Mucosal Generation Of Prostaglandins Research Articles

Role of melatonin in mucosal gastroprotection against aspirin‐induced gastric lesions in humans

Melatonin and its precursor, l-tryptophan, have been shown to exert gastroprotective effects in animals, but their influence on the gastric damage by aspirin (ASA) in humans has been sparingly investigated. In this study, we designed to determine the effects of melatonin and l-tryptophan on ASA-induced gastric mucosal damage, gastric microbleeding, mucosal generation of prostaglandin E(2), and plasma melatonin, and gastrin levels. Three groups of healthy male volunteers (n = 30) with intact gastric mucosa received daily for 11 days either ASA alone or that combined with melatonin or tryptophan. Gastric blood loss and mucosal damage were evaluated at 3rd, 7th, and 11th days of ASA administration by endoscopy using Lanza score. ASA alone caused a marked rise of gastric damage and gastric blood loss, mainly at day 3rd and 7th, but they were significantly reduced at 11th day. Pretreatment with melatonin or tryptophan remarkably reduced ASA induced gastric lesions and microbleeding. Gastric mucosal generation of PGE(2) was suppressed by about 90% in all subjects treated with ASA alone without or with addition of melatonin or tryptophan. Plasma melatonin was markedly increased after treatment with melatonin or tryptophan plus ASA, but it was also raised significantly after application of ASA alone. Plasma gastrin levels were raised in subjects given melatonin or tryptophan plus ASA, but not in those with ASA alone. We conclude that melatonin and its precursor tryptophan given orally significantly reduce gastric lesions induced by ASA possibly due to (a) direct gastroprotective action of exogenous melatonin or that generated from tryptophan and (b) gastrin released from the gastric mucosa by melatonin or tryptophan.

Day/night differences in stress‐induced gastric lesions in rats with an intact pineal gland or after pinealectomy

The formation of acute gastric lesions depends upon the balance between the aggressive factors promoting mucosal damage and the natural defense mechanisms. Previous studies have shown that melatonin inhibits gastric acid secretion, enhances the release of gastrin, augments gastric blood flow (GBF), increases the cyclooxygenase-2 (COX-2)-prostaglandin (PG) system and scavenges free radicals, resulting in the prevention of stress-induced gastric lesions. Besides the pineal gland, melatonin is also generated in large amounts in the gastrointestinal tract and due to its antioxidant and anti-inflammatory properties; this indole might serve as local protective endogen preventing the development of acute gastric damage. The results of the present study indicate that stress-induced gastric lesions show circadian variations with an increase in the day time and a decline at night. These changes are inversely related to plasma melatonin levels. Following pinealectomy, stress-induced gastric mucosal lesions were more pronounced both during the day and at night, and were accompanied by markedly reduced plasma melatonin levels with a pronounced reduction in mucosal generation of prostaglandin E(2) (PGE(2)), GBF and increased free radical formation and by small rise in plasma melatonin during the dark phase. We conclude that stress-induced gastric ulcerations exhibit a circadian variation with an increase in the day and attenuation at night and that these fluctuations of gastric stress ulcerogenesis occur also after pinealectomy, depending upon the interaction of COX-PG and free radicals, probably mediated by the changes in local gastric melatonin.

Effect of Helicobacter pylori on delay in ulcer healing induced by aspirin in rats

Helicobacter pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) are major pathogenic factors in peptic ulcer disease but whether these two factors exert synergistic or antagonistic effects on ulcer healing has been a subject of controversy. We compared the effect of aspirin alone with that of aspirin combined with H. pylori on gastric acid secretion and healing of acetic acid gastric ulcers in rats. The H. pylori colonization of gastric mucosa was determined by viable H. pylori culture, histology and assessment of bacterial DNA using polymerase chain reaction (PCR). The area of ulcers, gastric blood flow, mucosal generation of prostaglandin E 2 and plasma gastrin levels and expression of cyclooxygenase-1, cyclooxygenase-2 and growth factors was determined. Aspirin delayed significantly the healing of chronic gastric ulcers, decreased the gastric blood flow at the ulcer margin and gastric mucosal prostaglandin E 2 generation being without significant influence on gastric acid output. H. pylori acquisition that produced moderate gastric inflammation at the ulcer margin delayed significantly the healing of gastric ulcers, decreased significantly both the gastric blood flow at the ulcer margin and the gastric secretion while raising significantly the gastric mucosal prostaglandin E 2 generation and plasma gastrin levels. H. pylori infection attenuated the aspirin-induced inhibition of ulcer healing and accompanying fall in the gastric blood flow. Both aspirin and H. pylori up-regulated significantly cyclooxygenase-2 messenger RNA (mRNA) and protein but not that of cyclooxygenase-1 at the ulcer margin. Aspirin reduced significantly the transforming growth factor alpha- and vascular endothelial growth factor mRNAs, but these effects were significantly attenuated by H. pylori. We conclude that H. pylori antagonizes, in part, aspirin-induced delay of ulcer healing due to suppression of acid secretion, the enhancement in prostaglandin E 2 possibly derived from cyclooxygenase-2 and the overexpression of transforming growth factor alpha and vascular endothelial growth factor in the ulcer area.

Gastrointestinal safety of selective COX-2 inhibitors.

It appears that selective Cox-2 inhibitors do not affect the gastro duodenal mucosa whilst having anti-inflammatory and analgesic efficacy similar to non-selective NSAIDs. Two broad categories of drugs are Cox-2 selective: coxibs and a number of pre-existing NSAIDs retrospectively found to have selectivity. Cox-2 inhibitors cause less dyspepsia than NSAIDs. They spare gastrointestinal mucosal generation of prostaglandins (PGs) and PG-dependent bicarbonate secretion. Coxibs cause no acute mucosal injury in endoscopic ulcers compared to NSAID comparators. In the VIGOR study all upper GI events were reduced from 4.5 per 100 patient years to 2.1 per 100 patient years with supra-therapeutic doses of rofecoxib compared with naproxen. In the CLASS study, over a period of 3 days to 6 months, incidence of ulcer complications was 0.76% with celecoxib and 1.45% for ibuprofen or diclofenac. The less substantial reduction in events in the CLASS study compared with the VIGOR may be due, at least in part, to the fact that 21% of the patients were also on low dose aspirin. However it is premature to say that the benefit of Cox-2 inhibitors is lost in patients taking aspirin. There is continuing debate on the role of Cox-2 inhibitors in patients who have other risk factors for complicated ulcer disease e.g. patients who are elderly, on aspirin or corticosteroids, have a previous ulcer or have H. pylori infection.

Gastroprotective and ulcer healing effects of nitric oxide-releasing non-steroidal anti-inflammatory drugs

Background & Aim. New class of nitric oxide-releasing non-steroidal anti-inflammatory drugs was shown to inhibit cyclooxygenase and prostaglandin generation without causing mucosal damage but whether these agents are capable of affecting gastric mucosal damage induced by strong irritants and healing of chronic gastric ulcers remains to be studied. In this investigation, effects of nitric oxide-releasing aspirin and nitric oxide-releasing naproxen were compared with those of native agents on gastric lesions provoked by 100% ethanol and on healing of chronic acetic acid ulcers. Results. Both, nitric oxide-releasing aspirin and naproxen dose-dependently attenuated ethanol-induced damage and produced a significant rise in gastric blood flow but did not delay healing of gastric ulcers while native aspirin and naproxen had no influence on ethanol-induced gastric damage but significantly prolonged ulcer healing, reduced gastric blood flow and suppressed mucosal generation of prostaglandin E 2. The gastroprotective and hyperaemic effects of both nitric oxide-non-steroidal anti-inflammatory drugs were completely abolished by ODD, an inhibitor of guanylyl cyclase-CGMP system but not influenced by suppression of nitric oxide-synthase with L-NNA. The damaging effects of native acetyl salicylate acid or naproxen were aggravated by acidification of these non-steroidal anti-inflammatory drugs but the exogenous acid added to nitric oxide-acetyl salicylate acid or nitric oxide-naproxen failed to influence their effect. Despite inhibiting of PGE 2 generation, both nitric oxide-releasing derivatives and native aspirin and naproxen failed to affect expression of cyclooxygenase-1 mRNA but upregulated the cyclooxygenase-2 mRNA. Concurrent inhibition of cyclooxygenase-2 by selective inhibitor NS-39B which by itself delayed ulcer healing and attenuated the gastric blood flow at ulcer margin, significantly worsened the effects of these nitric oxidenon-steroidal anti-inflammatory drugs and their parent drugs on ulcer healing and the gastric blood flow at the ulcer margin. Conclusions. 1) Coupling of nitric oxide to aspirin or naproxen attenuates ethanol-induced damage, possibly due to an increase in gastric microcirculation mediated by excessive release and action of nitric oxide that probably compensates for PG deficiency induced by non-steroidal anti-inflammatory drugs; and 2) nitric oxide-non-steroidal anti-inflammatory drug, unlike classic non-steroidal anti-inflammatory drugs, does not affect intact gastric mucosa and fails to delay the healing of pre-existing ulcers.

Role of prostaglandins generated by cyclooxygenase-1 and cyclooxygenase-2 in healing of ischemia–reperfusion-induced gastric lesions

In this study, ischemia–reperfusion produced in rats by clamping the celiac artery for 0.5 h followed by 1 h of reperfusion was used to develop a new model of superficial gastric erosions progressing to deeper ulcers. Ischemia alone resulted in an immediate fall in gastric blood flow but no gross mucosal lesions were observed. When ischemia was followed by reperfusion, gastric erosive lesions occurred, reached a maximum at 12 h and then declined after 24 h. These acute erosions progressed into deeper lesions 24 h after ischemia–reperfusion and reached a peak after 3 days. Gastric blood flow and the mucosal generation of prostaglandin E 2 were significantly suppressed immediately following ischemia–reperfusion, but with the healing of deeper gastric ulcers, both gastric blood flow and prostaglandin E 2 generation were gradually restored. Cyclooxygenase-1 mRNA was detected by reverse transcription-polymerase chain reaction in intact gastric mucosa and throughout the recovery of the mucosa from acute ischemia–reperfusion lesions, whereas cyclooxygenase-2 mRNA, was recorded only after ischemia–reperfusion. NS-398 and rofecoxib, selective inhibitors of cyclooxyganase-2, failed to affect prostaglandin E 2 generation in the non-ulcerated gastric mucosa but inhibited it significantly in the ulcer area. The two cyclooxygenase-2 inhibitors as well as resveratrol, a specific cyclooxygenase-1 inhibitor and indomethacin and meloxicam, non-specific inhibitors of cyclooxygenase, augmented acute gastric erosions induced by ischemia–reperfusion and delayed significantly the progression of these lesions into deeper ulcers at each time interval after ischemia–reperfusion. We conclude that prostaglandins generated by both cyclooxygenase-1 and cyclooxygenase-2 contribute to the healing of gastric lesions induced by ischemia–reperfusion.

Activation of genes for growth factors and cyclooxygenases in rat gastric mucosa during recovery from stress damage

Growth factors and prostaglandins protect the gastric mucosa against stress-induced lesions but their role in the recovery of the mucosa from these lesions has been little studied. We evaluated gastric mucosa lesions, gastric blood flow, mucosal generation of prostaglandin E2 and mucosal gene expression of epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) as well as constitutive prostaglandin cyclooxygenase-1 and inducible cyclooxygenase-2 and the effect of the inhibition of these enzymes on the recovery of mucosa from the stress-induced lesions. Rats were exposed to 3.5 h of water immersion and restraint stress and killed at 0, 2, 4, 6, 8, 12 and 24 h after stress. The number of gastric lesions was determined and gastric blood flow was measured by H2-gas clearance. Gastric acid secretion was tested in separate gastric fistula rats. Gastric mucosa biopsies were taken for determination of immunoreactive EGF and TGF alpha. Expression of EGF and TGF alpha mRNA and cyclooxygenase-1 and cyclooxygenase-2 mRNA was also determined by reverse-transcriptase polymerase chain reaction. The number of gastric lesions induced by 3.5 h stress averaged approximately 20 per rat and declined significantly at 2, 4, 6, 8 and 12 h, to disappear almost completely after 24 h. This was accompanied by a gradual rise in gastric blood flow, mucosal generation of prostaglandin E2 and mucosal EGF and TGF alpha contents, while the increased gastric acid secretion returned to normal. In the intact mucosa, EGF mRNA was not detected but TGF alpha mRNA was found in measurable amounts. Following exposure to stress, the expression of both these factors was significantly increased. Similarly, the expression of cyclo-oxygenase-1 and cyclooxygenase-2 mRNA was detected in the oxyntic mucosa at all time intervals after exposure to stress. Indomethacin (5 mg/kg i.p.), an inhibitor of cyclooxygenase-1 and cyclooxygenase-2, and meloxicam (1 mg/kg i.p.), an inhibitor of cyclooxygenase-2, both prolonged the healing of stress lesions and reduced the gastric blood flow, while enhancing gastric acid secretion at all times tested. We conclude that healing of stress lesions results in the restoration gastric blood flow and mucosal prostaglandin generation and that these effects are accompanied by overexpression of EGF and TGF alpha as well as cyclooxygenase-1 and cyclooxygenase-2 mRNA and by increased biosynthesis of gastroprotective prostaglandin.

Co-regulation of mucosal prostanoids and substance P by indomethacin in rat stomachs

The present investigation examined the correlation between the regulation of mucosal prostaglandin (PG) biosynthesis and the release of the neuropeptide substance P (SP) in rat stomachs by indomethacin, a cyclooxygenase inhibitor. When given subcutaneously at the dose of 5 mg kg , indomethacin reduced mucosal biosynthesis of PGE 2 and concurrently lowered mucosal SP level. The inter-relationship between mucosal generation of PG and SP was further demonstrated by using [D-Pro 2, D-Trp 7,9]-SP, which also inhibited PGE 2 production besides its suppression on SP release. Co-administration of either arachidonic acid, the PGE 2 precursor, or SP reversed the inhibitory actions of indomethacin and [D-Pro 2, D-Trp 7,9]-SP, respectively, on mucosal levels of PGE 2 and SP. Our findings suggest that indomethacin, aside from its depletion of endogenous PG, also exerts a secondary action in regulating the release of SP, which is mediated indirectly through PG in the gastric mucosa. These actions may play a role in the modulation of gastric mucosal integrity.

Activation of arachidonoyl phospholipase A 2 in prostaglandin-mediated action of sucralfate

1. The mechanism of sucralfate-induced gastric mucosal prostaglandin generation was investigated using mucosal cells labeled with [ 14C]choline and [ 3H]arachidonic acid. 2. In comparison to the controls, the cells maintained in the presence of sucralfate showed a concentration dependent increase in lysophosphatidylcholine (LPC) synthesis and PGE 2 generation. The maximal effect was attained at 25 μM sucralfate giving a 45.7% increase in LPC and 70% increase in PGE 2. 3. Pretreatment with indomethacin prior to sucralfate, while causing inhibition in PGE 2 generation, had no effect on LPC production and led to accumulation of free arachidonic acid. In the case of pretreatment with NDGA, the sucralfate caused increased LPC synthesis accompanied by enhanced PGE 2 generation without free arachidonic acid accumulation. 4. The stimulatory effect of sucralfate on LPC synthesis and PGE 2 generation was inhibited by phospholipase A 2 inhibitors, mepacrine and BPB. The inhibitory effect was concentration dependent and attained maximum at 40 μM for BPB and 80 μM for mepacrine. 5. The results for the first time demonstrate that the enhancement in gastric mucosal prostaglandin generation by sucralfate results from the stimulation of mucosal phospholipase A 2 for arachidonic acid release.

Nicotine has no effect on rat gastric mucosal prostaglandin generationin vitro

Previous studies have shown that cigarette smoking depresses prostaglandin generation by human gastric mucosa, but the component of smoke that is responsible for that action is not known. To investigate whether nicotine has a direct effect on gastric mucosal prostaglandin generation, we performed the following study. Eight rats were sacrificed and the stomachs removed. Using a biopsy forceps, small pieces of gastric mucosa were resected and placed in incubation vials containing either buffered Krebs solution alone (control), Krebs solution plus indomethacin (5 micrograms/ml), or Krebs solution plus one of several concentrations of nicotine ditartrate (10, 100, 500, 1000 ng/ml). The nicotine concentrations we used ranged below and above the plasma nicotine concentrations of smokers shortly after smoking cigarettes. Three separate incubations of gastric mucosa were performed per experimental group from each animal. After 30 min of incubation, prostaglandin E2 and 6-keto-prostaglandin F1 alpha concentrations in the incubation medium were measured by radioimmunoassay. We found that nicotine at any concentration tested had no effect on the generation of prostaglandin E2 and 6-keto-prostaglandin F1 alpha by rat gastric mucosa. Thus, this study indicates that, if nicotine is involved in the depression of prostaglandin generation in the gastric mucosa of smokers, its role is an indirect one and not by direct action on the gastric mucosa.

Hydrocortisone has a biphasic effect on rat gastric mucosal prostaglandin generation in vivo: Inhibition at low doses, stimulation at high doses

To determine the effect of different doses of hydrocortisone sodium succinate (HC) on rat gastric mucosal prostaglandin synthesis, two experiments were performed. In the first experiment, 20 male Lewis rats were divided into 4 groups of 5 rats each and gavaged either with 2 ml of water (control) or different concentrations of HC (10 mg/ml, 100 mg/ml and 500 mg/ml). In the second experiment in a similar design, lower doses of HC were used (water, 0.1 mg/ml, 0.50 mg/ml and 5.0 mg/ml). The rats were killed after 1 h and three 3 × 3 mm pieces of gastric tissue were removed from each rat and incubated for the determination of prostaglandin E 2 and 6-keto-prostaglandin F 1α accumulation in the medium measured by radioimmunoassay. At low doses HC inhibits rat gastric mucosal prostaglandin synthesis whereas at higher doses HC stimulates it. This biphasic effect of HC on gastric mucosal prostaglandin synthesis may help explain its role in ulcerogenesis.

Role of acid milieu in the gastroprotective and ulcer-healing activity of sucralfate

Sucralfate prevents the formation of acute gastric lesions induced by various ulcerogens and enhances the healing of chronic gastroduodenal ulcerations, but the mechanism of these effects has not been fully explained. This study was designed to determine the importance of intragastric pH in the sucralfate-induced gastroprotection against 100% ethanol, acidified aspirin, taurocholate, or stress, and in the healing of chronic gastroduodenal ulcerations induced by acetic acid. Sucralfate acidified to pH 2.0 showed significantly stronger protective activity against all four irritants, its protective potency against 100% ethanol being about eight times greater and the duration of the protection about four times longer than those obtained with sucralfate at its pH of 5.0. Pretreatment with indomethacin to suppress mucosal generation of prostaglandin or the removal of salivary glands to eliminate the endogenous source of epidermal growth factor failed to affect sucralfate-induced gastroprotection. In contrast, the rate of healing of chronic gastric ulcerations was significantly delayed by indomethacin or sialoadenectomy; but sucralfate enhanced the healing, and a marked inhibition of gastric acid secretion by ranitidine did not eliminate this enhancement. We conclude that the protective activity of sucralfate depends on the presence of acid milieu in the stomach, but that the ulcer-healing effects of this drug occur even after a marked inhibition of gastric acid secretion.

Gastroduodenal mucosal prostaglandin generation in patients withHelicobacter pylori before and after treatment with bismuth subsalicylate

To determine whether Helicobacter pylori has an effect on gastroduodenal mucosal prostaglandin generation, mucosal biopsies were obtained from the gastric body, antrum, and duodenal bulb of 30 patients who were undergoing upper gastrointestinal endoscopy for clinical indications. One biopsy from the gastric body and one from the antrum were tested for urease activity (urea broth) and one biopsy from each area including the duodenum was processed for histology. Two other biopsies form each area were incubated and the accumulation of prostaglandin E2 and 6-keto prostaglandin F1 alpha in the incubation medium was measured by radioimmunoassay. Twelve of the 17 H. pylori-positive patients and seven of the 13 H. pylori-negative patients agreed to take bismuth subsalicylate (Pepto-Bismol) two tablets four times a day for four weeks. One week after treatment, these patients again underwent endoscopy and the above studies. This study indicates that: (1) mucosal PGE2 generation may be increased in the duodenum, gastric body, and antrum in H. pylori-positive patients compared to H. pylori-negative patients, and (2) treatment with bismuth subsalicylate for four weeks results in reduction of mucosal PGE2 in the duodenum, gastric body, and antrum of H. pylori-positive patients and fails to eradicate H. pylori or reduce gastric inflammation.

Intragastric pH in the Gastroprotective and Ulcer-Healing Activity of Aluminum-Containing Antacids

Antacids containing aluminum have been shown to stimulate the protective processes in the gastric mucosa and to enhance the healing of chronic gastroduodenal ulcerations, but the mechanisms of these effects are still unexplained. This study was designed to compare the protective effects of unmodified and acidified (pH 2.0) Maalox 70 and Al(OH)3 on the formation of acute gastric mucosal lesions induced by absolute ethanol, taurocholate, acidified aspirin and stress, and to determine the role of gastric acid in healing of chronic gastroduodenal ulcerations by these antacids in rats. Acidified Maalox 70 and Al(OH)3 were significantly more potent than unmodified agents against all four tested types of acute mucosal lesions, and this action was probably due to their 'mild irritant' effect as evidenced by extensive exfoliation of the surface epithelial cells observed microscopically after the exposure of the mucosa to these agents. Mucosal generation of prostaglandins does not appear to be involved in the gastroprotection by acidified Maalox because the pretreatment with indomethacin did not affect this protection. In contrast to the protective effect, the ulcer-healing capacity of Maalox or Al(OH)3 does not appear to be dependent upon the presence of gastric acid because the reduction or elimination of endogenous acid by the pretreatment with ranitidine or omeprazole did not affect the healing of gastroduodenal ulcerations. We conclude that aluminum-containing antacids induce the mucosal protection that is enhanced in the presence of luminal acid but exhibit an ulcer-healing property that appears to be unrelated to gastric acid secretion or mucosal generation of prostaglandins.

Prostaglandins and gastric mucosal protection by esaprazole in rats

Esaprazole, N-cyclohexyl-1-piperazineacetamide monohydrochloride, was studied for its activity to prevent gastric mucosal damage induced by several necrotizing agents in the rat. Its effects on acid gastric secretion and the role of gastric mucosal prostaglandin generation were also investigated. Esaprazole, given orally, dose dependently prevented the formation of mucosal damage induced by absolute ethanol, 0.2 N NaOH or 0.6 N HCl. This activity occurred at doses lower than the antisecretory doses. Esaprazole was also found to increase the gastric mucosal prostaglandin content but at doses that exceeded the cytoprotective doses. The failure of indomethacin to impair the gastric mucosal protection provided by esaprazole suggests that mechanisms other than mobilization of endogenous prostaglandins may be involved.

Vagotomy Effect on Gastric Prostaglandins

Prostaglandins have been implicated in gastric mucosal cytoprotection. Vagotomy results in both cytoprotection and increased mucosal prostaglandin concentrations. However, the mechanism by which vagotomy affects prostaglandin generation remains unknown. In this study we compared vagotomy with long-term acid suppression using anticholinergic (atropine sulfate) or histamine2-receptor antagonism (cimetidine) and assessed mucosal injury and prostaglandin generation during graded stress. Vagotomy correlated with decreases in injury only in severe stress, while both atropine and cimetidine decreased injury also during moderate stress. Prostaglandin generation decreased in all groups during severe stress. Compared with sham operation, vagotomy, atropine, and cimetidine were all associated with increased mucosal prostaglandin generation in all stress periods. During severe stress, both atropine and cimetidine also evidenced higher prostaglandin generation than did vagotomy. These results suggest that vagotomy primarily decreases acid secretion, which then secondarily results in increased mucosal generation.

Effects of Stress on Gastric Mucosal Prostaglandin Generation in Intact, Adrenalectomized, and Sham-Operated Rats

To study the effects of (a) cold restraint stress and (b) adrenalectomy in association with cold restraint stress on gastric mucosal ulceration and prostaglandin generation, we performed two experiments. In the first, 40 rats were divided into four groups of 10 rats each: (a) unstressed and (b) stressed for 0.5 h, (c) stressed for 2 h, and (d) stressed for 4 h. In the second experiment, another 80 rats were divided into four groups of 20 rats each: (a) adrenalectomy plus cold restraint stress for 2 h, (b) adrenalectomy plus no stress, (c) sham operated plus 2 h of stress, and (d) sham operated plus no stress. In both experiments we recorded an ulcer index and measured mucosal generation of prostaglandin E2 (PGE2) and prostaglandin I2 (6-keto-PGF1a). (a) Cold restraint stress is associated with a time-dependent decrease in gastric mucosal PGE2 generation, but no change in 6-keto-PGF1a generation, and an increase in mucosal injury that is maximal by 2 h. (b) Adrenalectomy augments the effects of stress on mucosal injury but has no effect on prostaglandin generation; thus, the ulcerogenic effect of adrenalectomy appears to be independent of an effect on prostaglandin generation.

Effect of sialoadenectomy on adaptive cytoprotection in the rat

In the present study we have investigated the effect of sialoadenectomy in the rat on adaptive cytoprotection induced by intragastric instillation of an irritant concentration of ethanol (10% wt/vol). Gastric mucosae were examined 1 h after oral administration of 100% ethanol. In animals with intact salivary glands, pretreatment with saline was followed 15 min later by 100% ethanol. This treatment was associated with a significant degree of mucosal damage. However, prior administration of 10% ethanol in place of saline reduced the area of ulceration. In sialoadenectomized rats, the irritant concentration of ethanol did not protect the gastric mucosa from the damaging actions of absolute ethanol. The effect was partially restored if sialoadenectomized rats were treated for 3 days with an aqueous extract of rat salivary gland tissue. Histologic examination revealed no differences in the extent of epithelial damage or adherent mucus between rats with intact salivary glands and sialoadenectomized rats following pretreatment with either saline or 10% ethanol. Although adaptive cytoprotection in animals with intact salivary glands was not associated with increases in mucosal capacities for prostaglandin E2 or 6-keto prostaglandin F1α biosynthesis, sialoadenectomy resulted in a reduction in the mucosal biosynthetic capacities for both prostanoids. Salivary gland extract administration to sialoadenectomized rats did not significantly alter mucosal prostaglandin biosynthesis levels. These data suggest that salivary gland factors affected adaptive cytoprotection induced by an irritant dose of ethanol. Although endogenous prostaglandin biosynthesis capabilities do not appear to be altered in adaptive cytoprotection, salivary factors appear to influence mucosal generation of prostaglandins.

Epidermal growth factor in the gastroprotective and ulcer-healing actions of sucralfate in rats

Sucralfate exhibits gastroprotective properties in laboratory animals and enhances the healing of chronic gastroduodenal ulcers, but the mechanisms of these actions have not been entirely elucidated. The present study was designed to determine whether or not epidermal growth factor (EGF), which also has gastroprotective and ulcer-healing properties, contributes to the action of sucralfate in rat stomach. It was confirmed that sucralfate, like 16,16-dimethyl prostaglandin E 2, protects the gastric mucosa against ethanol damage and increases mucosal generation of prostaglandins. Removal of the endogenous source of EGF (sialoadenectomy) did not abolish the protective and prostaglandin-stimulating effects of sucralfate. Exogenous EGF and 16,16-dimethyl prostaglandin E 2 were also protective in rats with intact and removed salivary glands. Sucralfate, like EGF, enhanced the healing of chronic gastric and duodenal ulcerations induced by serosal application of acetic acid. Sucralfate was found to bind EGF in a pH-dependent manner and to accumulate it in ulcer areas. Thus, the peptide is available locally in high concentrations to accelerate tissue repair and the healing process in ulcerated mucosa. The ulcer-healing effects of sucralfate were reduced with sialoadenectomy and partially restored with oral administration of EGF. It was concluded that EGF is not essential for the gastroprotection induced by sucralfate, but seems to play an important role in the ulcer-healing action of this drug.

Gastric anti-ulcer and cytoprotective effect of selenium in rats

Selenium, a trace element, in the form of sodium selenite has been studied for its ability to protect the gastric mucosa against the injuries caused by hypothermic restraint stress, aspirin, indomethacin, reserpine, dimaprit, and various other gastric mucosal-damaging (necrotizing) agents in rats. The results demonstrate that oral administration of sodium selenite produces a significant inhibition of the gastric mucosal damage induced by all the procedures used in this study. 4, in a nonantisecretory dose, produced a marked cytoprotective effect against all the necrotizing agents. The cytoprotective effect of selenium against the effects of 80% ethanol and 0.6 m HCl was significantly reversed by prior treatment with a dose of indomethacin that inhibits prostaglandin biosynthesis. These data indicate that sodium selenite inhibits the formation of these lesions by the mucosal generation of prostaglandins. The concentrations of nonprotein sulfhydryls (NP-SH) were significantly decreased in the gastric mucosa following the administration of necrotizing agents—80% ethanol and 0.6 m HCl. Treatment with sodium selenite, which significantly reduced the intensity of gastric lesions, did not replenish the reduced levels of gastric mucosal NP-SH, thus ruling out the mediation of its protective effect through sulfhydryls. The antisecretory effect of sodium selenite, which becomes evident only in the high dose of 20 μmol/kg, may be responsible for the inhibition of gastric lesions induced by aspirin, indomethacin, reserpine, and dimaprit. Our findings show that selenium possesses significant anti-ulcer and adaptive cytoprotective effects. However, further detailed studies are required to confirm these effects, to establish its mechanism(s) of action, and to determine its role in the prophylaxis and treatment of peptic ulcer disease.