Previous structure-activity and pharmacologic studies with duodenal ulcerogens cysteamine and propionitrile implicating catecholamines in the pathogenesis of duodenal ulceration have now been followed up by dose- and time-response biochemical investigations to assess the importance of monoamines in the development of duodenal ulcers. The concentrations of norepinephrine (noradrenaline), dopamine, serotonin and their metabolites were measured in total brain, brain regions, stomach, duodenum, pancreas and adrenals in the rat. Turnover of catecholamines was determined in rats pretreated with the inhibitor of tyrosine hydroxylase α-methyl-p-tyrosine. The duodenal ulcerogens caused a dose- and time-dependent depletion of norepinephrine in virtually all the tissues examined. The effect was maximal 4 or 7 hr after cysteamine or propionitrile, and norepinephrine levels returned to normal in 24 hr. Dopamine changes were selective and often biphasic, e.g., elevation in adrenals, biphasic in brain cortex, hippocampus and midbrain, but uniformly decreasing in glandular stomach and duodenum. In the median eminence dopamine levels decreased by 181 and 324% at 15 and 30 min, respectively, after cysteamine, but neither dopamine nor 3,4-dihydroxyphenylacetic acid was modified in the periventricular nucleus. Serotonin levels were relatively stable, revealing slight elevations or no changes in most of the tissues. The turnover of norepinephrine was accelerated by both chemicals in virtually all brain regions, but dopamine turnover was affected only in a few areas, e.g., in the corpus striatum and medulla oblongata cysteamine decreased dopamine turnover, whereas propionitrile first (at 1 hr) accelerated then (at 8 hr) significantly suppressed it. Correlation of ulcer intensity after a single dose of cysteamine with concentrations of monoamines revealed a significant negative association between dopamine levels in the brain and duodenal ulcer severity (r = -0.633, P <.05). Thus, the development of experimental duodenal ulcers is preceded and accompanied by change in central and peripheral tissue levels of catecholamines. Inasmuch as nonspecific stress which is alone unable to cause duodenal ulcer is accompanied by tissue norepinephrine depletion, the unusual changes in dopamine levels might have a pathogenetic role in duodenal ulceration and represent a pharmacologic target for preventive therapeutic intervention.
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - Sep 9 1987|
ASJC Scopus subject areas
- Molecular Medicine