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

9-1本课题的目的：我们以前报道了一种新颖的诱导大鼠胃窦溃疡的方法，从药理学的角度来看，这种方法是非常独特的。因此，我们的目的是改进这种方法，使其更有用的药理学研究，并澄清胃溃疡的病因，以及胃功能的神经控制机制。9 -2大鼠胃窦溃疡模型的建立：我们以前报道的方法有些复杂，其中三种药物联合使用。我们再次设计了一种新的胃溃疡模型，采用限制进食负荷和0.6- 1.0N盐酸灌胃的方法。通过这种简单的治疗，在治疗后4天内诱导了局限于胃窦区域的非常广泛的溃疡。通过对溃疡病因的药理学研究，发现自由基的产生，血流量的减少， ...更多信息 静脉胃酸的产生与溃疡过程密切相关，发现盐酸的直接坏死作用是一个相当小的因素。9 -3幽门螺杆菌在胃溃疡中的作用最近对胃溃疡病因学的兴趣集中在幽门螺杆菌在胃中的作用上。我们先前研究了胃中的氨产生，并注意到这种细菌中含有的脲酶通过水解尿素产生氨。结果表明，灌胃稀氨水可明显延缓胃窦溃疡的愈合。几种抗溃疡药物具有抑制尿素酶的作用，并具有杀菌作用，特别是在模拟胃粘膜环境的低pH条件下。其中，硫糖铝被发现非常有效，并且仅在低pH条件下显示出与底物尿素的竞争性脲酶抑制。9 -4辣椒素敏感的传入神经参与胃粘膜防御系统我们发现，通过重复辣椒素治疗，在初级传入神经去神经后，胃窦溃疡显著加重。这意味着感觉传入神经系统参与了胃窦区胃粘膜的防御机制。9 -5非肾上腺素能、非胆碱能（NANC）神经系统与胃功能我们以前设计了一种方法来测量离体小鼠全胃标本的胃运动功能和酸分泌。通过这种方法，我们发现迷走神经刺激胃的舒张是由NANC神经介导的，并且还发现参与这种舒张的介质必须是一氧化氮。由此可见NO在胃功能中的重要性。发现一氧化氮合成酶抑制剂对胃窦溃疡有加重作用。9 -6肠氯亲和素样细胞在胃粘膜中的功能作用众所周知，胃酸分泌是由含胃组胺的细胞介导的。我们发现一氧化氮合成酶抑制剂强烈抑制离体小鼠全胃标本中迷走神经刺激诱导的酸分泌。这意味着NO在控制酸分泌中的刺激作用。我们报道的证据表明，内源性NO刺激组胺释放从胃肠chloromaffin样细胞。9 -7结论在本研究项目中，我们建立了一种新的和有用的方法，诱导胃溃疡的大鼠胃窦区，这是密切相关的人类胃溃疡。对NO、初级传入神经、毛滴虫等药理学因素进行了研究。少

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