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.
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| Szabo, S; Cho, C H (1988) From cysteamine to MPTP: structure-activity studies with duodenal ulcerogens. Toxicol Pathol 16:205-12 |
