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S Szabo

Publications and source records attributed to S Szabo.

At least 91 records · Page 5Linked to original sources
PubMed1990

Experimental pathogenesis: drugs and chemical lesions in the gastric mucosa.

The goals of this article are to review the similarities and differences in the pathogenesis of acute gastric mucosal injury induced by alcohol, exemplified mostly by ethanol, and aspirin, as a representative of nonsteroidal anti-inflammatory drugs, and to deduce implications from pathogenetic studies for a better understanding of the concept of gastric cytoprotection. The main similarity between the hemorrhagic erosions caused by ethanol and aspirin is their localization in the acid-producing glandular stomach, the rate-limiting step in their pathogenesis being the extent of microvascular injury in the gastric mucosa. The major differences include the fast healing and low probability of transition into chronic gastritis after a single exposure to aspirin. On the other hand, perforated ulcer may develop, especially in the elderly, after chronic aspirin but not ethanol consumption. The main implications of pathogenetic investigations include the relative nature of gastroprotection: that is, initially, the superficial epithelial layer is not protected against concentrated luminal solutions, but it is rapidly replaced by migrating, adjacent, surviving cells if blood flow is maintained and the basement membrane is relatively intact. Vascular changes thus seem to be the rate-limiting step both in the pathogenesis and prevention of chemically induced acute gastric mucosal injury. The ultimate biochemical mechanisms of gastroprotection seem to include an effect on structural and enzymic proteins, and vascular mediators which influence vascular permeability and, indirectly, the extent of tissue injury.

Animals↗
PubMed1990

Experimental gastric and duodenal ulcers. Advances in pathogenesis.

New developments in the study of the pathogenesis of experimental gastric and duodenal ulcers indicate a complex multifactorial process leading to ulceration. The concept of gastric cytoprotection with prevention of hemorrhagic mucosal lesions by PG, SH, or other compounds without inhibiting acid secretion was discovered while investigating animal models of gastric erosions and ulcers. Subsequent research into the pathophysiology of gastric ulcer has been revitalized. New studies have demonstrated that the development or prevention of vascular injury in the gastric mucosa plays a crucial role in gastric mucosal injury and protection. The pathophysiology of experimental duodenal ulcer disease has shown that controlling gastric acid secretion is not the only approach to the prevention or treatment of this disorder. Data from human and animal experiments suggest that duodenal dysmotility contributes to the decreased neutralization of acid whether secreted at a normal or subnormal rate, in the duodenal bulb. Dopamine infusion corrected experimentally induced duodenal hypermotility, but other neurotransmitters may also be involved. Multidisciplinary investigations using experimental models of gastric and duodenal ulcers lead not only to the discovery of new concepts and pathogenetic mechanisms but also to the recognition of new chemicals that may exert gastroprotective and antiulcerogenic effects.

Animals↗
PubMed1989

Pathways of gastrointestinal protection and repair: mechanisms of action of sucralfate.

Protection, i.e., prevention of major lesions and the mechanisms of repair/healing of major tissue loss in the gastrointestinal mucosa, are multifactorial processes. Conceptually, it is useful to categorize the components and mechanisms of gastroprotection and distinguish between: (1) Preservation of existing cells either by enhanced resistance of cells or by decreased exposure to damaging agents that can be achieved by maintenance of proper blood flow, vascular permeability, motility, mucus and bicarbonate secretion. If these mechanisms fail and tissue necrosis ensues, (2) replacement of lost tissue is achievable by either the original cells (e.g., epithelia), by cell migration (restitution) and proliferation (regeneration), and/or by connective tissue repair (e.g., fibroblasts, collagen) through cell proliferation and production of extracellular matrix. For acute gastroprotection ("cytoprotection"), maintenance of blood flow in the upper mucosa and epithelial restitution are listed as key mechanisms. For the long-term safeguarding of the mucosa, proper mucus and bicarbonate secretion, as well as ability to respond by cell proliferation, are the proposed key mechanisms of mucosal defense. The mechanisms of action of sucralfate are also multifactorial. The acute gastroprotection by sucralfate is a prostaglandin- and sulfhydryl-sensitive process: after early protection of microvasculature and maintenance of blood flow, along with direct or indirect preservation of the proliferative zone, rapid restitution repairs the initial epithelial defect. The mechanisms of accelerated healing by sucralfate of chronic ulcers include enhanced mucus and bicarbonate secretion, increased ability of mucus to maintain pH gradient, stimulated binding of epidermal growth factor and other growth factors, and maintained or enhanced blood flow resulting in increased cell proliferation leading to granulation tissue formation and re-epithelialization. The slight direct antipeptic and bile-acid binding property of sucralfate might also contribute to its ability to accelerate ulcer healing.

Animals↗
PubMed1989

Effect of duodenal ulcerogens cysteamine, mepirizole, and MPTP on duodenal myoelectric activity in rats.

Increased gastric acid secretion, enhanced acid delivery to the duodenum, and reduced alkaline secretion in the proximal duodenum are relatively well-established pathophysiologic abnormalities in duodenal ulcer. Impaired duodenal motility, however, may also contribute to duodenal ulceration by altering the distribution of acid and alkaline secretions along the upper digestive tract. We tested the hypothesis that the duodenal ulcerogens cysteamine, MPTP, and mepirizole modify duodenal motility in the rat and that motility changes might be a common and early alteration in experimental duodenal ulceration. All three duodenal ulcerogens rapidly produced extensive changes in duodenal myoelectric activity and reduced the frequency of myoelectric slow waves. Cysteamine induced marked hypermotility for at least 6 hr; MPTP rapidly decreased motility and fragmented the myoelectric migrating pattern. Mepirizole induced biphasic changes: an early hypermotility phase of about 30 min was followed by profound hypomotility. These results indicate that marked alterations of duodenal motility are common during experimental duodenal ulceration. In light of the differential effect of the ulcerogens on duodenal motility, it remains to be determined how these changes influence acid neutralization in the proximal duodenum. Nevertheless, our results suggest that all three duodenal ulcerogens, which are different in structure, alter duodenal motility.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Protection of gastric mucosa against hypertonic sodium chloride by 16,16-dimethyl prostaglandin E2 or sodium thiosulfate in the rat: evidence for decreased mucosal penetration of damaging agent.

Protection of the gastric mucosa may be the result of either increased cellular resistance to injury (cytoprotection) or, alternatively, decreased exposure of mucosal cells to the damaging agent. To determine whether decreased exposure of mucosal cells to damaging agents plays a role in mucosal protection by 16,16-dm PGE2 or sodium thiosulfate, we estimated the intramucosal concentration of 22NaCl and measured its absorption from the gastric lumen into the systemic circulation 1 and 5 min after intragastric administration of hypertonic (25% w/v) 22NaCl. In an attempt to explain the differences observed, we also measured the net transmucosal water flux in control animals and rats pretreated with the protective agents. Administration of hypertonic NaCl rapidly (within 1 min) induced extensive hemorrhagic mucosal lesions that were significantly reduced by pretreatment with 16,16-dm PGE2 or sodium thiosulfate. Ultra-low temperature autoradiography indicated that luminal hypertonic 22NaCl penetrates the upper layers of the mucosa in relatively high concentrations (12.5% w/v) within 1 min but its concentration decreases rapidly and reached low levels (3.12% w/v) by 5 min. Absorption of NaCl from the gastric lumen into the systemic circulation 1 and 5 min after hypertonic NaCl was lower in both pretreatment groups than in the control. Net gastric transmucosal water flux (from serosa to mucosa) increased (P less than 0.05) from 100 +/- 2 in controls, to 1470 +/- 8 and 715 +/- 9 microliters in rats pretreated with 16,16-dm PGE2 and sodium thiosulfate, respectively. We conclude that 16,16-dm PGE2 and sodium thiosulfate protect the gastric mucosa against hypertonic NaCl, diminish mucosal penetration of NaCl, decrease mucosal absorption of NaCl, and significantly increase serosal to mucosal transmucosal water flux.(ABSTRACT TRUNCATED AT 250 WORDS)

16,16-Dimethylprostaglandin E2↗
PubMed1989

Adrenal gland: chemically induced structural and functional changes in the cortex.

The adrenal cortex is the target of a surprisingly large number of exogenous chemicals. Until recently, the toxic action of these chemicals was discovered serendipitously. Following our observations that acrylonitrile, cysteamine or pyrazole induces hemorrhagic adrenocortical necrosis in the rat, we recently recognized a structure-activity correlation which predicts the adrenocorticolytic property of alkyl chemicals, i.e., 2-3 carbons with double or triple bonds and with nucleophilic terminal radicals (e.g., -CN, -SH, -NH2). On the basis of our results obtained with electron microscopic, histochemical and biochemical studies as well as those of others, we propose the following sequence of events in the pathogenesis of chemically induced adrenocortical necrosis: 1) Depletion of glutathione and increased dopamine concentration in the adrenals; 2) Endothelial damage and rupture of capillary walls in the adrenal cortex due to either direct attack by the chemicals (metabolites) and/or released monoamines; 3) Retrograde embolization of medullary tissue fragments into the cortical capillaries; 4) Enhanced destruction of cortical vascular walls with subsequent platelet aggregation, fibrin deposition which is often associated with a systemic drop in platelet counts, and changes in blood coagulation; 5) Escape of plasma and cellular elements of blood into extravascular spaces and damage of adrenocortical parenchymal cells; and 6) Hemorrhage and necrosis in the adrenal cortex. This pathogenetic sequence was investigated in detail with acrylonitrile, and studied in various aspects with thioguanine, cysteamine and pyrazole.

Adrenal Cortex↗
PubMed1989

Individual gustatory reaction times to various groups of chemicals that provoke basic taste qualities.

Reaction times (RTs) to four groups of substances that provoke different taste qualities were measured. Measurements for all substances with the same taste, equalized in perceived intensity and provoking a very strong taste, were made concurrently for each subject. The comparisons were made on the individual level. No significant differences in RTs to substances with the same taste quality were found. When the factor of perceived intensity is kept constant, no effect of the stimulus chemical composition on RTs seems to be present. RTs to stimuli with different tastes differ significantly, the shortest being to salt and the longest to bitter. The difference in RTs for sour and sweet substances is small, and the subjects were not all alike in terms of the order of RTs with respect to these stimuli.

Humans↗
PubMed1989

The role of gastric and duodenal pH in the cysteamine-induced duodenal ulcer in the rat.

Many secretory studies reported an increase in gastric acid secretion by the duodenal ulcerogen cysteamine. A detailed analysis of these experiments, especially the results from rats with chronic gastric fistula suggest that direct stimulation of gastric acid secretion may not be the primary mechanism of the duodenal ulcerogenic action of cysteamine. We used a different approach and measured the pH at the site of ulceration in the proximal duodenum. A duodenal ulcerogenic dose of cysteamine did not change the pH at the anterior or posterior wall of the duodenum during 4 hr. In the same dose and by the same route of administration, cysteamine nevertheless induced duodenal ulcers in 24 hr. These experiments demonstrate that in addition to the effect on gastric acid secretion, other factors are needed to the effect on gastric acid secretion, other factors are needed to explain the early duodenal ulcerogenic action of cysteamine.

Animals↗
PubMed1988

The influence of cysteamine and propionitrile on duodenal phosphoprotein phosphatase in rats.

Cysteamine and propionitrile cause severe duodenal ulcers with perforation within 24-48 h after a single injection in rats. These animal models were used to gain insight into the early, preulcerogenic biochemical changes in the duodenal mucosa. The results indicate that a single sc injection of cysteamine and propionitrile induced dose- and time-dependent decreases in the activity of phosphoprotein phosphatase (PPPase) in homogenate and particulate fractions of rat duodenal mucosa. The decrease in enzyme activity was detectable 4 h after the injection of the ulcerogens, it was maximal at 12 h, and hardly detectable at 24 h. No effect on the enzyme activity was found under in vitro conditions. PPPase activity in the liver was not influenced by either cysteamine or propionitrile. Furthermore, the toxic but nonulcerogenic derivative of cysteamine ethanolamine had no effect on PPPase in the duodenum. Thus, the effect of the duodenal ulcerogens on PPPase activity was indirect and organ specific, related only to the target organ (i.e., duodenal mucosa). The effect of the drugs was also selective at the level of mucosal cells: both duodenal ulcerogens depleted protein and alkaline phosphatase but not lysosomal acid phosphatase. The decrease of PPPase activity could be a general property of the duodenal ulcerogens since it is independent of their effect on endogenous somatostatin.

Acid Phosphatase↗
PubMed1988

Gastric mucosal protection by new aryl sulfhydryl drugs.

Alkyl sulfhydryl drugs protect against acute gastric hemorrhagic mucosal lesions. We tested the protective effect of cyclic drugs containing oxidized (KT1-32, KT1-39, KT1-94), or reduced (KT1-66, KT1-109, KT1-293, KT1-720, KT1-756) sulfhydryls. The most potent protective agents (KT1-32, KT1-109, KT1-720, KT1-756) were investigated in detail. Drugs were administered intragastrically to fasted rats 30 min before 100% ethanol (1 ml) or acidified aspirin (10 mg/100 g), and mucosal lesions were measured planimetrically 1 hr later. Control rats receiving only ethanol had lesions involving 14.5% of the glandular mucosa. KT1-32, KT1-109, KT1-720, or KT1-756 (10 mg/100 g) reduced lesions to 0.7, 2.7, 1.8, or 0.7% of glandular stomach respectively. Aspirin-induced lesions involved 1.52% of the glandular mucosa and 10 mg/100 g of KT1-32, KT1-109, or KT1-720, or 2 mg/100 g of KT1-756 diminished the damage to 0.13, 0.02, or 0.04, or 0.00%, respectively. Indomethacin interfered with protection against ethanol by KT1-109, while the sulfhydryl alkylator N-ethylmaleimide abolished protection by both KT1-32 and KT1-109. Among the drugs investigated in detail, KT1-756 increased gastric acid output, while KT1-720 and KT1-756 significantly enhanced pepsin secretion. All four compounds studied in detail (ie, KT1-32, KT1-109, KT1-720, KT1-756) decreased the extent of vascular lesions in the gastric mucosa as revealed by monastral blue 1 min after ethanol. Thus, the mechanism of gastric mucosal protection by these novel aryl sulfhydryl compounds cannot be ascribed to an antisecretory effect, but may be related to prevention of vascular injury.

Animals↗
PubMed1988

Biphasic effect of duodenal ulcerogens on gastric emptying in the rat.

The effect of the duodenal ulcerogen cysteamine on gastric emptying of a liquid meal was compared to that of two newly identified duodenal ulcerogens, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and mepirizole. Emptying rates after acute and chronic treatment with duodenal ulcerogens were obtained. Acute administration of cysteamine, MPTP, or mepirizole significantly delayed gastric emptying of the meal. Chronically treated rats, however, showed either no change or accelerated gastric emptying after cysteamine, MPTP, or mepirizole. Gastric emptying in chronically treated animals was faster in rats that developed the most severe duodenal ulcers. These results indicate that delayed gastric emptying instead of accelerated emptying is a more common abnormality during duodenal ulceration. After the ulcer develops, however, unaltered or accelerated gastric emptying is observed experimentally, thus suggesting that accelerated gastric emptying in duodenal ulcers is an acquired alteration. The implications that these experimental findings may have in the pathogenesis of duodenal ulcer, in light of the clinical data available, are discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Vascular injury in acute gastric mucosal damage. Mediatory role of leukotrienes.

Recent investigations indicate that microvascular injury, leading to increased vascular permeability and capillary stasis, precede the development of chemically induced hemorrhagic mucosal lesions in the stomach. The vascular damage is more amenable to protection by prostaglandins and sulfhydryls than the diffuse surface mucosal cell injury. The vascular and mucosal lesions may be the result of direct toxicity of damaging agents (eg, ethanol, HCl, NaOH) and the release of vasoactive amines and leukotrienes. We review here our recent studies performed in rats indicating that intraarterial infusion of LTC4 or LTD4 in the stomach caused vascular injury as revealed by monastral blue. Infusion of leukotrienes alone caused no hemorrhagic mucosal lesions but aggravated the damage caused by 25, 50, or 100% ethanol and 0.2 N HCl given intragastrically. The ethanol-induced mucosal lesions were slightly diminished by the lipoxygenase inhibitor L-651,392 and markedly decreased by eicosapentaenoic acid, which competes with arachiconic acid as a substrate for 5-lipoxygenase. These results are discussed and correlated with biochemical results from other laboratories demonstrating increased levels of leukotrienes in the gastric mucosa after administration of ethanol and decreased release following pretreatment with prostaglandins or sulfhydryl-related agents. New data thus support a mediatory role for leukotrienes in the pathogenesis of vascular injury and mucosal lesions in the stomach.

Animals↗