Stress Ulcer Development Research Articles

Asymmetrical influence of mesocortical dopamine depletion on stress ulcer development and subcortical dopamine systems in rats: Implications for psychopathology

The effects of left, right or bilateral depletion of the mesocortical dopamine innervation (medial prefrontal and anterior cingulate) with 6-hydroxydopamine were examined in male Sprague-Dawley rats tested for susceptibility to cold restraint-induced gastric stress pathology. All three types of lesions tended to potentiate the development of stress pathology (i.e. ulceration) in comparison to restrained shams, but only right cortical dopamine depletion produced a highly significant increase. The results support a protective role for mesocortical dopamine in helping the organism cope with stressful situations, and extend previous findings suggesting that dopamine activation in the right cortex is preferentially associated with uncontrollable stress. The right cortex is hypothesized to be at the top of a hierarchy in the processing of such stressful inputs, and endogenous dopaminergic modulation facilitates adaptive responses. Subcortical dopamine terminal regions were also examined for dopamine content and turnover. In addition to depleting cortical dopamine, the three lesion groups showed highly specific alterations in the status of subcortical dopamine systems, compared to either restrained or non-restrained shams. Left brain lesions resulted in significant bilateral increases in amygdala dopamine turnover. Right cortical lesions induced significant bilateral reductions of striatal dopamine content. Bilateral lesions increased dopamine content in the left amygdala and decreased dopamine in the right nucleus accumbens. Also in this group, dopamine turnover was increased in the right nucleus accumbens and decreased in the right amygdala. The data suggest that increases in stress vulnerability induced by cortical lesions may be related, in part, to neurochemical alterations in subcortical structures previously shown to modulate gastric stress pathology. The results also indicate that brain organization is inherently asymmetrical with respect to the regulation of responses to stress, which may be of significance for human psychopathology and its exacerbation by stress.

The role of thyrotropin-releasing hormone (TRH) in the pathogenesis of water-immersion stress in rats--inhibition of TRH release from the stomach by atropine, ranitidine or omeprazole.

The role of thyrotropin-releasing hormone (TRH) in the development of gastric erosions and ulcers induced by water-immersion stress was studied. Intraperitoneally administered bethanechol induced a decrease in the gastric wall immunoreactive TRH (ir-TRH) concentrations and an increase in gastric juice ir-TRH concentrations in a dose-related manner, while atropine induced an increase in gastric wall ir-TRH concentrations and a decrease in gastric juice ir-TRH concentrations under non-stress condition. Intraperitoneally administered omeprazole did not influence gastric wall ir-TRH concentrations but elevated gastric pH. Water-immersion stress induced a decrease in gastric wall ir-TRH concentrations and an increase in gastric juice ir-TRH concentrations with a decrease in gastric pH prior to ulcer formation. Pretreatment with atropine or ranitidine inhibited the development of stress ulcers, reduced changes in ir-TRH concentrations in the gastric wall and gastric juice, and induced an increase in gastric pH. Omeprazole inhibited stress ulcer formation and changes in gastric wall and gastric juice ir-TRH concentrations. These results suggest that TRH release from the stomach wall into gastric juice is of importance in the pathogenesis of stress ulcer and that its release is mediated by both muscarinergic and histaminergic (H2) systems. Furthermore, omeprazole has an inhibitory effect on TRH release under stress ulcer.

Reduced incidence of stress ulcer in germ-free sprague dawley rats

Recent findings with respect to the role of spiral gram-negative bacteria in peptic ulcer disease have stimulated interest in discerning the role of these agents in stress ulcer disease. We tested the hypothesis that a standard restraint-cold ulcerogenic procedure would fail to produce ulcers in axenic rats. Axenic, as well as normal Sprague Dawley rats, were exposed to a cold-restraint procedure. The germ-free condition was maintained throughout the study in the axenic rats. Axenic rats had significantly fewer ulcers as compared to normal rats exposed to the standard cold-restraint procedure, as well as handling control rats. The data represent the first report suggesting a microbiologic component in the development of stress ulcer using the rat model.

Vulnerability to stress ulcerogenesis in rats differing in anxiety: A dopaminergic correlate

Dopamine and its agonists, acting through D1/DA1 receptors, have been shown to be effective protective factors against stress ulcerogenesis. Since anxiety has been related to stress ulcer development, we chose to examine dopaminergic activity in rats screened for the extremes of behaviorally manifest anxiety. High anxious rats develop more stress ulcers and more ethanol ulcers, relative to low anxious animals. High anxious rats require greater amounts of dopaminergic agonists for 50% protection against stress ulcer formation. In conditions of exposure to a stressor, high anxious rats lose amygdalar dopamine at a faster rate than do low anxious rats. These results suggest that anxiety is a significant factor in stress ulcer development and that central dopaminergic function is critically involved in mediating this pathogenetic factor.

Halt stress ulcer development

Halt stress ulcer development

Changes in Gastric Mucosal Microcirculation and Purine Nucleotide Metabolism during Hemorrhagic Shock in Rats

Intravital fluorescence microscopy and morphometry were used to study the microcirculation in the rat gastric mucosa during and after hemorrhagic shock. Under control conditions the circulation appeared homogeneous and unaffected by superfusion with 0.1 N HCl. During hemorrhagic shock, scattered areas of the mucosa lost circulation. Morphometry showed that the number of perfused mucosal vessels decreased significantly in the abluminal part of the mucosa both in perfused and ischemic areas, the reduction being most pronounced in the ischemic areas, where the number of perfused luminal vessels also decreased significantly. During reperfusion, bleedings occurred from the mucosa. A key finding was that the bleedings always had their origin at the border zone between ischemic and perfused areas. After hemorrhagic shock adenosine triphosphate and energy charge levels dropped significantly in both perfused and ischemic areas but with significantly lower levels in the ischemic areas. The hypoxanthine levels increased in both perfused and ischemic areas. The experiments show that local mucosal ischemia and accelerated nucleotide degradation are of pathogenetic importance in the development of stress ulcers after hemorrhagic shock. The border zone between circulated and ischemic areas seems to be an area of special interest.

Hippocampal pathway to the amygdala and stress ulcer development

The objective of the first study was to localize the reported aggravation of stress ulcers found after large bilateral hippocampal lesions in rats. Lesions in the ventral hippocampus produced a similar increase in the severity of gastric erosions after cold-restraint, as was seen after large bilateral lesions. Dorsal hippocampal damage produced no differential effects. In the second experiment, high-frequency electrical stimulation of the ventral CA1 region of the hippocampus, a procedure known to induce long-term potentiation, increased the evoked potentials in the lateral central nucleus of the amygdala, and in adjacent parts of the lateral and basolateral nuclei. The increase in the efficacy of synaptic transmission in this pathway attenuated stress ulcer development. It was concluded that the ventral hippocampus is part of a coping system, and a strengthening of synaptic connections with the central amygdala increases the coping ability of rats under stress conditions.

A Biochemical and Pharmacological Approach to the Genesis of Ulcer Disease II

Biochemical and molecular pharmacological studies were carried out in the gastric fundic mucosa during the development of stress ulcer in rats. The aims of this study were: (1) to evaluate the changes in membrane-bound ATP-dependent energy systems during the development of stress ulcer; (2) to prove (or to exclude) the presence of tissue hypoxia in the rat gastric mucosa during the development of stress ulcer; (3) to obtain further evidence of the existence of a feedback mechanism between ATP-ADP, ATP-cAMP, and cAMP-AMP transformations during the development of stress ulcer; (4) to analyze the different biochemical changes in the gastric mucosa before and after the macroscopic appearance of stress-induced gastric mucosal lesions (ulcers). The observations were carried out on both sexes of CFY-strain rats of 180 to 210 g body weight. The animals were deprived of food for 24 hours before the experiments. The animals were forced to swim in water (at 24 degrees C) for five hours. They were sacrificed at 0, 1, 2, 3, 4, and 5 hours after the introduction of stress. The tissue levels of ATP, ADP, AMP/ADP, and lactate were enzymatically measured; the cAMP was measured by radioimmunoassay. The adenylate pool (ATP + ADP + AMP), ratio of ATP/ADP, and "energy charge" [(ATP + 0.5 ADP)/(ATP + ADP + AMP)] were calculated. The membrane (Mg2(+)-Na(+)-K(+)-dependent) ATPase was prepared from the rat gastric fundic mucosa. Dose-response curves for epinephrine, cAMP, and AMP were determined on Na(+)-K(+)-dependent ATPase; also, the affinity, intrinsic activity curves, pD2, pA2 and alpha were calculated for all components. It was found that: (1) gastric mucosal lesions appeared and increased gradually from three hours after introduction of stress; (2) the extent of ATP-cAMP and cAMP-AMP transformations was increased considerably during the development of stress ulcer; (3) the extent of ATP-ADP transformation was completely inhibited; (4) the activity of Na(+)-K(+)-dependent ATPase from rat gastric fundic mucosa could be inhibited by epinephrine, cAMP, and AMP; (5) the ratio of ATP/ADP was unchanged in the first time period (from 0 to 3 hours), after which its value increased; (6) the value of "energy charge" (e.g., the extent of phosphorylation and/or dephosphorylation) of cells was decreased at two and three hours, after which its value returned to a normal level; (7) there was no increase in the tissue level of lactate; (8) several biochemical changes (decrease of ATP, ADP, "energy charge," increase of cAMP, AMP) preceded the macroscopic appearance of stress ulcer.(ABSTRACT TRUNCATED AT 400 WORDS)

Limbic System Modulation of Stress Ulcer Development

Limbic System Modulation of Stress Ulcer Development

The GABA/benzodiazepine receptor complex in the central amygdalar nucleus and stress ulcers in rats

The effects of bilateral microinjections of chlordiazepoxide and GABA into the central amygdalar nucleus on gastric ulcer formation induced by cold-restraint were examined in chronically implanted Wistar rats. Higher doses of chlordiazepoxide (20 and 30 micrograms/amygdala) significantly reduced stress ulcer development, whereas a lower dose (2.5 micrograms) produced a nonsignificant increase in ulcer severity. A similar dose/response pattern was observed following GABA administration. The benzodiazepine receptor antagonist Ro15-1788, applied to the amygdala, abolished the protective effects of both chlordiazepoxide and GABA. In addition, when Ro15-1788 (10 micrograms) was injected into the amygdala by itself, it aggravated the gastric stress pathology. However, a lower dose (5 micrograms) had an attenuating effect, opposite to the pattern of effects produced by chlordiazepoxide and GABA. The role of the amygdalar GABA-benzodiazepine receptor complex in stressful conditions is discussed.

Influence of rearing conditions on voluntary ethanol intake and response to stress in rats

The effects of exposure to four environmental rearing conditions on subsequent voluntary ethanol intake and response to immobilization stress were examined. Male weanling rats were reared in an enriched environment, with a female partner, with a male partner, or individually, for 90 days. At 111 days of age, voluntary consumption of ethanol in increasing concentrations (3 to 9%, v/v) was assessed. Following the ethanol-exposure period, rats were randomly divided into stressed and nonstressed groups and exposed to 3 h of immobilization. Results indicated that the enriched animals consumed greater amounts of ethanol as compared to all other groups, suggesting that the enriched environment and not handling, housing conditions, or the presence of another male or female is responsible for the observed increase in ethanol drinking behavior. Ulcer data indicated that among environmentally enriched rats, ethanol attenuated stress ulcer development relative to their non-ethanol-exposed but stressed controls. In nonstressed enriched rats, ethanol alone exacerbated stomach damage. We suggest that environmental rearing conditions markedly influence the complex interaction between ethanol intake and the response to stress.

<b>GASTRIN-RELEASING PEPTIDE (GRP)-CONTAINING NEURONS IN THE RAT OXYNTIC MUCOSA VVITH SPECIAL REFERENCE TO EXPERIMENTALLY INDUCED PEPTIC </b><b>ULCERS </b>

The relation between gastrin-releasing peptide (GRP)-immunoreactive nerves and development of stomach ulcers was studied in rats. The ulcer was induced by exposure of animals to restraint plus water immersion or by administration of insulin, serotonin, aspirin, indomethacin or ethanol. Immunohistochemistry demonstrated a network of nerves exhibiting the immunoreactivity for GRP in the oxyntic mucosa of normal animals. A marked decrease in number of the GRP-immunoreactive nerves was seen to accompany with the ulcers induced by the restraint stress or by insulin. On the other hand, no appreciable change in number of the GRP-immunoreactive nerves was found in ulcers induced by indomethacin, serotonin, ethanol or aspirin. Vagotomy prevented not only the development of ulcers by stress or insulin, but also the decrease in the GRP-immunoreactive nerves. Electrical stimulation of the vagal nerve resulted in ulcer formation and also caused a marked decrease in number of the GRP-immunoreactive nerves in the oxyntic mucosa. The results suggest the possibility that depletion of GRP from nerves in the oxyntic mucosa may be involved in the development of stress or insulin ulcers and that such a release of GRP may be caused by hyperactivity of the vagal nerve.

Adrenergic modulation of gastric stress pathology in rats: a cholinergic link

The effects of some adrenergic drugs were evaluated on cold restraint-induced gastric ulcers in rats. The beta-adrenergic antagonist, (+/-)-propranolol (1 and 10 mg/kg), as well as the beta-agonist, isoproterenol (0.05 and 0.5 mg/kg) potentiated the gastric pathology. On the other hand, the alpha-agonist, clonidine (0.5 mg/kg) attenuated and the alpha-antagonist, yohimbine (1 mg/kg) aggravated stress ulcer development. The anticholinergic agent, atropine methylnitrate (1 mg/kg), reduced both the frequency and severity of stress ulcers and also antagonized the potentiating effects of (+/-)-propranolol, isoproterenol and yohimbine. The results suggest a cholinergic role in the adrenergic modulation of gastric stress pathology.

Effects of GABA on gastric acid secretion and ulcer formation in rats

The effects of γ-aminobutyric acid (GABA), bicuculline and baclofen, orally and intraperitoneally (i.p.) administered, on the development of stress and pyloric ligation-induced gastric ulcers, were studied in rats. GABA, but not baclofen, significantly reduced the frequency and severity of both models as assessed by ulcer index, incidence and number of ulcers/animal. Gastric protection was dose-related in both experimental models and was completely antagonized by pretreatment with bicuculline methiodide, that blocks peripheral, but not central GABA receptors. All GABA effects were observed after oral and i.p. administration, but inhibition of gastric lesions was greater by the last route. Furthermore, GABA did not affect the acidity or the volume of gastric secretion in pylorus-ligated rats. Consequently its antiulcer activity appears to be mediated by factors unrelated to gastric acid secretion. Since the entry of GABA across blood-brain barrier is greatly restricted it may be concluded that stimulation of peripheral GABA receptors is primarily involved in its antiulcer action.

Experimental stress ulcer and gastric catecholamine contents in spontaneously hypertensive rats.

To determine the role of the sympathetic nervous system in the development of stress ulcer, we carried out experiments on spontaneously hypertensive rats (SHR) exposed to restraint and water immersion stress for 7 h. Normotensive Wistar-Kyoto rats (WKY) were used as controls. Catecholamine (CA) contents in gastric tissues, divided into mucosal and muscular layers of both antrum and corpus, were quantitated by high-performance liquid chromatographic electrochemical detection (HPLC-EC). The stress ulcer formation was much less frequently induced in SHR than in WKY. The noradrenaline (NA) contents in all regions of gastric tissues were higher in SHR than in WKY. The contents of adrenaline (A) and dopamine (DA), present in small quantities in gastric tissues showed no difference between SHR and WKY. After exposure to stress, the NA contents in mucosal and muscular layers of the gastric corpus decreased significantly in both SHR and WKY, whereas the value remained higher in the former. On the contrary, a remarkable increase of A contents (probably released from the adrenal medulla by the stress) was observed in all gastric tissues, of both SHR and WKY. Increase of the A contents in the mucosal layer was remarkable in the SHR. The DA contents increased in both strains. These results suggest that the peripheral sympathetic hyperfunction in the stomach in the SHR may have an inhibitory role in stress ulcer formation.

The effects of thyroid hormones on the formation of stress ulcers in the rat

The Low T 3 Sick Syndrome is a syndrome of low triiodothyronine (T 3), low to normal thyroxine (T 4), and a nonelevated thyrotropin despite the low T 3 levels. This syndrome is frequently encountered in critically ill patients. These same patients are also at higher risk to develop acute stress ulcerations. The objective of this study was to access the effects of low circulating thyroid hormone levels on the development of stress ulcers in the rat. Rats having had previous surgical thyroidectomies were subjected to individual restraint stress; these animals had a significantly increased incidence of stress ulcers when compared to euthyroid stressed controls (1.6 ± 0.4 ulcers vs 0.5 ± 0.2 ulcers per animal, P < 0.05). Surgically thyroidectomized (hypothyroid) animals who were given T 3 replacement and then stressed, had ulcer rates similar to normal stressed controls (0.5 ± 0.2 ulcers per animal). We conclude that low circulating thyroid hormones have an ulcerogenic effect, and that replacement of T 3 in rats with surgical hypothyroidism reverses this effect.

Antiplatelet Aggregators Inhibit Development of Stress Ulcers in Sprague-Dawley Rats

Antiplatelet aggregators such as sulfinpyrazone (10 mg/kg), ticlopidine (200 mg/kg), and pyridine (0.1 mg/kg) significantly inhibited the degree of gastric ulceration in Sprague-Dawley rats subjected to cold restraint stress. The inhibition of platelet aggregation and that of microthrombus formation were evident in rats given antiplatelet aggregating drugs and exposed to cold stress. Therefore, platelet aggregation does play an important role in stress ulcer formation, and drugs which inhibit this aggregation should be given greater attention as to possible clinical application for treatment of stress ulcers.

Central regulation of gastric acid secretion: The role of neuropeptides

A variety of stimuli can act through the central nervous system to alter gastric acid secretion. Lesioning and stimulation experiments have established roles for the lateral and ventromedial hypothalamus and the limbic system in the central regulation of gastric acid secretion. Recently a number of neuropeptides have been demonstrated to alter gastric acid secretion after central administration. Thyrotropin-releasing hormone (TRH) and gastrin both increase gastric acid secretion, whereas bombesin, calcitonin, the endogenous opioid peptides and neurotensin decrease gastric acid secretion. With the exception of bombesin, all the other neuropeptides appear to produce their effects through a vagally mediated mechanism. In addition, a number of these neuropeptides, when centrally administered, have been demonstrated to exert a potent cytoprotective effect against stress ulcer development. This review develops a peptidergic hypothesis of gastric acid secretion, suggesting that the final integration of the cephalic phase of gastric acid secretion is brought about by maintaining a delicate balance in the concentration of a number of interacting peptides and monoamines.

A new prostaglandin E 1 analogue (CL115, 574) : I. Antisecretory and cytoprotectige effects in the rat

The effect of a new analogue of PGE 1 (CL115, 574) on gastric acid secretion, mucus secretion and protection against stress and indomethacin- induced ulcers were studied in the rat. CL115, 574 was more potent than PGE 1 and cimetidine in inhibiting acid secretion. CL115, 574 protected against the development of stress and indomethacin-induced ulcers prevented the indomethacin-induced decrease in hematocrit at an ED 50 (3 μg/kg) far below the antisecretory ED 50 (1 mg/kg). While the inhibiting acid secretion, CL115, 574 increased the volume of gastric secretion indicating a stimulation of nonparallel cell secretion by the rat stomach. In addition the compound stimulated the secretion of mucus into the gastric juice. On the basis of its potency as an inhibitor of acid secretion and these additional effects which are indicative of cytoprotective activity, CL115, 574 should be further studied as a possible anti-ulcer agent in man.

Influence of method of feeding on stress ulcer development in the rat.

Maintenance of rats on total parenteral nutrition for 10 days increased the susceptibility of these animals to gastric ulceration and death due to cold-temperature restraint stress. Animals fed the identical diet orally were much less susceptible. Serum gastrin concentrations were increased by stress in both groups of animals despite initially low serum levels. Glucosamine synthetase specific activity was not altered by the method of feeding but tended to be decreased by restraint. These results suggest that orally administered food protects the animal from stress-induced damage by a mechanism(s) involving neither dietary composition nor gastrin.