oxide synthetase inhibitors were found to have the aggravating effect on the antral ulceration.9-6 Functional role of enterochlomaffin-like cells in gastric mucosaGastric acid secretion is well known to be mediated by gastric histamine containing cells. We found niric oxide synthetase inhibitors strongly inhibit the acid secretion induced by vagal stimulation in the isolated mouse whole stomach preparations. This means the stimulatory role of NO in the control of acid secretion. We reported the evidence that the endogenous NO stimulates the histamine release from the gastric enterochlomaffin-like cells.9-7 ConclusionIn the present research project, we established a novel and useful method to induce the gastric ulcer in antral erea of the rat stomach which is closely related with the human gastric ulcer. Pharmacological factors involved in its etiology such as NO,primary afferent nerve, as well as H.pilori were studied. Less