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PATHOPHYSIOLOGY OF EXPERIMENTAL GASTRODUODENAL ULCER

实验性胃十二指肠溃疡的病理生理学

基本信息

批准号：
3234248
负责人：
SANDOR SZABO
金额：
$ 18.13万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-12-01 至 1986-11-30
项目状态：
已结题

项目摘要

Our main interest is the elucidation of pathogenesis of duodenal and gastric ulcers in animal models. The duodenal ulcerogens cysteamine, propionitrile or n-butyronitrile and gastric irritants ethanol, aspirin or stress (restraint+cold) will be used. The specific aims are limited to three agents which according to our hypothesis play an important role in the pathophysiology of gastroduodenal ulcers. 1. Dopamine. Measurements of dopamine, dopamine metabolites and binding sites by radioligands will be performed in the stomach, duodenum and brain regions. Pharmacologic dose- and time-response studies with novel dopamine-related drugs will be tested for preventive and curative actions in duodenal ulcer. Simultaneous measurement of gastric and duedenal/pancreatic secretions in conscious rat with chronic gastric fistula will be performed with dopamine and sulfhydryl drugs. The role of dopamine will also be investigated as an endogenous modulator of the recently discovered diurnal variations in experimental duodenal ulcerations. 2. Sulfhydryls. Fractions of nonprotein and protein sulfhydryls in gastric and duodenal mucosa will be measured biochemically and histochemically after exposure to gastric irritants. On the other hand, since not all sulfhydryls offer cytoprotection, derivatives of cysteine will be tested in a structure-activity study for gastric cytoprotection. The prostaglandin- or sulfhydryl-sensitive increased blood vessel permeability, recently detected in the early course of action of ethanol on gastric mucosa, will be investigated quantitatively and qualitatively by using vascular tracers in both biochemical and morphologic studies. 3. Somatostatin. Somatostatin depletion in gut and brain by certain duodenal ulcerogens will be characterized to document possible somatostatin-dependent forms of duodenal ulcer disease. The specificity of somatostatin depletion of cysteamine will be studied by biochemical and morphologic methods. These investigations will provide new insight into the pathogenesis of duodenal and gastric ulcers in general and will characterize the ulcerogenic properties of chemicals which may have a role in the etiology of ulcer disease in man. New elements in the pathogenesis of ulcer (e.g., dopamine, sulfhydryls, blood vessel permeability) as well as the availability of a new group of anti-ulcerogenic drugs (e.g., dopamine agonists) and cytoprotective agents (i.e. sulfhydryl drugs) are also among the potential benefits of this research project.

我们的主要兴趣是阐明十二指肠和十二指肠疾病的发病机制动物模型中的胃溃疡。十二指肠溃疡原半胱胺，丙腈或正丁腈以及胃刺激物乙醇、阿司匹林或将使用压力（约束+寒冷）。具体目标仅限于根据我们的假设，三个因素在其中发挥着重要作用胃十二指肠溃疡的病理生理学。 1.多巴胺。测量值多巴胺、多巴胺代谢物和放射性配体的结合位点将在胃、十二指肠和大脑区域进行。药理剂量- 并将测试新型多巴胺相关药物的时间反应研究用于十二指肠溃疡的预防和治疗作用。同时清醒大鼠胃和十二指肠/胰腺分泌物的测量患有慢性胃瘘的患者将使用多巴胺和巯基进行治疗药物。多巴胺的作用也将作为内源性物质进行研究最近在实验中发现的昼夜变化的调节剂十二指肠溃疡。 2. 巯基。非蛋白质和蛋白质的分数将通过生化方法测量胃和十二指肠粘膜中的巯基以及暴露于胃刺激物后的组织化学。另一方面另一方面，由于并非所有的巯基都提供细胞保护作用，因此半胱氨酸将在胃的结构活性研究中进行测试细胞保护。前列腺素或巯基敏感的血液增加血管渗透性，最近在早期作用过程中检测到乙醇对胃粘膜的影响，将进行定量研究通过在生化和形态学方面使用血管示踪剂来定性研究。 3.生长抑素。肠道和大脑中生长抑素的消耗某些十二指肠溃疡原将被表征以记录可能的情况生长抑素依赖性十二指肠溃疡病。的特异性将通过生化和研究研究半胱胺的生长抑素消耗形态学方法。这些调查将为我们提供新的见解十二指肠溃疡和胃溃疡的一般发病机制描述化学物质的致溃疡特性，这可能具有一定的作用人类溃疡病的病因学。发病机制中的新元素溃疡（例如多巴胺、巯基、血管通透性）随着一组新的抗溃疡药物的出现（例如，多巴胺激动剂）和细胞保护剂（即巯基药物）也是该研究项目的潜在好处之一。