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Title: Biochemical changes in tissue catecholamines and serotonin in duodenal ulceration caused by cysteamine or propionitrile in the rat

Abstract

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 alpha-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 bymore » 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.(ABSTRACT TRUNCATED AT 250 WORDS)« less

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Brigham and Women's Hospital, Boston, MA
OSTI Identifier:
6786625
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Pharmacol. Exp. Ther.; (United States); Journal Volume: 3
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.; CATECHOLAMINES; TISSUE DISTRIBUTION; MEA; BIOLOGICAL EFFECTS; PROPIOLONITRILE; SEROTONIN; ULCERS; PATHOGENESIS; ADRENAL GLANDS; BRAIN; DOPAMINE; DOSE-RESPONSE RELATIONSHIPS; NITRILES; RADIOPROTECTIVE SUBSTANCES; RATS; SMALL INTESTINE; STOMACH; AMINES; ANIMALS; AROMATICS; AUTONOMIC NERVOUS SYSTEM AGENTS; AZAARENES; AZOLES; BODY; CARDIOTONICS; CARDIOVASCULAR AGENTS; CENTRAL NERVOUS SYSTEM; DIGESTIVE SYSTEM; DISTRIBUTION; DRUGS; ENDOCRINE GLANDS; GASTROINTESTINAL TRACT; GLANDS; HETEROCYCLIC COMPOUNDS; HYDROXY COMPOUNDS; INDOLES; INTESTINES; MAMMALS; NERVOUS SYSTEM; NEUROREGULATORS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; ORGANIC SULFUR COMPOUNDS; ORGANS; PATHOLOGICAL CHANGES; PHENOLS; POLYPHENOLS; PYRROLES; RODENTS; SYMPATHOMIMETICS; THIOLS; TRYPTAMINES; VERTEBRATES 560152* -- Radiation Effects on Animals-- Animals

Citation Formats

Szabo, S., Horner, H.C., Maull, H., Schnoor, J., Chiueh, C.C., and Palkovits, M.. Biochemical changes in tissue catecholamines and serotonin in duodenal ulceration caused by cysteamine or propionitrile in the rat. United States: N. p., 1987. Web.
Szabo, S., Horner, H.C., Maull, H., Schnoor, J., Chiueh, C.C., & Palkovits, M.. Biochemical changes in tissue catecholamines and serotonin in duodenal ulceration caused by cysteamine or propionitrile in the rat. United States.
Szabo, S., Horner, H.C., Maull, H., Schnoor, J., Chiueh, C.C., and Palkovits, M.. 1987. "Biochemical changes in tissue catecholamines and serotonin in duodenal ulceration caused by cysteamine or propionitrile in the rat". United States. doi:.
@article{osti_6786625,
title = {Biochemical changes in tissue catecholamines and serotonin in duodenal ulceration caused by cysteamine or propionitrile in the rat},
author = {Szabo, S. and Horner, H.C. and Maull, H. and Schnoor, J. and Chiueh, C.C. and Palkovits, M.},
abstractNote = {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 alpha-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.(ABSTRACT TRUNCATED AT 250 WORDS)},
doi = {},
journal = {J. Pharmacol. Exp. Ther.; (United States)},
number = ,
volume = 3,
place = {United States},
year = 1987,
month = 3
}
  • Dose- and time-response studies have been performed with dopamine agonists and antagonists using the cysteamine and propionitrile duodenal ulcer models in the rat. The experiments demonstrate that the chemically induced duodenal ulcer is prevented by bromocriptine, lergotrile and reduced by apomorphine or L-dopa. Aggravation of cysteamine-induced duodenal ulcer was seen especially after (-)-butaclamol, (-)-sulpiride, haloperidol and, less effectively, after other dopaminergic antagonists. The duodenal antiulcerogenic action of dopamine agonists was more prominent after chronic administration than after a single dose, whereas the opposite was found concerning the proulcerogenic effect of dopamine antagonists. In the chronic gastric fistula rat, both themore » antiulcerogens bromocriptine or lergotrile and the proulcerogens haloperidol, pimozide or (-)-N-(2-chlorethyl)-norapomorphine decreased the cysteamine- or propionitrile-induced gastric secretion. No correlation was apparent between the influence of these drugs on duodenal ulcer development and gastric and duodenal (pancreatic/biliary) secretions. In the chronic duodenal fistula rat, decreased acid content was measured in the proximal duodenum after haloperidol, and diminished duodenal pepsin exposure was recorded after bromocriptine. Furthermore, the aggravation by dopamine antagonists of experimental duodenal ulcer probably involves a peripheral component. The site of dopamine receptors and physiologic effects which modulate experimental duodenal ulcer remain to be identified, but their elucidation may prove to be an important element in the pathogenesis and treatment of duodenal ulcer.« less
  • Neutralization of acid was evaluated in rat proximal duodenal segments isolated from biliary and pancreatic secretions. Duodenal ulcerogenic doses of cysteamine produced a significant decrease in acid disposal 0.5-2 hr after treatment. Oral or subcutaneous administration of the duodenal ulcerogen was effective. The potent ulcerogen cysteamine produced a more pronounced decrease than propionitrile (a weak duodenal ulcerogen). The failure of ethanolamine, a nonulcerogenic structural analog of cysteamine to significantly alter acid disposal suggests that the effect is not due to the toxic properties of the duodenal ulcerogen. The results reinforce the concept that the duodenum is able to dispose ofmore » significant quantities of acid. The decrease in acid-handling may contribute to duodenal susceptibility to acid after treatment with ulcerogens and possibly reflects pathophysiologic changes early in duodenal ulceration.« less
  • Cysteamine and propionitrile are members of a family of compounds which induce the formation of acute duodenal ulcers in fasted and fed rats. Gastric acid secretion is increased by both agents, and acid hypersecretion appears to be required for ulcer formation. To determine the role of gastrin in the ulcerogenic mechanism, cysteamine and propionitrile were administered to fasted rats and their effect on fasting and food-stimulated serum gastrin levels was studied. Intragastric administration of cysteamine caused a 3- to 4-fold increase in fasting serum gastrin levels over the values of controls. Propionitrile was a less effective stimulant of gastrin release,more » causing a 1.5- to 2-fold increase in gastrin levels over matched control rats. The food-stimulated rise in serum gastrin levels after either a chow meal or intragastric instillation of a peptone solution was markedly enhanced by cysteamine pretreatment. Three hours after feeding the serum gastrin levels of cysteamine pretreated rats were 6 times higher than those of feed controls. The high serum gastrin levels of cysteamine-pretreated fed rats could not be explained solely by the additive effects of cysteamine and food, indicating that a potentiating interaction may exist between the two stimulants of gastrin release. The importance of this drug-induced stimulation of gastrin release, under both fasted and fed conditions, in the ulcerogenic process has yet to be ascertained.« less
  • Cysteamine (CSH) and its close derivatives deplete immunoreactive somatostatin (SS) in rat organs. The effect of CSH is dose and time dependent and reversible. Structural requirements of the analogs are the presence of either -SH or -NH2 on a two- or three-carbon alkyl molecule; both radicals together increase, whereas insertion of carboxyl abolishes potency. The duodenal ulcerogenic potency of CSH derivatives is correlated significantly with their SS-depleting activity in the gastric mucosa. The mechanism of this action of CSH is poorly understood, but it is not caused by increased release, enhanced degradation of the peptide, or selective necrosis of SSmore » cells. It is likely that in the intracellular environment CSH causes a conformational change in the peptide that affects the antigenic and functional properties of SS.« less