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Biomedical subjects

S Szabo

Publications and source records attributed to S Szabo.

At least 127 records · Page 7Linked to original sources
PubMed1987

Effect of tyrosine administration on duodenal ulcer induced by cysteamine in the rat.

Duodenal ulcers were produced by administering cysteamine to rats. Pretreatment with the catecholamine precursor, L-tyrosine (40 mg/100 g i.p. for 5 days), decreased the intensity of duodenal ulcers induced by cysteamine. Equimolar doses of tyrosine methyl ester (51.2 mg/100 g i.p. or s.c.) were equally effective in reducing ulcer intensity. Other amino acids (i.e., alanine, aspartic acid, glutamic acid, glycine, leucine, lysine, tryptophan and valine) did not prevent experimental duodenal ulcers. Coadministration of other large neutral amino acids (e.g., leucine and valine) that compete with tyrosine for uptake into the brain did not inhibit the effect of tyrosine on duodenal ulcers induced by cysteamine. Gastric, duodenal and brain dopamine concentrations were increased 1 hr after the injection of tyrosine methyl ester (25.6 mg/100 g s.c.). These results suggest that the effect of tyrosine on duodenal ulcer induced by cysteamine may be mediated by changes in gastrointestinal dopamine metabolism.

Amino Acids↗
PubMed1987

Effect of dopamine-related drugs on duodenal ulcer induced by cysteamine or propionitrile: prevention and aggravation may not be mediated by gastrointestinal secretory changes in the rat.

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 the 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.

Animals↗
PubMed1987

Development of cysteamine-induced ultrastructural surface changes on duodenal mucosa.

Duodenal ulcers were induced acutely in female rats by a single oral administration of cysteamine, 70 mg/100 gm, in order to study morphologic progression of lesion development from the perspective of cellular surface changes by scanning electron microscopy. Thick sections of resin-embedded specimens were also studied by light microscopy, and animals were sacrificed at intervals of 30 minutes, 1, 2, 4, 8, 12, 20, and 24 hours post-treatment. Earliest evidence of cytologic lesions was apparent at 2 hours and data confirmed earlier reports that alterations began at villous tips. Both cellular sloughing and in situ cellular injury were evident, the latter phenomenon constituting the principal mode of cysteamine-induced erosion. In situ change began, from surface perspective, as a minute cavitation on the apical aspect of an isolated, single epithelial cell which was surrounded by normal cells. These early lesions progressed to in situ necrosis either of isolated cells or of small clusters of adjacent cells. This phenomenon occurred concurrently on multiple villi, all within the localized site at which cysteamine-induced duodenal ulcers are known to develop. An additional early morphologic change was the occasional appearance of a background of pleomorphic cellular apices of variable size on the villous ridges. By 8 to 12 hours, cellular damage advanced to erosions with some cells in the preulcer area still showing initial stages of in situ cellular injury. Precipitated mucus on the surface was increased in the preulcer area, and by 20 to 24 hours typical duodenal ulcers were evident. These scanning electron microscopic data confirm the significance of surface damage at villous tips very early in the cysteamine-induced ulcerogenesis. The present higher resolution findings demonstrated that earliest cellular damage, principally in situ cell injury, occurred simultaneously at multiple sites in the preulcer zone rather than at a single cluster of cellular damage which enlarges peripherally.

Animals↗
PubMed1987

Ethanol-induced acute gastric injury in mast cell-deficient and congenic normal mice. Evidence that mast cells can augment the area of damage.

The authors used stereomicroscopy and planimetry to measure the area of glandular stomach mucosa acutely injured by oral ethanol in mast cell-deficient and congenic normal (+/+) mice, and examined the damaged areas in 1-mu sections. Ethanol caused degranulation and/or disruption of gastric mucosal mast cells, and, at certain concentrations of ethanol, mast cell-deficient WBB6F1-W/Wv or WCB6F1-Sl/Sld mice developed significantly less (43-90% less) acute gastric injury than either congenic +/+ mice or WBB6F1-W/Wv mice whose mast cells were restored by bone marrow transplantation from WBB6F1-+/+ mice. Nevertheless, ethanol produced detectable, and in some cases substantial, gastric injury even in the complete absence of mast cells. Thus, ethanol can produce some damage to the gastric mucosa independently of mast cells. But these data suggest that under certain circumstances mast cells can augment the area of acute gastric injury induced by ethanol.

Alcoholic Intoxication↗
PubMed1986

Early microcirculatory stasis in acute gastric mucosal injury in the rat and prevention by 16,16-dimethyl prostaglandin E2 or sodium thiosulfate.

We used in vivo microscopy and laser-Doppler velocimetry to examine the effects on the gastric mucosal microcirculation and in gastric mucosal blood flow of agents that induce acute gastric mucosal damage. In vivo microscopic observation of superficial mucosal capillaries revealed vascular stasis within a mean of 54, 81, or 61 s after 100% ethanol, 0.6 N HCl, or 0.2 N NaOH, with the subsequent development of hemorrhagic mucosal lesions. Mucosal blood flow estimated by laser-Doppler velocimetry decreased by 30% at 5 min after luminal application of 100% ethanol, and decreased further to about 40% of basal levels by 15 min. The decreased mucosal blood flow 15 min after application of 50% ethanol correlated with the extent of hemorrhagic mucosal lesions. Examination of the submucosal vessels that supply and drain the mucosa showed moderate dilation of small arterioles 1, 3, and 6 min after exposure to 100% ethanol but there were no consistent changes in venules. Mild vasoconstriction of small- and medium-sized venules could be detected 6, 10, and 15 min after NaOH but not after exposure to HCl. Pretreatment with 16,16-dimethyl prostaglandin E2 or sodium thiosulfate before exposure of the mucosa to ethanol prevented capillary stasis, maintained mucosal blood flow, and prevented the development of hemorrhagic gastric mucosal lesions. Topical mucosal application of 16,16-dimethyl prostaglandin E2 decreased, whereas topical exposure to sodium thiosulfate increased gastric mucosal blood flow, indicating that change in blood flow per se is an unlikely mediator of protection.

16,16-Dimethylprostaglandin E2↗
PubMed1986

Protection by metals against ethanol-induced gastric mucosal injury in the rat. Comparative biochemical and pharmacologic studies implicate protein sulfhydryls.

Recent evidence suggests a role of endogenous sulfhydryls (SHs) in gastric "cytoprotection." Because divalent metals bind to or oxidize SH groups, their effect on ethanol-induced gastric erosions was studied. For comparative biochemical studies the SH cysteamine, the glutathione depletor diethylmaleate. and SH alkylating agent N-ethylmaleimide (NEM) were also used. Rats pretreated with CdCl2, ZnCl2, or Cu(NO3)2 6 h before absolute ethanol showed a significant dose-dependent decrease in the mucosal lesions. Copper was effective in preventing the lesions up to 15 min before the ethanol. Iron and manganese were active at 30 min, but not at 6 h before the ethanol lesions. Indomethacin administration decreased the protection afforded by iron, manganese, and cadmium, but did not modify that by lead and copper. N-ethylmaleimide abolished the protection by iron, manganese, and cadmium, but did not affect the protection caused by lead and copper when given after the metals. However, when NEM was given before lead and copper, it diminished the protection. Secretory studies revealed that cadmium and zinc slightly inhibited gastric acid secretion, but a similar reduction of acid output by cimetidine did not decrease the ethanol-induced gastric erosions. Biochemical studies of endogenous SH showed that the protective metals and NEM decreased the glutathione concentration in the nonprotein fraction, whereas these metals diminished and NEM, which antagonizes mucosal protection, elevated the cysteine concentration in the protein fraction of the gastric mucosa. The common factor with the protective agents thus seems to be the blocking of protein SH by binding or oxidation by protective agents. These endogenous SHs may mediate cellular responses to injury.

Animals↗
PubMed1986

Dose-dependent effects of linear and cyclic somatostatin on ethanol-induced gastric erosions: the role of mast cells and increased vascular permeability in the rat.

Somatostatin prevents hemorrhagic gastric erosions produced by ethanol. In this paper we describe studies with linear (reduced) and cyclic (oxidized) synthetic somatostatin-14 in the rat model of ethanol-induced gastric mucosal injury. The linear form of somatostatin was more potent at concentrations of 10(-9) to 10(-8) mol per rat than the cyclic isomere. However, at a concentration of 10(-7) mol per rat i.p. injection of linear somatostatin significantly (P less than 0.01) enhanced gastric erosions caused by the alcohol. The area of hemorrhagic mucosal lesions correlated significantly (r = -0.846) with mast cell depletion in the gastric mucosa of the animals. Increased vascular permeability and mast cell degranulation were also observed after intradermal injection of linear or cyclic somatostatin. The 'cytoprotective' as well as the aggravating potency of linear somatostatin may be connected to gastric mucosal mast cell activity in the rat.

Animals↗
PubMed1986

Cysteamine induces duodenal ulcer in the mouse.

A new model of duodenal ulcer disease has been developed in the mouse. The ulcers were produced after either oral or subcutaneous administration of cysteamine which has been shown to cause duodenal ulcer in the rat. Cysteamine induced duodenal ulcers in a time- and dose-dependent manner after oral administration. The new mouse model shares many similarities with both the rat model and human ulcer disease. Cysteamine caused a significant increase in gastric acidity and pepsin activity. The mouse can be protected against the cysteamine-induced duodenal ulcer by either the dopamine agonist lergotrile or histamine H2 receptor antagonist cimetidine. This new model of duodenal ulcer disease in the mouse may represent a simple and inexpensive way to screen for new antiulcerogenic drugs.

Administration, Oral↗
PubMed1986

Alterations in blood vessels during gastric injury and protection.

Recent investigations suggest that the mucosal vascular endothelium is not a passive bystander, and that alterations within the blood vessel wall actively participate in the pathogenesis of gastric mucosal injury. We review here our data on rapidly developing vascular injury as detected by monastral blue deposition and increased vascular permeability measured by Evan's blue extravasation in dose- and time-dependent experiments with ethanol, HCl, and NaOH in the rat. In addition, using in vivo microscopy and laser-Doppler velocimetry, we demonstrate circulatory stasis in the superficial capillaries within about 1 min after topical application of damaging agents, and a gradual decrease in blood flow that correlates with the extent of hemorrhagic erosions. Prostaglandins or sulfhydryl agents prevented the circulatory standstill and the development of hemorrhagic mucosal lesions. We conclude that microvascular damage, increased vascular permeability, and capillary stasis precede the development of hemorrhagic mucosal lesions.

Animals↗
PubMed1986

Gastric mucosal protection by somatostatins.

Somatostatin and somatostatin derivatives were tested for their ability to prevent gastric hemorrhagic erosions induced by ethanol. The somatostatin analogues were cyclohexapeptides with the rearranged amino acids 7-14 of somatostatin (S-14): Phe-Thr-Lys(Z)-Trp-Phe-D-Pro(I), Phe-Thr-Lys-Trp-Phe-D-Pro(II), Phe-Thr-Lys-D-Trp-Phe-Tyr(III) and Tyr-Phe-D-Trp-Lys-Thr-Phe(IV). In Spraque-Dawley rats receiving ethanol alone, the lesions involved 18.1 +/- 3.2% of the glandular stomach while after S- 14 (10(-7) mol/rat) the lesioned area was reduced to 6.3 +/- 1.1% (p less than 0.05). Peptide I and peptide II (doses 10(-7) -10(-9) mol/rat) decreased the area of erosions to less than 5%. Peptide III was less active and peptide IV was inactive. In rats with chronic gastric fistula S- 14 and peptide II decreased the cysteamine-stimulated acid secretion without affecting the pepsin output. We also continuously measured the intraluminal pH in the stomach of Wistar rats which develop gastric erosions after subcutaneous injection of cysteamine. The erosions were reduced by S- 14 or SMS while the intraluminal pH did not change under the influence of cysteamine or the combination of cysteamine plus S- 14 or SMS. Thus some of the peptides derived from S- 14 exert prominent gastric mucosal protection without influencing gastric secretion.

Animals↗
PubMed1986

Evidence for the involvement of dopamine agonists and antagonists in duodenal ulcer disease.

In experimental duodenal ulceration, dopamine levels, turnover, and binding sites are influenced. Dopamine agonists and antagonists exert anti- and proulcerogenic effect, respectively, probably by influencing duodenal hyper- or hypomotility, rather than effecting gastric secretion. The duodenal ulcerogenic effect of the dopamine neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) given to rats in multiple daily doses (p.o. or s.c.) also induced in a dose-dependent manner duodenal ulcers. Duodenal ulcers were prevented by pretreatment with dopamine agonists (e.g. bromocriptine, lergotrile) or monoamine oxidase inhibitors (e.g. pargyline or 1-deprenyl). Our hypothesis suggests that duodenal ulcerogens may interfere with the action of dopamine resulting in loss of the inhibitory function of dopamine, and producing tissue damage from the accumulated auto-oxidation products of dopamine. Alternatively a motility disorder induced by cysteamine, propionitrile or MPTP may contribute to the pathogenesis probably by involving localized hyperacidity in the duodenal bulb because of decreased neutralization and impaired duodenal emptying of acid.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Experimental basis for a role for sulfhydryls and dopamine in ulcerogenesis: a primer for cytoprotection--organoprotection.

This brief review presents the evolution of the concept of cytoprotection which was originally described by Robert (1979) to represent prevention of chemically induced hemorrhagic gastric erosions without inhibiting acid secretion. Prostaglandins (PG) and sulfhydryls (SH) protect only against deep hemorrhagic necrosis in the mucosa without altering the initial damage to surface epithelial cells. Organ integrity and function are thus maintained (i.e., organoprotection) despite the loss of several layers of mucosal cells. While both PG and SH are natural products it must be stressed that only SH compounds can enter directly into protective reactions (e.g., free radical scavenging, modification of receptor SH groups, oxidation of certain structural and enzyme proteins). In addition, SH compounds also stimulate PG synthesis. A major target of gastroprotection by either PG or SH is the preservation of mucosal microvasculature to maintain blood flow for rapid restitution and cell proliferation. Dopamine-related compounds are reviewed because of their possible role in duodenal ulceration. Dopamine and dopamine agonists are antiulcerogens in duodenal ulcer models. Dopamine antagonists are proulcerogens and the dopamine neurotoxin MPTP causes duodenal ulcer in experimental animals. The mechanism of duodenal antiulcerogenic effect involves inhibition of gastric acid and pepsin secretion, stimulation of duodenal bicarbonate secretion, correction of duodenal dysmotility, and maybe increased blood flow. Because of their multiple beneficial effects, SH compounds and dopamine drugs are good models for gastroenteroprotection.

Animals↗
PubMed1986

Effect of acrylonitrile on the rat pituitary: enlargement of Golgi region in prolactin cells, crinophagy in prolactin cells and growth hormone cells.

Since it has been shown that acrylonitrile prevents the appearance of spontaneous pituitary adenomas, we have investigated its effect in acute experiments on rat pituitaries by histology, immunocytochemistry, electron microscopy and morphometry; in addition, serum prolactin and growth hormone levels were measured by radioimmunoassay. Electron microscopy of prolactin cells revealed hypertrophy of the Golgi region without significant change in volume densities and diameters of forming and storage granules. In the 24 h group, crinophagy was observed in prolactin cells and growth hormone cells. Corticotrophs, thyrotrophs and gonadotrophs were unaltered. Dilation, congestion and rupture of capillaries, as well as pericapillary and intercellular oedema were evident in the 24 h group. One hour after intravenous acrylonitrile injection, serum prolactin levels were within the normal range, whereas at 24 h, hyperprolactinemia was noted. Serum growth hormone concentrations were unchanged. It can be concluded that acrylonitrile has a complex effect on prolactin cells. Hypertrophy of Golgi complex and hyperprolactinemia may reflect increased prolactin synthesis and release. Since volume densities and diameters of secretory granules in prolactin cells remained unchanged, it appears that newly synthesized prolactin was preferentially released and not the prolactin stored in secretory granules. Crinophagy may be the morphological manifestation of a discrepancy between hormone synthesis and release suggesting increased degradation of unused hormone by lysosomes.

Acrylonitrile↗
PubMed1985

Biliary and pancreatic secretions influence experimental duodenal ulcer without affecting gastric secretion in the rat.

The effect of the absence of biliary and/or pancreatic secretions in the duodenum or the enhanced presence of bile at the proximal duodenum on the incidence, severity, number, and location of cysteamine-induced duodenal ulcers was investigated in the rat. Cysteamine produced ulcers on the anterior wall of the duodenum in 75% and on the posterior wall ("kissing ulcers") in 50% of the animals. Diversion of biliary and/or pancreatic secretions from the duodenum increased both the severity and the incidence of the posterior duodenal ulcers. Diversion of bile to the proximal duodenum, on the other hand, decreased the severity as well as the incidence of the anterior duodenal ulcers. Mortality in rats receiving cysteamine correlated with the severity of ulcers. Taurocholic acid at nontoxic doses given subcutaneously or orally to nonoperated rats and rats which had bile diverted to the proximal duodenum aggravated the cysteamine-caused duodenal ulcers. Neither proximal nor distal diversion of bile had a major effect on gastric secretion of acid and pepsin in normal or cysteamine-treated rats. We conclude that both bile and pancreatic secretions may directly influence the development of cysteamine-induced duodenal ulcers in the rat.

Animals↗
PubMed1985

A quantitative method for assessing the extent of experimental gastric erosions and ulcers.

Evaluation of acute gastric erosions and ulcers induced by chemicals such as ethanol or aspirin is difficult because these lesions are predominantly multiple and irregularly shaped. A commercially available, relatively inexpensive microprocessor-linked planimeter (Micro-Plan II) with a stereomicroscope was used to measure the area of gastric mucosa damaged following intragastric administration of various doses of ethanol or aspirin. An enlarged image of rat glandular stomach was projected from the stereomicroscope onto a planimeter on which the perimeter of the entire glandular stomach and each lesion was traced with an electronic cursor. An attached printer recorded the area of stomach assessed, the number of lesions, the surface area of each lesion and the total area of mucosal damage. The technique was compared with semiquantitative methods used previously to assess experimentally induced gastric mucosal damage. The quantitative morphometric method was sufficiently sensitive to demonstrate a dose-response effect of ethanol and aspirin. The stereomicroscope--planimeter combination provides a sensitive method to quantitate either a few small, or numerous large, regularly or irregularly shaped hemorrhagic and nonhemorrhagic gastric mucosal lesions.

Animals↗