Stress-induced Gastric Erosions Research Articles

Glucocorticoids are gastroprotective under physiologic conditions

Stress may contribute to the development and progression of gastrointestinal disorders. Activation of the hypothalamic-pituitary-adrenocortical (HPA) axis is one of the main characteristics of stress. For several decades it was generally accepted that glucocorticoids released during stress are ulcerogenic hormones. We designed some experimental studies in rats to clarify the validity of this widely held view. To achieve this goal, we examined the effect of glucocorticoid deficiency followed by corticosterone replacement or the glucocorticoid receptor antagonist, RU-38486, on stress-induced gastric erosion and the parameters of gastric function in rats. The data obtained shows that the reduction in the stress-induced corticosterone release, or its actions, aggravates stress-caused gastric erosion. It is suggested that an acute increase in corticosterone during stress protects the stomach against stress-induced injury. According to our results, various ulcerogenic stimuli, similar to stress, induce an increase in corticosterone that helps the gastric mucosa to resist against a harmful action of ulcerogenic stimuli. Glucocorticoids exhibit their gastroprotective effect by both maintaining local defensive factors and inhibiting pathogenic elements. Furthermore, the contribution of glucocorticoids to gastroprotection is tightly related to their contribution to general body homeostasis. Glucocorticoids provide gastroprotective actions in co-operation with prosta-glandins, nitric oxide and capsaicin-sensitive sensory neurons. The results obtained do not support the traditional paradigm and suggest that glucocorticoids released during acute activation of the HPA axis are naturally occurring gastroprotective factors. In this article, we review our recent publications on the role of glucocorticoids in gastroprotection.

Aggravation of nonsteroidal antiinflammatory drug gastropathy by glucocorticoid deficiency or blockade of glucocorticoid receptors in rats

Our previous investigations suggest that the reduction of stress-induced corticosterone release, or inhibition of corticosterone actions, promotes stress-induced gastric erosions in rats. In this study the effect of glucocorticoid deficiency on susceptibility to gastric mucosal injury by nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated in rats. Gastric erosions induced in male rats by indomethacin (25 mg/kg sc) or acidified aspirin (40 mM po) were studied one week after adrenalectomy with or without corticosterone replacement or after occupation of glucocorticoid receptors by the antagonist RU-38486 during the period of erosion formation. Corticosterone for replacement (4 mg/kg sc) was injected 15 min before the administration of indomethacin or acidified aspirin to adrenalectomized rats. The antagonist RU-38486 (10 mg/kg po) was administered twice, 20 min before and 60 min after NSAID administration. Plasma corticosterone levels were measured by fluorometry. Gastric erosions were quantitated by measuring the area of damage. Indomethacin or acidified aspirin induced both plasma corticosterone rise and gastric erosions. Adrenalectomy decreased both basal and NSAID-induced corticosterone levels and markedly promoted gastric erosion formation caused by the NSAID. An acute corticosterone replacement mimicking indomethacin-and aspirin-induced corticosterone rise prevented the effect of adrenalectomy on the gastric erosions. The administration of the glucocorticoid/progesterone antagonist RU-38486 significantly potentiated the formation of gastric erosions induced by indomethacin as well as aspirin. These observations suggest a gastroprotective action of glucocorticoids released in response to NSAID treatment against NSAID-induced injury.

Factor XIII Improves Gastric Stress Lesions in Rats

Background/Aims: Tissue transglutaminase has been reported to be involved in the healing of experimental gastric ulcer; nevertheless, other type(s) of transglutaminase could be involved. The present experiments aimed at examining whether plasma transglutaminase (factor XIIIa) contributes to such healing and at evaluating whether factor XIII supplementation improves gastric mucosal lesions. Methods: The healing effect of 200 U/kg of factor XIII administered intravenously was examined using a water immersion restraint rat model of stress gastric damage. The rats were sacrified 0, 2, 4, and 12 h after stress. The gastric mucosa was examined macroscopically and microscopically, and the transglutaminase activities were assayed in serum and gastric mucosa. Factor XIIIa and tissue transglutaminase protein levels in the gastric mucosa were analyzed by immunoblot. Immunohistochemistry was used to identify the location of tissue transglutaminase, factor XIIIa, and fibronectin in the gastric mucosa. Results: The transglutaminase activity, reduced by stress in the gastric mucosa, increased up to 12 h after stress, peaking at 4 h, when the ulcer index significantly decreased. The serum transglutaminase level was low at all time points. Exogenous administration of factor XIII allowed a faster reduction of the ulcer index that was coincident with an increased transglutaminase activity in the mucosa. Both tissue transglutaminase and factor XIIIa protein levels were reduced by 6 h of stress and increased after factor XIII administration. Immunohistochemistry showed a colocalization of both factor XIIIa and tissue transglutaminase with fibronectin in the extracellular matrix of the damaged area. Conclusions: Two forms of transglutaminase are involved in the healing of stress-induced gastric erosions, and factor XIII administration allows faster gastric mucosa healing.

Effect of acute verapamil treatment on cold restraint-induced gastric lesions in rats with lesioned nucleus basalis magnocellularis

Our recent studies suggested that there were no differences in the number and type of cold restraint-induced gastric lesions (petechiae and erosions) between control and nucleus basalis magnocellularis (NBM)-lesioned rats. Having in mind that calcium antagonists can prevent the development of gastric stress ulcer in control rats, the aim of the present study was directed to compare the effect of verapamil in the prevention of cold restraint-induced gastric lesions in control and NBM-lesioned rats. Therefore, 30 min before the stress, control (intact control and sham-operated) rats as well as rats with bilateral electrolytic lesions of NBM were treated with saline (1 ml/kg s.c.) or verapamil (1.0, 2.5, 5.0 and 10.0 mg/kg s.c.) and exposed to cold restraint for 2 hr. Verapamil, in doses of 5.0 and 10.0 mg/kg, significantly decreased the number and length of gastric erosions (p < 0.05) in control rats, while in NBM-lesioned rats, the same doses of verapamil significantly decreased the number of gastric petechiae (p < 0.01). Since the antiulcer treatment with verapamil express different effects in the prevention of the two types of gastric lesions in control and NBM-lesioned rats, it can be concluded that in NBM-lesioned rats there may exist an alteration of the mechanisms involved in stress-induced gastric petechiae and erosions.

Effect of Saiboku-to, an Oriental Herbal Medicine, on gastric lesion induced by restraint water-immersion stress or by ethanol treatment.

The effect of saiboku-to on gastric lesions induced by restraint water-immersion stress and ethanol has been examined in rats. Thirty minutes after oral administration of saiboku-to, the rats were placed in restraint cages and immersed in water at 23 degrees C for 7 h, or orally administered 99.5% ethanol (1 mL) and placed in normal cages for 1 h. The stress for 7 h or the ethanol treatment for 1h induced erosion in the glandular area of the stomach. Histology showed that the surface epithelial cells were desquamated and part of the lamina propria mucosae was injured. The evaluation of lesion index, the cumulative length of the gastric lesion, on the gross appearance of the stomach, revealed that saiboku-to dose-dependently inhibited both the water-immersion stress-induced gastric erosion and ethanol-induced gastric erosion. To determine whether the anti-erosion effect of saiboku-to was because of a mild irritant effect, saiboku-to or 20% ethanol, which is known as a typical mild irritant, were given orally. After 30 min a strong irritant, 99.5% ethanol, was given orally. Histological examination was performed 30 min after administration of saiboku-to or the mild irritant, and 1 h after administration of the strong irritant. The mild irritant induced a reduction in surface epithelial cells 30 min after administration. Furthermore, the mild irritant protected the stomach against mucosal erosion produced by the strong irritant. Saiboku-to protected the strong irritant-induced erosion without producing mild irritation as observed in stomach treated with 20% ethanol. Pretreatment with saiboku-to also inhibited the decrease in the levels of hexosamine, gastric mucus glycoprotein, induced by the strong irritant. In pylorus-ligated rats, saiboku-to dose-dependently inhibited gastric acid secretion, a gastric aggressive factor. These results suggest that the anti-erosion effect of saiboku-to which is not a mild irritant, involves both inhibition of aggressive factors, such as gastric acid secretion, and augmentation of defensive factors, such as gastric mucus cells.

Corticosterone increase inhibits stress-induced gastric erosions in rats.

The role of glucocorticoids released in response to stress in the pathogenesis of stress-induced gastric erosions has been reevaluated. Gastric erosions elicited in male rats by 3-h cold-restraint or water-restraint stresses were studied after acute reduction of corticosterone release or occupation of glucocorticoid receptors by the antagonist RU-38486 during stress. Stress-induced corticosterone production was reduced by creating a lesion on the hypothalamic paraventricular nucleus (PVN) 4 days before stress as well as by pretreatment with a rabbit antiserum to adrenocorticotropin (ACTH) 30 min before stress. RU-38486 (10 mg/kg po) was administered 20 min before and 60 min after the onset of stress. Corticosterone for replacement was injected 15 min before the onset of stress to mimic stress-induced corticosterone response. Plasma corticosterone levels were measured by fluorometry or RIA. Gastric erosions were quantitated by measuring the area of damage. Four days after PVN lesion, stress-induced corticosterone release was decreased and gastric erosions were increased. Injecting corticosterone significantly attenuated the effect of PVN lesion on gastric erosions. The ACTH antiserum inhibited corticosteroid secretion in response to stress and markedly increased gastric erosions. The administration of the glucocorticoid/progesterone antagonist RU-38486 significantly potentiated the formation of stress-induced gastric erosions. These observations support the suggestion that glucocorticoids released during stress have a gastroprotective action rather than an ulcerogenic effect as was generally accepted.

The effects of control on stress-induced gastric erosions: The use of active shuttle-box avoidance learning with yoked controls

The aim of the present study was to investigate effects of instrumental control on the development of stress-induced gastric erosions by using a shuttle-box paradigm with yoked controls. In Experiment 1 the learning conditions had a reinforcement ratio of only 70% to increase stress during the short-term learning session. No significant differences of the mean cumulative length of gastric erosions between active avoiding and yoked groups were found. Experiment 2 tested three different reinforcement conditions (70%, 90%, 100%) with yoked groups. Again, no significant differences of the mean cumulative length of erosions between active avoiding and yoked control groups were obtained. Instead, the length of erosions decreased with increasing reinforcement. Taken together, the data show that the frequency of unavoided noxious stimuli as a function of the reinforcement schedule can be seen as a major influence on the development of gastric erosions in a shuttle-box paradigm.

Glutathione, protein sulfhydryls and cysteine proteases in gastric mucosal injury and protection

Glutathione is one of the endogenous protective chemicals, like prostaglandins, in the gastric mucosa. Depletion of these agents aggravate the chemical- or stressinduced gastric erosions and ulcers. However, gastroprotection can be achieved even in the presence of low mucosal concentration of glutathione and prostaglandins, indicating the presence of other protective chemicals (e.g. polyamines, growth factors, neurotransmitters, steroids) in the stomach. Protein sulfhydryls were also implicated in the mechanism of action of gastroprotective drugs. We recently tested the hypothesis that cysteine proteases might be a target of gastroprotective and antiulcer agents, and decided to look for the presence of proteases and protease inhibitors (PI) in the gastric mucosa and juice. Protease activity and PI were measured with general substrates hemoglobin, azocasein and albumin at optimal pH (2.0, 5.6, 7.4) of aspartic, cysteine and serine proteases. Homogenates of glandular stomach mucosa and gastric juice from fasted rats were incubated in the presence or absence of specific inhibitors and gastroprotective SH alkylators such as NEM or iodoacetate. PI was measured after acid and heat inactivation of endogenous proteinases and addition of pepsin, cysteine proteinase papain, or trypsin. Our results indicate that of the proteases found in the stomach 98% was pepsin at pH 2.0, and up to 56% or 24% was SH-sensitive at pH 5.6 or 7.4, respectively. Intragastric administration of SH alkylators such as NEM or iodoacetate exerted a dose- and time-dependent gastroprotection against chemically induced acute erosions and ulcers. Thus, in addition to glutathione, proteinases and their specific endogenous inhibitors may also be involved in gastric mucosal injury and protection.

Interleukin-1 inhibits stress-induced gastric erosion in rats

The effect of interleukin (IL)-1 on the occurence of stress-induced gastric erosions was examined in rats. The intracerebroventricular (icv) administration of IL-1β significantly inhibited the occurence of water-immersion restraint stress-induced gastric erosion at doses of 200 ng, 500 ng and 1 μg, whereas the intravenous (iv) administration of IL-1β altered the occurence of gastric erosion only at a dose of 1 μg. The inhibitory effect of IL-1α icv administered on the occurence of gastric erosion was found only at a dose of 1 μg. The inhibitory effect of IL-1β icv administered on the occurence of stress-induced gastric erosion was not influenced by icv administration of α-helical CRF(9–41), a corticotropin-releasing factor (CRF) receptor antagonist. Indomethacin completely blocked the inhibitory action of IL-1β icv administered on stress-induced gastric erosion. It is concluded from these results that IL-1 acts mainly in the central nervous system to inhibit the occurence of stress-induced gastric erosion and that the IL-1β-induced inhibition of gastric erosion is mediated by prostaglandin in a manner that is independent of brain CRF.

Brain corticotropin-releasing factor acts as inhibitor of stress-induced gastric erosion in rats

Gastric lesions are known to be caused by stress. Corticotropin-releasing factor (CRF) is a key peptide initiating various stress response. This study was designed to investigate how brain CRF is involved in the occurence of stress-induced gastric erosion in rats. Intracerebroventricular (icv) administration of CRF suppressed the occurrence of gastric erosion induced by water-immersion restraint stress, and its suppressive effect was blocked by coadministration of a CRF receptor antagonist in rats. The peripheral administration of CRF had no influence on the occurrence of erosion. The icv administration of a CRF receptor antagonist or anti-rat CRF γ-globulin increased gastric erosion induced by the stress. Ganglionic blockade with chlorisondamine, muscarinic blockade with atropine, or bilateral adrenalectomy by itself significantly inhibited the occurrence of stress-induced gastric erosion, and no additional effect of CRF on these treatments-induced inhibition of erosion was found. These results, therefore, suggest that the occurrence of stress-induced gastric erosion is mediated by the autonomic nervous system- and adrenal-dependent pathway, and that brain CRF reduces the occurrence of stress-induced gastric lesions by acting on its specific receptor within the central nervous system, probably through the autonomic nervous system- and adrenal-dependent mechanism.

Antiulcer activity of the calcium antagonist propyl-methylenedioxyindene. IV. Effects on gastric lesions in rats induced by cold-restraint stress and thyrotropin-releasing hormone

Propyl-methylenedioxyindene (pr-MDI; 30 mg/kg, i.p.), an intracellular calcium antagonist, significantly reduced the number and size of erosions per stomach induced by cold-restraint stress by 69% and 86%, respectively. Our previous findings indicate that the antiulcer activity of pr-MDI is highly correlated with its inhibitory effect on gastric motor activity. Since central TRH is suggested as the brain mediator responsible for cold-restraint stress gastric ulcers in rats, the inhibitory action of pr-MDI was evaluated in the TRH-induced gastric lesion model. Pr-MDI (30 mg/kg) did not reduce the gastric erosions induced by intracisternal administration of 100ng RX77368, a stable thyrotropin-releasing hormone (TRH) analogue, even though it abolished the RX77368-induced stimulation of gastric emptying, gastric acidity, and acid output. Since pr-MDI (30 mg/kg, i.p.) significantly inhibited the stimulation of gastric motility by both cold-restraint stress and TRH, but only cold-restraint stress-induced gastric erosions were effectively reduced by the drug, the present findings suggest a possible dissociation between the ulcerogenic mechanisms of cold-restraint stress and intracisternal administration of TRH.

Intracerebroventricular neuropeptide Y protects against stress-induced gastric erosion in the rat

The effects of intracerebroventricular administration of neuropeptide Y (NPY) on stress-induced gastric erosion in the rat were investigated. Animals were exposed to water immersion stress after a single injection of 2 nmol NPY. Stress-induced erosion was reduced by approximately 50%. The plasma corticosterone levels were not affected. We interpret the protective effect of NPY as a manifestation of its sedative properties.

Efficacy of enteral diets in the prevention of stress-induced gastric erosions in rats.

This study compares the prophylactic effects of two different diets and routes of feeding on restraint stress-induced gastric erosions in the rat. Thirty male Sprague-Dawley rats were food-deprived and immobilized for 24 hours using a steel wire mesh. A small silicone tube was placed into either the proximal jejunum or the stomach via a laparotomy. There were three groups of ten rats (five jejunum-fed, five stomach-fed), receiving infusions (50 ml/24 h) of: (A) normal saline; (B) free amino acids (Vivonex HN, Norwich Eaton Pharmaceuticals) (60 cal and 0.318 G nitrogen); or (C) a peptide diet, with the nitrogen source as lactalbumin hydrolysate, otherwise identical to B. Gastric acidity was measured every 4 hours. At 24 hours, blood was collected and serum gastrin levels determined. The animals were then sacrificed and the stomachs examined. The results were analyzed using one-way analysis of variance. Fewer gastric erosions and lower serum gastrin levels and gastric acidity were found in animals fed diets B and C, versus animals fed normal saline (p less than 0.05). There was no difference between groups B and C. Our results also show that enteral diets using the jejunal route are better than those using the gastric route in reducing the incidence of stress-induced gastric erosions in rats.

P.7 Efficacy of enteral diets in the prevention of stress-induced gastric erosions in rats

P.7 Efficacy of enteral diets in the prevention of stress-induced gastric erosions in rats

A Benzodiazepine—Anticholinergic Drug Synergism in the Prevention of Stress‐Induced Gastric Mucosal Erosion in Mice

Chlordiazepoxide and clidinium each, as a function of dose, prevent stress-induced gastric mucosal erosion in mice. Clidinium was 2.5 times more potent than chlordiazepoxide. When used in a combination of 2 parts chlordiazepoxide and 1 part clidinium, the protective effect was nearly five times greater than that produced by clidinium alone. Furthermore, the combination dosing proved nearly three times more potent than the potency that was predicted from simple additivity of the individual drug effects. This potentiation appears related to the number of ways in which the combination treatment can decrease autonomic input to the gastric mucosa. Thus, the peripheral cholinergic blockade by clidinium may be potentiated by a central chlordiazepoxide suppression of both sympathetic and parasympathetic activities. Therefore, the combined use of these drugs in the therapy of stress-induced gastric disorder appears to have a rational pharmacologic basis.

Pharmacological studies on the root bark of Paeonia moutan. II. Anti-inflammatory effect, preventive effect on stress-induced gastric erosion, inhibitory effect on gastric juice secretion and other effects of paeonol

牡丹皮についてその主成分であるペオノールと, 本成分を除いた牡丹皮エキスの末梢薬理作用を比較検討した.テスト項目は抗炎症作用, ストレス胃エロジオンと胃液分泌に対する抑制作用, 血圧呼吸, 摘出臓器, 生体位子宮におよぼす諸作用である.そしてこれらの薬理効果と牡丹皮の治療効果との関係につき若干考察した.

Nucleic acid metabolism in the gastrointestinal tract of the mouse during fasting and restraint-stress

The uptake of thymidine-methyl- 3H and uridine-5- 3H into DNA and RNA of gastrointestinal tissues of mice has been measured after 16 and 40 hours of fasting and restraint. Fasting had little effect on DNA or RNA metabolism in the gastrointestinal tract except for increases in the uptake of uridine in the small intestine. These increases are thought to represent changes in uridine pool size. Restraint caused a reduction in DNA synthesis along the entire gastrointestinal tract and affected RNA metabolism in the stomach but not in the small intestine or colon. The changes in the stomach included early loss of total RNA followed by a decrease in the uptake of uridine-5- 3H. The latter appeared to coincide wit the occurrence of gastric erosions. The importance of RNA metabolism in mucus production and in the maintenance of the mucosal cell population has been discussed in relation to the development of stress-induced gastric erosions.