Stress-induced Gastric Lesions Research Articles

Epidermal growth factor and prostaglandin E 2 accelerate mucosal recovery from stress-induced gastric lesions via inhibition of apoptosis

The repair of damaged gastric mucosa is a complex process involving prostaglandins (PG) and mucosal growth factors such as epidermal growth factor (EGF). Recently, we postulated that the increased occurence of apoptosis in the gastric epithelium might be of pathophysiological importance in the development of stress lesions. The aim of the present study was to assess the effect of the pretreatment of rats, exposed to 3.5 h of water immersion and restraint stress (WRS), with EGF and PG (16,16 dmPGE 2) on the number of stress lesions, recovery of gastric mucosa from stress and the expression of apoptosis related genes such as caspase-3 and antiapoptotic bcl-2. Rats were divided in following groups: (1) vehicle; (2) EGF 100 μg/kg i.p.; (3) 16,16 dm-PGE 2 (5 μg/kg i.g.) and caspase-1 inhibitor (ICE-I; 100 μg/kg i.p.). One hour later, the rats were exposed to 3.5 h of WRS and then sacrificed immediately (0 h) or at 6, 12, or 24 h after WRS. The number of acute gastric lesions was determined. Gastric epithelial apoptosis was assessed by TUNEL staining. In addition, mRNA expression of caspase-3, Bcl-2 and proinflammatory cytokines (IL-1β, TNFα) was assessed by RT-PCR. PGE 2 generation in gastric mucosa and luminal EGF were determined by RIA. Exposure to WRS resulted in the development of multiple acute stress erosions (∼18) which almost completely healed during 24 h. The gastric blood flow was significantly reduced (∼70% of intact mucosa) immediately after WRS. The expression of mRNA for IL-1β and TNFα reached their peak at 12 h after stress exposure. The apoptosis rate was highest at 6 h after WRS and was accompanied by the highest caspase-3 expression. In rats pretreated with EGF or 16,16 dm-PGE 2, a significant decrease in caspase-3 mRNA and upregulation of bcl-2 mRNA as observed as compared to vehicle controls. Caspase-1 inhibitor significantly reduced the number of stress lesions. We conclude that EGF and PGE 2 accelerate healing of stress-induced lesions due to the attenuation of apoptosis via upregulation of bcl-2 in gastric mucosa. Inhibitors of apoptosis accelerate healing of stress lesions and may be potentially effective agents in the healing of damaged gastric mucosa.

Stress-induced gastric findings in critically ill newborn infants: frequency and risk factors.

To evaluate whether infants treated in neonatal intensive care units have stress-induced bleeding from gastrointestinal tract or gastric lesions and to define risk factors for these findings. Part one: retrospective; part two: prospective. Tampere University Hospital, neonatal intensive care unit. In part one, 100 consecutive newborn infants treated in intensive care were retrospectively evaluated for gastrointestinal tract bleeding and risk factors, and in part two 89 gastroscopied and mechanically ventilated infants were prospectively evaluated for further risk factors for gastric mucosal lesions. The statistical evaluation of risk factors was made by multivariate analysis using logistic regression modeling. Of infants treated in the neonatal intensive care unit 20 % had signs of gastrointestinal bleeding. Mechanical ventilation was the only risk factor (OR = 4.06, 95 % confidence interval 1.21-12.3). In part two, when mechanically ventilated infants were prospectively evaluated, 53 % had remarkable gastric mucosal lesions. The analysis showed three other risk factors: abnormal and delayed delivery and hypotension after birth. Newborn infants treated in the intensive care unit had a high frequency of stress-induced gastric hemorrhage with gastric lesions similar to adults and children treated in intensive care. Mechanical ventilation is the main risk factor. Also mode of delivery and hypotension after birth increase the risk of stress-induced gastric lesions. These infants should be the target for prophylactic gastroprotective treatment.

Formula omitted] -sulpiride, at antidepressant dosage, prevents conditioned-fear stress-induced gastric lesions in rats

It has been previously shown that long-term treatment with low doses of l-sulpiride is highly effective in rat models of depression and of anticipatory anxiety/panic behavior. The present study was aimed at investigating whether the same treatment can prevent the ulcerogenic effect of repeated inescapable stresses. In adult rats, the repeated (7 consecutive days) exposure to an uncontrollable stressful condition (inescapable 2.5 mA scrambled shock for 60 s) produced the development of gastric lesions (multiple punctiform telangiectasias in all rats, with superficial erosions or more severe ulcerations in 10 out 13 rats; score 4.67 ± 0.44). l-sulpiride, intraperitoneally injected once a day at an antidepressant dose level (4 mg kg−1per day), starting 21 days before the beginning of the 7-day sequence of inescapable punishments ( = 28 daily treatments), almost completely prevented the stress-induced gastric injury (score 1.67 ± 0.29;P< 0.001 vs saline-treated rats, Mann–Whitney U test). These results show that, in rats, a long-term treatment with low doses of l-sulpiride prevents the development of gastric lesions induced by chronic exposure to uncontrollable stress.

Changes of serum calcitonin in stress load.

Calcitonin, one of the calcium-regulating hormones, is known to have diverse biological effects including those on the gastrointestinal tract. In this organ, the hormone is reported to inhibit gastric acid secretion, gastric motility, and gastrin secretion and to stimulate release of somatostatin, thereby exerting antiulcer and antilesion effects on stress-induced as well as other types of experimental gastric ulcers or lesions. This fact prompted us to examine changes in serum calcitonin concentration during the development of stress-induced gastric lesions in rats. DA rats were constrained in a stress cage after a 24-h fast and then immersed in 24 degrees C water to the level of the xiphoid process for 2 or 5 h. Serum calcitonin concentrations in stressed rats were significantly lower than those in control rats. To investigate the mechanism of the decline in serum calcitonin level under stress in these rats, we conducted a time-course study of serum calcitonin concentration and ionized calcium level during water-immersion stress, lasting 2 h, and during 4 h following release from the stress. Water immersion caused a remarkable decrease in serum calcitonin concentration as early as at 30 min. After release from stress, serum calcitonin concentration gradually recovered. The ionized calcium level in the blood did not change significantly throughout the experimental period. Furthermore, to examine if the sympathetic nerve system was involved in the stress-induced change of serum calcitonin concentration, alpha- and beta-receptor antagonists were administered intraperitoneally before stress exposure. Administration of alpha-receptor antagonist at a low dose that did not have any effect on serum calcitonin concentration in a preliminary study, restored the decline of serum calcitonin level, whereas beta-receptor antagonist did not. These results suggest that stress-provoked decrease of serum calcitonin concentration may be mediated not by a change of ionized calcium level but by alteration of sympathetic nerve activity (particularly via the alpha-receptor).

Gastroprotective effect from Calophyllum brasiliense Camb. bark on experimental gastric lesions in rats and mice

In order to establish the pharmacological basis for the ethnomedicinal use of stem bark extracts of Calophyllum brasiliense Camb. in gastrointestinal affections, this study examined the effects of a dichloromethane fraction (DCMF), obtained from the hexane extract of bark, on ethanol, indomethacin and hypothermic restraint stress-induced gastric lesions in mice and rats, respectively. Oral administration of DCMF at doses ranging from 12.5–250 mg/kg significantly inhibited the development of gastric lesions in all the three test models. It caused significant decreases of the pyloric-ligation and bethanechol-stimulated gastric secretion, and also the free and total acidities. Besides, DCMF offered protection against ethanol-induced depletion of stomach wall mucus and reduction in nonprotein sulfhydryl concentration. The results indicate that DCMF from C. brasiliense possesses antisecretory, antiulcer and cytoprotective properties.

Modulation of stress-induced gastric mucosal lesions by exogenous L-arginine

L-arginine, a nitric oxide (NO) precursor, can exert both ameriolative and deteriorative effects on gastric mucosal lesions. This study was designed to determine whether exogenous L-arginine modulates stress-induced gastric mucosal lesions through NO production by either constitutive NO synthase (cNOS) or inducible NO synthase (iNOS) in gastric mucosal tissues. In rats subjected to water immersion restraint stress over a 6-hour period, the concentration of gastric mucosal nitrite/nitrate, breakdown products of NO, increased with the development of gastric mucosal lesions and a decrease in cNOS activity and a drastic increase in INOS activity in the gastric mucosal tissue. Preadministration of L-arginine (150 to 600 mg/kg intraperitoneally) attenuated the lesion development with prevention of increases in gastric mucosal nitrite/nitrate concentration and INOS activity. In contrast, postadministration of L-arginine (150 to 600 mg/kg intraperitoneally) enhanced the lesion development with further increase in gastric mucosal nitrite/nitrate concentration. This deteriorative action of postadministration of L-arginine (300 mg/kg intraperitoneally) was prevented by pretreatment with aminoguanidine (100 mg/kg subcutaneously), a selective iNOS inhibitor, with inhibition of increases in gastric mucosal iNOS activity and nitrite/nitrate concentration. These results indicate that preadministered L-arginine protects against water immersion restraint stress-induced gastric mucosal lesions, possibly through restricted NO production by cNOS in gastric mucosal tissues, whereas postadministered L-arginine aggravates the stress-induced gastric mucosal lesions, possibly through excessive NO production by iNOS increasing in gastric mucosal tissues.

PREVENTIVE EFFECT OF TEPRENONE ON STRESS-INDUCED GASTRIC MUCOSAL LESIONS AND ITS RELATION TO GASTRIC MUCOSAL CONSTITUTIVE NITRIC OXIDE SYNTHASE ACTIVITY

Recently, we demonstrated that teprenone, an anti-ulcer agent, exerts protective and preventive actions against water immersion restraint (WIR) stress-induced gastric mucosal lesions in rats both by inhibiting neutrophil infiltration into the gastric mucosal tissue and by preserving gastric mucus synthesis and secretion. In rats with WIR stress we have also found a decrease in gastric mucosal constitutive nitric oxide synthase (cNOS) activity and a drastic increase in gastric mucosal inducible nitric oxide synthase (iNOS) activity. The decrease in gastric mucosal cNOS activity is closely related to an increase in neutrophil infiltration into the gastric mucosa and a decrease in the level of gastric mucus. In this study of WIR-stressed rats, therefore, we examined whether the inhibitory actions of teprenone on neutrophil infiltration and decreases in mucus synthesis and secretion in the gastric mucosa of rats are related to the change in gastric mucosal cNOS activity during the development of gastric mucosal lesions. Pre-administration of teprenone (200 mg kg−1) prevented the decrease in gastric mucosal cNOS activity with attenuations of neutrophil infiltration into gastric mucosal tissues and decreased levels of gastric mucosal hexosamine, an index of gastric mucin, and adherent mucus in rats with 3 or 6 h of WIR stress. These preventive effects of teprenone on the gastric mucosal neutrophil infiltration and the decrease in gastric mucus levels in rats with WIR stress were completely reversed with inhibition of gastric mucosal cNOS activity by co-administration ofNG-monomethyll-arginine (l-NMMA), a non-selective NOS inhibitor. These results suggest that the inhibitory actions of teprenone on neutrophil infiltration and decreases in mucus synthesis and secretion in the gastric mucosa of rats with WIR stress are closely related to the maintenance of cNOS activity in the gastric mucosal tissue.

Stress-Induced Gastric Lesion Formation Is Prevented in Rats With Daunomycin-Induced Nephrosis

In the present study, we investigated the susceptibility to restraint plus water-immersion stress (RWIS) in rats with daunomycin-induced nephrosis in comparison to that in normal rats. The severity of RWIS-induced gastric lesions was significantly less in nephrotic rats on the 20th and 40th days after a single i.v. injection of daunomycin (12mg/kg) than in the respective control rats. Acid secretion in pylorus-ligated rats significantly decreased under the 3-h stress. On the 20th day after treatment with daunomycin, acid secretion was significantly less in nephrotic rats than in control rats under both stress and unstressed conditions. Pretreatment of normal rats with methylene blue, a guanylate cyclase inhibitor, or phenylephrine, a vasoconstrictor, significantly prevented the stress-induced gastric lesions and decreased acid secretion. Nω-Nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor, prevented the stress-induced gastric lesion formation only. These results indicate that nephrotic rats are more resistant to RWIS-induced gastric lesions than normal rats. In addition, these results suggest that the decrease in acid secretion related to the decrease in the release of NO from endothelial cells may contribute, at least in part, to the prevention of the stress-induced gastric lesion formation in nephrotic rats.

Stress-induced gastric lesion formation is prevented in rats with daunomycin-induced nephrosis.

In the present study, we investigated the susceptibility to restraint plus water-immersion stress (RWIS) in rats with daunomycin-induced nephrosis in comparison to that in normal rats. The severity of RWIS-induced gastric lesions was significantly less in nephrotic rats on the 20th and 40th days after a single i.v. injection of daunomycin (12 mg/kg) than in the respective control rats. Acid secretion in pylorus-ligated rats significantly decreased under the 3-h stress. On the 20th day after treatment with daunomycin, acid secretion was significantly less in nephrotic rats than in control rats under both stress and unstressed conditions. Pretreatment of normal rats with methylene blue, a guanylate cyclase inhibitor, or phenylephrine, a vasoconstrictor, significantly prevented the stress-induced gastric lesions and decreased acid secretion. N(omega)-Nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor, prevented the stress-induced gastric lesion formation only. These results indicate that nephrotic rats are more resistant to RWIS-induced gastric lesions than normal rats. In addition, these results suggest that the decrease in acid secretion related to the decrease in the release of NO from endothelial cells may contribute, at least in part, to the prevention of the stress-induced gastric lesion formation in nephrotic rats.

P–336 - Effects of three gastric mucosal defensive drugs on ethanol-induced and water immersion stress-induced gastric mucosal lesions in rats.

P–336 - Effects of three gastric mucosal defensive drugs on ethanol-induced and water immersion stress-induced gastric mucosal lesions in rats.

Base variant of human pancreatic secretory trypsin inhibitor in healing of stress-induced gastric lesions in rats

Pancreatic secretory trypsin inhibitor (PSTI) is an inhibitor of serine-proteinases including pancreatic trypsin that prevents excessive digestion of the gastrointestinal mucus, but its role in the mechanism of mucosal defense has been little studied. This study was designed to determine the effect of base variant of human PSTI (R44S-PSTI) on gastric secretion, healing of gastric lesions induced by stress and the expression of PSTI during mucosal recovery from stress lesions. Recombinant R44S-PSTI was obtained using by site-directed mutagenesis due to replacement of arginine by serine that led to longer half life of this peptide than its natural form. Stress ulcerations were induced by exposure of rats to a standard 3.5 h of water immersion and restraint stress with or without pretreatment with vehicle or R44S-PSTI (0.1 mg/kg) applied s.c. 30 min before and immediately after the end of stress. Rats were then sacrificed immediately (time 0) and at 6 h or 12 h after the termination of stress. The gastric blood flow (GBF) was measured by H 2-gas clearance technique at each time period and gastric mucosal samples were excised for assessment of PSTI immunohistochemical expression and PSTI messenger RNA by reverse transcriptase polymerase chain reaction (RT-PCR) and Southern hybridization. Stress produced numerous gastric lesions and decreased the GBF by about 30% as compared to the respective value in vehicle-treated non-stressed gastric mucosa. R44S-PSTI given s.c. in graded doses (0.01–1 mg/kg) inhibited dose-dependently gastric acid and pepsin outputs, in rats with gastric fistula and accelerated the healing of stress-induced gastric lesions significantly. The healing effects of R44S-PSTI (0.1 mg/kg s.c.) recorded at 6 h and 12 h after the end of stress were accompanied by a significant rise in the GBF. The expression of PSTI mRNA in the intact mucosa was weak, but following exposure to stress it was significantly augmented to reach the highest observed value at 6 h after the stress. We conclude that (1) base variant of human PSTI accelerates healing of stress-induced gastric lesions probably due to its antisecretory activity and enhancement of mucosal blood flow and (2) the expression of genes for PSTI plays an important role in the mechanism of mucosal recovery from gastric lesions induced by stress.

Relation of Inducible Nitric Oxide Synthase Activity to Lipid Peroxidation and Nonprotein Sulfhydryl Oxidation in the Development of Stress-Induced Gastric Mucosal Lesions in Rats

We have reported that increases in lipid peroxide (LPO) formation, nonprotein sulfhydryl (NP-SH) oxidation, and inducible NO synthase (iNOS) activity and a decrease in constitutive NO synthase (cNOS) activity in the gastric mucosa of rats with water immersion restraint (WIR) stress are closely related to gastric mucosal lesion development. Peroxynitrite, which is produced by the reaction of nitric oxide (NO) with superoxide anion, can initiate intracellular LPO formation and NP-SH oxidation, resulting in producing an extreme cellular membrane damage. In this study, the relation of changes in cNOS and iNOS activities to LPO formation and NP-SH oxidation was examined in the gastric mucosa of rats with WIR stress. An increase in iNOS activity, but not a decrease in cNOS activity, correlated well with an increase in LPO concentration (r= 0.750) and NP-SH concentration (r= −0.808) in the gastric mucosa of rats with WIR stress. In addition, the above-mentioned changes in iNOS activity and LPO and NP-SH concentrations with lesion development in the gastric mucosa of rats with WIR stress were attenuated with both prevention of the lesion development and an increase in the concentration of gastric mucosal nitrite/nitrate, the breakdown products of NO, by pretreatment with aminoguanidine, a selective iNOS inhibitor. These results suggest that in the gastric mucosa of WIR-stressed rats, NO produced by increased iNOS could contribute to enhanced LPO formation and NP-SH oxidation, resulting in lesion development.

Protective and preventive effects of teprenone on gastric mucosal lesions in rats

We have reported that neutrophil infiltration into gastric mucosa is closely related to gastric mucosal lesion development in rats with water immersion restraint stress. In this study, we examined the effect of teprenone, which is known to prevent gastric mucosal injury through stimulation of gastric mucus synthesis and secretion, on neutrophil infiltration into the gastric mucosa of rats with water immersion restraint stress. Pre- and post-administration of teprenone (200 mg/kg, p.o.) significantly attenuated the neutrophil infiltration into the gastric mucosa and the lesion development found at 6 h of water immersion restraint stress with preservation of gastric mucosal hexosamine and adherent mucus levels. These results indicate that teprenone exerts protective and preventive actions against water immersion restraint stress-induced gastric mucosal lesions in rats and suggest that these actions could be related to the preservation of gastric mucus synthesis and secretion and inhibition of neutrophil infiltration into the gastric mucosal tissue.

Oral anti-inflammatory and anti-ulcerogenic activities of a hydroalcoholic extract and partitioned fractions of Turnera ulmifolia (Turneraceae)

Anti-inflammatory studies were conducted on rats or mice using a crude hydroalcoholic extract of the aerial parts of Turnera ulmifolia and it's partitioned fractions, i.e. the aqueous, ethyl acetate and ethanolic fractions. The hydroalcoholic extract and it's fractions (aqueous and ethanolic) inhibited carrageenan-induced edema. However, only the ethanolic fraction was used in the other experiments due to it's yield. The extract also inhibited the cotton pellet granuloma and the increase of vascular permeability induced by histamine, 5-hydroxytryptamine and prostaglandin E 2, but not that produced by bradykinin. The extract or the fraction did not present analgesic activity in the writhing test using acetic acid and did not reduce croton oil-induced ear edema in mice. When the ethanolic fraction and LPS were administered i.p. to Balb/C mice 72 h before blood or peritoneal fluid collection, no changes were observed in the white or total blood cell counts in the peripheral blood. On the other hand, changes were observed in both total and differential cell counts in the peritoneal exudate since all doses of the fraction reduced the number of total leukocytes (mainly lymphocytes) obtained from the peritoneal exudate. In contrast to nonsteroidal anti-inflammatory drugs, the administration of the hydroalcoholic extract or the ethanolic fraction alone did not potentiate gastric mucosal lesions induced by aspirin. The extract and the fraction inhibited the appearance of gastric lesions induced by indomethacin, ethanol and pylorus ligature, but not those induced by stress. As also observed with carbenoxolone, the ethanolic fraction increased the wall mucus in hypothermical-restraint stress-induced gastric lesions. The anti-ulcerogenic effect of the extract and of the ethanolic fraction may be related to an increase of mucosal defensive factors, such as prostaglandin and mucus. The anti-inflammatory actions of the extract and the fraction may be due to an inhibitory effect on histamine and cyclooxygenase II, but not on cyclooxygenase I, because the extract and it's fraction present both anti-inflammatory and anti-ulcerogenic effects. The major substances present in the ethanolic fraction are flavonoids which will be isolated and identified.

Involvement of ornithine decarboxylase and polyamines in epidermal growth factor-induced recovery of gastric mucosa from gastric lesions provoked by stress

Polyamines such as spermine or putrescine, resulting from increased activity of ornithine decarboxylase (ODC), are known for gastroprotective and mucosal growth promoting effects but little information is available about their role in the acceleration of the healing of stress-induced gastric lesions by epidermal growth factor (EGF). In this study, rats with intact or suppressed ODC activity by α-difluoromethylornithine (DFMO, 400 mg/kg i.p.) were subjected to 3.5 h of water immersion and restraint stress (WRS) without or with intragastric (i.g.) administration of spermine and putrescine or with subcutaneous (s.c.) injection of EGF. At 0, 2, 6, 12 and 24 h after stress, rats were killed and the number of gastric lesions was counted, gastric blood flow (GBF) was recorded by the H 2-gas clearance technique, the gene expression of ODC mRNA using reverse-transcriptase polymerase chain reaction (RT-PCR) and the ODC activity in this mucosa were determined in oxyntic mucosa. Stress produced gastric lesions combined with decreased GBF (by ∼43%), but at 2, 6, 12 and 24 h after stress, these lesions and the fall in GBF were gradually attenuated. Healing of stress lesions was accompanied by strong stimulation of ODC mRNA expression and by an immediate increase in enzyme activity, with a peak occurring about 6 h after stress. Pretreatment with DFMO or salivectomy (which resulted in a marked fall in luminal EGF levels and mucosal DNA synthesis) delayed significantly the healing of stress lesions. EGF or spermine significantly accelerated the ulcer healing and raised the GBF. Suppression of endogenous generation of prostaglandins (PGs) with indomethacin (5 mg/kg i.p.) almost completely reversed the EGF- and spermine-induced acceleration of the healing of stress lesions and the accompanying rise in GBF. DFMO significantly reduced the enhancement in healing and the rise in the GBF induced by EGF, but failed to influence those induced by exogenous spermine. The acceleration of the healing induced by spermine or EGF and accompanying hyperemia were not affected by salivectomy. We conclude that (1) upregulation of the ODC transcript, increased ODC activity and polyamines play an important role in mucosal recovery from stress lesions due to acceleration of mucosal repair and an increase in gastric microcirculation, (2) increased ODC activity and resulting excessive polyamine release appear to act as primary mediators of EGF-induced acceleration of healing of stress lesions and (3) endogenous PGs cooperate with EGF and polyamines in mucosal repair from stress ulcerations.

Antiinflammatory drugs: COX 2 selective and stress-induced gastric lesions

Antiinflammatory drugs: COX 2 selective and stress-induced gastric lesions

Polyamines and growth factors in the recovery of gastric mucosa from stress-induced gastric lesions

Polyamines and growth factors in the recovery of gastric mucosa from stress-induced gastric lesions

Implication of aging on nitric oxide synthase activity in the genesis of water immersion stress-induced gastric lesions in rats

Implication of aging on nitric oxide synthase activity in the genesis of water immersion stress-induced gastric lesions in rats

Polyamines and epidermal growth factor in the recovery of gastric mucosa from stress-induced gastric lesions.

Polyamines such as spermine or putrescine, resulting from increased activity of ornithine decarboxylase (ODC), are known for gastroprotective and mucosal growth-promoting effects. EGF exhibits similar effects, but little is known about the involvement of polyamines in acceleration of the healing of stress-induced gastric lesions by epidermal growth factor (EGF). In this study, rats with intact or suppressed ODC activity by alpha-difluoromethy-ornithine (DFMO, 400 mg/kg i.p.) were subjected to 3.5 h of water immersion and restraint stress (WRS) without or with addition of spermine or EGF. At 0, 2, 6, 12, or 24 h after stress, rats were sacrificed. The number of gastric lesions was determined and gastric blood flow (GBF) was recorded by the H2 gas clearance technique. Stress produced gastric lesions (mean number 18+/-2 per stomach) and decreased GBF (by approximately 43%), but at 2, 6, 12, and 24 h after stress, these lesions and the decrease in GBF were gradually attenuated. Pretreatment with DFMO or removal of an endogenous source of EGF by salivectomy resulted in a marked decrease in mucosal DNA synthesis and significantly delayed the healing of stress lesions. EGF or spermine significantly accelerated ulcer healing and increased the GBF in rats with intact or removed salivary glands. DFMO significantly reduced the enhancement of healing and the increase in GBF induced by EGF, but failed to influence those induced by exogenous spermine. We conclude that polyamines play an important role in mucosal recovery from stress lesions due to acceleration of mucosal repair and increase in gastric microcirculation and that increased ODC activity and resulting excessive polyamine release appear to act as primary mediators of EGF-induced acceleration of the healing of stress lesions.

Protective role of melatonin and the pineal gland in modulating water immersion restraint stress ulcer in rats.

We investigated the protective effect of melatonin on stress-induced gastric lesions in rats. Fasted rats were subjected to water immersion restraint stress for 4 h and the percentage of corpus mucosa containing hemorrhagic lesions was determined. Thirty minutes before restraint stress, melatonin or vehicle was administered i.p. In another experiment, pinealectomy was performed 1 week before water immersion restraint stress. Administration of melatonin at 1 and 5 mg/kg significantly decreased gastric lesions by 46 and 74%, respectively. In contrast, pinealectomy significantly enlarged the lesion area, although this effect was counteracted by melatonin at a dose of 1 mg/kg i.p. However, this protective effect of melatonin was abolished by i.p. pretreatment with indomethacin at 5 mg/kg. These results suggest that melatonin has gastroprotective properties against stress-induced gastric injury in rats and that the pineal gland contributes to gastric protection via prostaglandin-dependent mechanisms.