Aspirin and gastric ulceration: light and electron microscopic observations in a model of aspirin plus stress-induced ulcerogenesis.

The gastric mucosa of rats given aspirin orally and concomitantly exposed to mild (cold) stress conditions has been examined under the electron microscope. In this model of gastric ulceration greater involvement is seen of the parietal and zymogen cells than is evident after aspirin treatment alone (which leads to mucosal erosions but not ulceration per se). Evidence of considerable autolytic and proteolytic activity is seen in aspirin-plus-stress-treated animals developing in ulceration. Little damage was observed in animals exposed to these mild stress conditions. The synergistic interaction between aspirin and stress could have its basis in greater sensitizing of parietal and zymogen cells to damage not seen in aspirin-treated animals.     

-Deprenyl attenuates stress ulcer formation in rats

Both intraperitoneal and intracerebroventricular (i.c.v.) administration of the monoamine oxidase-B inhibitor -deprenyl markedly attenuated restraint stress-induced gastric ulcers in rats. -Deprenyl given i.c.v. attenuated stress ulcers in microgram doses and virtually abolished ulcer formation at a dose of 2.0 μg. These data suggest that intact or augmented central dopaminergic function may be an essential component of gastric mucosal protection.     

The interrelationships between the lipid peroxidation, superoxide dismutase activity, development of gastric H+ secretion and gastric mucosal damage produced by intragastric administration of aspirin in pylorus-ligated rats

Gastric mucosal damage of pylorus-ligated rats was induced by the intragastric administration of aspirin at 200 mg/kg at the time of ligation. The animals were sacrificed at 0, 1, 2, 3, and 4 h after the treatment. The gastric lesions (ulcers) were counted and their severities were calculated, and the volume of gastric secretion and the H+ output were measured. The extent of lipid peroxidation was assessed by measuring the malondialdehyde (MDA) in the gastric mucosa, simultaneously with measurement of the activity of superoxide dismutase (SOD). It was found in these pylorus-ligated rats that: the number of visible gastric lesions was significantly higher 1 h after aspirin administration than at other times; the severity of gastric lesions increased significantly at the 3rd and 4th hour after administration of aspirin; the volume of gastric secretory responses increased gradually after administration of aspirin and to a higher extent than the H+ output; the H+ output was significantly less after aspirin administration than that after pylorus ligation only; the gastric mucosal SOD activity significantly increased 1 h after administration of aspirin, decreasing significantly and gradually thereafter; the tissue level of MDA remained unchanged 1 h after aspirin administration, decreasing significantly thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electron microscopic observations comparing the gastric mucosal damage induced in rats and pigs by benoxaprofen and aspirin,reflecting their differing actions as prostaglandin-synthesis-inhibitors.

The ultrastructural changes in the gastric mucosa induced by oral administration of aspirin (2 x 125 mg/kg/day) were compared with the effects of benoxaprofen (20 mg/kg/day) in pigs and normal and arthritic rats after 10 or 14 days'' treatment respectively. The object was to compare the effects of drugs having different effects on prostaglandin-synthesizing systems on the development of gastric mucosal damage. Benoxaprofen caused less gastric damage than aspirin. There were fewer lesions in benoxaprofen-treated animals and those which were seen were much less extensive. There were qualitative similarities between the effects of the drug treatments. There were also differences in the mucosal changes produced by both drugs in pigs and rats. This included (1) extravasation of erythrocytes which was seen in rats but not pigs, and (2) interstitial changes also seen in rats but not pigs. These interspecies variations may be due to differences in the resistance of the capillaries to drug effects. There were no differences in the mucosal-cell damage seen in normal compared with arthritic rats.     

Analysis of the cold-water restraint procedure in gastric ulceration and body temperature

Gastric mucosal injury induced by body restraint can be enhanced when combined with cold-water immersion. Based on this fact, the present study had two main purposes: (i) to examine the contribution of each of these two forms of stress on the development of gastric ulceration and regulation of body temperature and (ii) to investigate the importance of the animal's consciousness on gastric ulceration induced by the cold-water restraint. Independent groups of animals were exposed for 3 h to one of the following stressful treatments: body restraint plus cold-water (20+1 degrees C) immersion, body restraint alone or cold-water immersion alone. Control animals were not exposed to any form of stress. Half of the animals submitted to each of the four treatments were anesthetized with thionembutal (35 mg/kg), whereas the other half was injected with saline. Results indicated that body restraint alone was not sufficient to induce gastric ulceration or changes in body temperature. On the other hand, cold-water exposure, either alone or in conjunction with body restraint, induced the same amount of stomach erosions and hypothermia. Therefore, it appears that body restraint does not play an important role on gastric ulceration induced by the cold-water restraint procedure. Present results also indicated that conscious and anesthetized animals immersed in cold water presented robust gastric ulceration and a marked drop in body temperature. However, conscious animals developed more severe gastric damage in comparison to anesthetized animals although both groups presented the same degree of hypothermia. These findings suggest that hypothermia resulting from cold-water exposure has a deleterious effect on gastric ulceration but the animal's conscious activity during the cold-water immersion increases the severity of gastric mucosal damage. It is concluded that cold-water restraint is a useful procedure for the study of the underlying mechanisms involved in stress-induced ulceration.     

Gastric and duodenal anti-ulcer activity of sulpiride,a dopamine D2 receptor antagonist,in rats

The gastric and duodenal anti-ulcer activity of sulpiride, a dopamine D₂ receptor antagonist, was studied on various types of experimentally induced ulcers in rats, viz., pylorus ligation and water immersion + restraint stress-induced gastric ulcers, gastric mucosal damage induced by nonsteroidal anti-inflammatory drugs and reserpine, and duodenal ulcers induced by cysteamine hydrochloride. It has been found to possess significant anti-ulcer activity against all these models. In 19 h pylorus ligated rats, it significantly reduced the gastric secretion, increased the fucose and sialic acid concentration of the gastric juice and reduced its protein content, thus increasing the total carbohydrate: protein (TC/PR) ratio. These results suggest that the antisecretory and gastric mucosal barrier strengthening effects of sulpiride may be responsible for its anti-ulcer activity. A central component also appears to be involved in its anti-ulcer action against water immersion + restraint stress model. The results of this study provide a rationale for its beneficial effect seen in the therapy of peptic ulcer disease.     

Shock predictability and gastric secretion in the chronic gastric fistula rat

In Experiment 1 rats exposed to unpredictable grid shock demonstrated a significant decrease in gastric secretion and total acid output as compared to rats exposed to predictable shock and rats exposed only to the tone stimulus. In Experiment 2 rats were immobilized in restraint cages. Restraint plus predictable shock and restraint plus unpredictable shock resulted in a significant decrease in stomach acid output as compared to restrained no-shock controls. These results do not support a gastric hypersecretion hypothesis for studies which have reported the development of stomach ulcers by using unpredictable shock stress.     

Increased glucocorticoid response to a novel stress in rats that have been restrained

Rats exposed to repeated restraint stress (3 h of restraint on each of 3 days) lose weight during stress and do not return to the weight of nonstressed controls once stress ends. Others have reported that chronic stress raises the daily nadir of corticosterone release and increases the adrenal response to subsequent stress; therefore, we examined glucocorticoid release in rats that had been exposed to repeated restraint. Repeated restraint had no effect on the diurnal pattern of corticosterone or insulin release, measured 12 days after restraint had ended, indicating that the reduced weight of the rats is not associated with an elevated corticosterone-insulin ratio. In contrast, rats that had been exposed to repeated restraint, 12 days previously, showed a blunted corticosterone release during a second restraint stress, a normal response to the novel physiological stress of 2-deoxy glucose (2-DG) injection, but an exaggerated corticosterone response to the novel mild stress (MS) of either placement in a unfamiliar environment or an intraperitoneal injection of saline. Mice exposed to repeated restraint showed a similar hyperresponsiveness to novel MS, suggesting that repeated restraint lowers the threshold for stress-induced activation of the adrenal gland. MS caused a small, but significant, degree of hypophagia in rats that had been exposed to repeated restraint stress. Therefore, multiple aspects of the stress response may be exaggerated in these animals and contribute to the chronic reduction in body weight.     

Cytoprotective and Antioxidant Effects of the Methanol Extract of Eremomastax Speciosa in Rats

Background

Ethno-botanical information shows that Eremomastax speciosa is used in the traditional management of various stomach complaints including gastro-duodenal ulcers.

Materials and Methods

In this study, we tested the cytoprotective potential of the whole plant methanol extract (100–200 mg/kg, p.o), against HCl/ethanol, absolute ethanol, cold/restraint stress rats, and pylorus legated rats pre-treated with indomethacin. The effects of the extract on gastric lesion inhibition, the volume of gastric juice, gastric pH, gastric acid output, mucus production and gastric peptic activity were recorded. Oxidative stress parameters were measured in blood and gastric tissue samples obtained from the animals in all the models tested.

Results

The extract significantly (p<0.05), reduced the formation of cold/restraint ulcers by (31–60%, inhibition), completely inhibited (100%) the formation of lesions induced by HCl/ethanol at the highest dose, but was less effective against absolute ethanol (22–46% inhibition). The extract (200 mg/kg), significantly reduced lesion formation (P<0.01), gastric acidity (P<0.01), and volume of gastric secretions (P<0.05), in the indomethacin/pylorus ligation model, and did not affect the activity of pepsin in gastric juice. Blood concentrations of antioxidant enzymes (catalase, SOD and GSH), increased significantly and MDA concentrations decreased in all models tested.

Conclusion

Cytoprotection by E. speciosa methanol extract was attributed to its ability to reduce acid secretion, and to enhance mucosal defence and in vivo antioxidant status.     

The role of apelin in the healing of water-immersion and restraint stress-induced gastric damage

The objective of this study was to explore the role of apelin in the healing of gastric lesions induced by stress. Male Wistar rats were exposed to water immersion and restraint stress (WIRS) for 6 h with or without the apelin receptor antagonist F13A. The rats were killed on the 1st, 3rd, 5th or 10th day after the end of stress induction. Apelin and hypoxia-inducible factor-1α expression was increased on the 1st day after the end of stress exposure and was decreased daily thereafter. However, F13A retarded the healing of gastric lesions by preventing the improvement of mucosal blood flow, prostaglandin E₂ production and vascular endothelial growth factor expression in rats exposed to WIRS. Additionally, F13A increased the gastric 4-hydroxynonenol + malondialdehyde content on the 1st and 3rd days after the end of stress induction but did not affect the change in gastric mucosal nitric oxide levels. In conclusion, apelin may be a regulatory protein involved in the healing mechanism of stress-induced gastric damage.     

Effects of simultaneous exposure to stress and nicotine on nicotine-induced locomotor activation in adolescent and adult rats

Preclinical studies have shown that repeated stress experiences can result in an increase in the locomotor response to the subsequent administration of drugs of abuse, a phenomenon that has been termed behavioral cross-sensitization. Behavioral sensitization reflects neuroadaptive processes associated with drug addiction and drug-induced psychosis. Although crosssensitization between stress- and drug-induced locomotor activity has been clearly demonstrated in adult rats, few studies have evaluated this phenomenon in adolescent rats. In the present study, we determined if the simultaneous exposure to stress and nicotine was capable of inducing behavioral sensitization to nicotine in adolescent and adult rats. To this end, adolescent (postnatal day (P) 28-37) and adult (P60-67) rats received nicotine (0.4 mg/kg, sc) or saline (0.9% NaCl, sc) and were immediately subjected to restraint stress for 2 h once a day for 7 days. The control group for stress was undisturbed following nicotine or saline injections. Three days after the last exposure to stress and nicotine, rats were challenged with a single dose of nicotine (0.4 mg/kg, sc) or saline and nicotine-induced locomotion was then recorded for 30 min. In adolescent rats, nicotine caused behavioral sensitization only in animals that were simultaneously exposed to stress, while in adult rats nicotine promoted sensitization independently of stress exposure. These findings demonstrate that adolescent rats are more vulnerable to the effects of stress on behavioral sensitization to nicotine than adult rats.     

Strain, age, but not gender, influence ulcer severity induced by water-restraint stress

Two ulcerogenic procedures, supine restraint (SR) and water restraint (WR) were compared. In Experiment 1, Fischer-344 (F344), Sprague-Dawley (S-D), Wistar, Long-Evans (L-E), Spontaneously Hypertensive rats (SHR) and Wistar Kyoto normotensive (WKY) rats were exposed to SR and WR. WR produced more ulcers than SR. There was no difference in ulcer scores between WKY, F344 and L-E but these rats had significantly more ulcers as compared to SHR, Wistar and S-D rats. In Experiment 2, 4- and 16-month-old SHR, WKY and F344 rats were exposed to SR and WR. The older WKY rats had more ulcers than all other treatment groups. Experiment 3 revealed no significant differences between male and female rats exposed to either SR or WR. Body temperature (BT) scores obtained after restraint and after 2-hr postrestraint rest were only marginally related to ulcer severity. Rats exposed to WR had lower BT scores but the strain and age ulcer differences did not have corresponding BT differences. These studies revealed the following: the ulcer susceptibility of WKY rats; the WR technique is a useful ulcerogenic procedure; and hypothermia is a weak covariant to restraint-induced stress ulcer.     

Repeated stress effects on nociception and on ectonucleotidase activities in spinal cord synaptosomes of female rats

It has been reported that animals submitted to repeated restraint stress present various adaptation responses which are dependent on the sex. These adaptations include changes in nociception and adenine nucleotide hydrolysis. In this study, we report the effect of chronic administration of a gonadal steroid (17beta-estradiol) on ATP, ADP and AMP hydrolysis in spinal cord synaptosomes of adult ovariectomized (OVX) Wistar rats submitted to repeated restraint stress over 40 days. We also measured nociceptive threshold in these animals using the tail-flick test. The results show that tail-flick latencies were decreased in both stressed groups, OVX and OVX rats receiving estradiol replacement therapy, indicating reduced nociceptive threshold after exposure to repeated stress. Repeated restraint stress caused no effect on ATPase or ADPase activities. On the other hand, AMP hydrolysis in spinal cord synaptosomes from repeatedly stressed rats was decreased in OVX rats compared to non-stressed OVX ones, indicating reduced extracellular adenosine production; this effect was reversed by hormonal replacement. These observations suggest that nociceptive sensitivity to noxious stimuli is affected by repeated stress and that modulation of neurotransmission by adenine nucleotides in spinal cord may be altered by the interaction of sexual hormones and psychological factors, such as exposure to stress.     

Influence of Cyclodextrin Complexation with NSAIDs on NSAID/Cold Stress-Induced Gastric Ulceration in Rats

The aim of this work was to study the ability of β-cyclodextrin (β-CD) or hydroxypropyl β-cyclodextrin (HP-β-CD) to ameliorate the induction of gastric ulcers by a nonsteroidal anti-inflammatory drug, indomethacin or piroxicam, in rats exposed to restraint and hypothermic stress at 4 °C. Using oral gavage, rats fasted for 72 h were administered the equivalent of a 100 mg/kg dose of the assigned drug, alone or with the designated cyclodextrin (CD). The rats were placed in suitable rodent restrainers and then placed inside a ventilated refrigerator maintained at a temperature of 4 °C. Six hours later, each animal was removed, anaesthetized with ether, and the abdomen opened. Each stomach was removed, opened along the greater curvature and gently rinsed with isotonic saline solution. The induced gastric ulcers were examined and assessed with the help of a 10x binocular magnifier. Pronounced and marked gastric ulceration with complete loss of the mucosa, extensive deposition of fibrin and dense neutrophilic infiltrate were observed in rats treated with each of the drugs alone. Treatment with indomethacin or piroxicam alone induced ulcer indices of 26 ± 2.3 or 14 ± 1.8, respectively. However, β-CD and HP-β-CD each significantly suppressed ulceration due to restraint and cold stress. Rats treated with indomethacin or piroxicam in the presence of either β-CD or HP-β-CD exhibited normal tissues. Therefore, β-CD and HP-β-CD act as protective agents against gastrointestinal disorders produced by restraint and cold stress, even with the added stress from administration of either indomethacin or piroxicam.     

Protective action of phosphatidylserine on stress-induced behavioral and autonomic changes in aged rats.

Phosphatidylserine (PS) was administered in aged rats subjected to various stressor stimuli in order to evaluate its effect on grooming behavior, core temperature and gastric ulcers. Novelty-induced grooming appeared to be increased in aged rats as compared to young controls. The subchronic intraperitoneal treatment with PS (20 mg/kg/day for 20 days) decreased grooming activity in aged rats, whereas it did not affect that of young animals. Restraint stress induced hyperthermia in both aged and young rats. However, 90 min after the beginning of restraint, PS-treated old rats showed a normalization of core temperature. Furthermore, restraint-plus-cold stress induced gastric ulcers in both aged and young rats. The treatment with PS was followed by a decreased incidence of gastric lesions in aged, but not in young rats. The mechanism of PS protective action against stress-induced behavioral and autonomic changes is unknown, but it may involve the brain level as this drug exerts a noteworthy influence on behavior and autonomic functions.     

Habituation of sympathetic-adrenal medullary responses following exposure to chronic intermittent stress

Two experiments examined sympathetic-adrenal medullary responses of laboratory rats after exposure to a brief period of stressful stimulation daily for 26 consecutive days. In the first experiment, rats were exposed to restraint stress for 30 minutes per day and in the second experiment, rats were exposed to inescapable footshock for 10 minutes per day. For each experiment, handled controls were stressed acutely to provide a basis for comparison with chronically stressed animals. In both experiments, chronically stressed rats gained less weight than controls. Basal plasma levels of norepinephrine (NE) and epinephrine (EPI) were similar in control and chronically stressed rats. However, there was a substantial attenuation of the plasma catecholamine response to the 27th episode of restraint or footshock compared to acutely stressed controls. These findings indicate that sympathetic-adrenal medullary responses are dampened considerably in animals exposed to a highly predictable regimen of chronic intermittent stress.     

Gastric histamine content and gastric ulcer formation in cold/restraint stressed rats: Effects of cinnarizine and flunarizine

The effects of the calcium channel blockers cinnarizine (20 mg/kg p.o.) and flunarizine (10 mg/kg p.o.) on gastric and small intestine histamine content and ulcer formation were determined in cold/restraint stressed rats (4°C for 3 h). The effects of cimetidine (100 mg/kg p.o.) were studied for comparison. After the stress, a significant increase (+27%) in gastric histamine content concomitant with gastric ulceration was observed. Pretreatment with cinnarizine or flunarizine restored histamine to the control value and reduced both the incidence (–22% and –44% respectively) and the severity (-nearly 35%) of gastric ulcers. Neither marked changes in histamine content nor mucosal lesions were detected in the small intestine. The effects of cinnarizine and flunarizine resembled those of cimetidine. The obtained data suggest a possible relation between the decrease in the elevated histamine content in stressed rats and the protection against ulcer formation exerted by cinnarizine and flunarizine.     

中枢神经降压素对大鼠胃应激性溃疡的作用及多巴胺的关系

目的和方法：用双侧中央杏仁核微量注射等方法,观察中枢内神经降压素（ＮＴ）在大鼠束缚加水浸诱发的应激性胃溃疡中的作用及其与多巴胺（ＤＡ）的关系。结果：（１）双侧中央杏仁核内注射微量ＮＴ或ＤＡ可显著减轻水浸加束缚应激所诱发的胃粘膜损伤（Ｐ＜００１）;（２）双侧中央杏仁核内注射微量抗ＮＴ血清,可诱发非应激大鼠出现胃溃疡;（３）双侧中央杏仁核注射ＮＴ前,双侧中央杏仁核注射微量６－羟多巴胺（６－ＯＨＤＡ）或腹腔注射氟哌啶醇（ｈａｌ）均可逆转ＮＴ的胃粘膜保护作用。结论：中央杏仁核内ＮＴ对胃应激性溃疡的细胞保护作用主要是通过调节多巴胺能神经传递实现的。     

Biochemical background of the development of gastric mucosal damage in pylorus-ligated plus aspirin-treated rats

Gastric mucosal damage was produced in rats after pyloric ligation by intragastric administration of 200 mg/kg aspirin diluted in 2 ml 150 mmol/l HCl. The animals in the control group received 2 ml saline solution, or submitted to pyloric ligation only. The animals were killed 4 h after the pyloric ligation, when the number and severity of gastric lesions (ulcers), and the gastric fundic mucosal level of adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), cyclic adenosine monophosphate (cAMP) and lactate, were noted and measured. The adenylate pool (ATP + ADP + AMP) and the energy charge (ATP + 0.5ADP). (ATP + ADP + AMP)-1 were calculated. It was found that: the gastric H+ output decreased significantly in the pylorus-ligated plus aspirin-treated animals; the number and severity of gastric lesions increased significantly in the pylorus-ligated aspirin-treated animals; the extent of ATP transformation into the ADP decreased significantly in the pylorus-ligated aspirin-treated animals; the extent of ATP transformation into the cAMP decreased significantly during the aspirin treatment; the values of adenylate pool and of "energy charge" remained unchanged in the different groups of animals. It is concluded that: the decreased H+ output in the pylorus-ligated plus aspirin-treated group can be obtained by the decreased extent of ATP transformation into the ADP by membrane ATPase, and the biochemical changes in the gastric mucosa indicate a decreased energy turnover.     

Effects of 4-acetylpyridine on stress ulcer formation in mice

4-Acetylpyridine, earlier reported by us to be an anticonvulsant, offers long-lasting protection after a single administration against hypothermic restraint stress-induced gastric ulceration in mice. Electroshock convulsions, marginally but not significantly protective against such ulcers themselves, when coupled with 4-acetylpyridine administration fully prevented gastric ulcers from occurring in this murine model of experimentally induced stress.