Gastroprotective effect of adrenomedullin administered subcutaneously in the rat

Subcutaneous injections of adrenomedullin prevented reserpine-induced gastric mucosal damage in a dose-dependent manner (1-1000 ng/kg), but did not interfere with the lesions produced by ethanol administration. In pylorus-ligated rats adrenomedullin significantly reduced gastric volume, total and free acid output as well as ulcer formation. The gastroprotective activity of adrenomedullin was not present in rats pretreated with cysteamine. These results suggest that adrenomedullin exerts its antiulcer effect, when it is administered subcutaneously (s.c.), probably by a mechanism which involves somatostatin related transmission.     

Study of the damaging effects of acetazolamide on gastric mucosa in rats

The present study demonstrated that acetazolamide (100 and 200 mg/kg, s.c.) induced severe gastric hemorrhagic ulceration in rats. The ulceration was aggravated by oral administration of HCl, but was inhibited by NaHCO3. Furthermore, the severity of ulceration was also decreased by pretreatment with methysergide, chlorpheniramine, or cimetidine. These protective effects were accompanied by an increase in serotonin and histamine released from the stomach. Acetazolamide injection also increased the protein level but reduced the sialic acid content in the gastric secretion, indicating that the gastric mucosal barrier may have been damaged. Prostaglandin E2 content of the gastric mucosa was not affected by the drug; however, carbonic anhydrase activity was markedly reduced in a dose-dependent manner. Thus, it is suggested that the ulceration induced by acetazolamide is mainly due to the inhibition of carbonic anhydrase activity and mucus secretion. The increase in serotonin and histamine release also may have been the contributing factors for gastric ulcer formation.     

Interleukin-1 is cytoprotective, antisecretory, stimulates PGE2 synthesis by the stomach, and retards gastric emptying

Human recombinant interleukin 1 beta (IL-1) administered intraperitoneally to rats produced the following gastric effects: 1. It was cytoprotective, preventing gastric mucosal necrosis produced by oral administration of one ml of absolute ethanol to fasted animals. The ED50 was 1200 units/kg (110 ng per animal). IL-1 was 125 times more potent than prostaglandin E2 (on a weight basis), and 6,000 times more potent (on a molar basis). 2. The cytoprotective effect of IL-1 was blocked by indomethacin (inhibitor of prostaglandin synthesis) and by IRAP (a specific interleukin-1 receptor antagonist protein). IRAP did not inhibit cytoprotection induced by PGE2. 3. IL-1 prevented the formation of gastric erosions induced by aspirin. 4. IL-1 inhibited gastric secretion (volume, acid concentration and output), in the pylorus-ligated rat, with an ED50 of 300 units/kg (3.2 ng per animal). 5. Indomethacin and IRAP blocked the antisecretory effect of IL-1. 6. IL-1 retarded gastric emptying, an effect blocked by IRAP, but not by indomethacin. 7. IL-1 increased synthesis of prostaglandin E2 by the gastric mucosa by 111%. IL-1 is the most potent of known agents that are gastric cytoprotective, antiulcer, antisecretory, and delay gastric emptying. It appears to act mostly by stimulating the synthesis of prostaglandins by the stomach. These studies suggest that the stomach possesses IL-1 receptors. These are probably located on parietal cells (that produce acid), on prostaglandin-producing cells, on smooth muscle cells (responsible for gastric emptying), and on as yet unidentified cells involved in gastric cytoprotection. Both IL-1 and IRAP, being natural substances, may play a physiological role in the maintenance of gastric mucosal integrity, and in the regulation of acid secretion and gastric motility.     

Prophylactic and healing properties of a new anti-ulcer compound from Enantia chlorantha in rats.

Decoctions prepared from Enantia chlorantha are used in the traditional treatment of some forms of ulcers. We have tested the anti-ulcer actions of a novel protoberberine-type alkaloid (7,8,-dihydro-8-hydroxypalmatine (1)) obtained from the bark of E. chlorantha using the HCl/ethanol, absolute ethanol and pylorus ligation techniques. The healing effect on chronic acetic acid-induced gastric ulcer was also tested. 1 (50 and 100 mg/kg) dose-dependently inhibited the formation of gastric ulcers induced by HCl/ethanol (35-52% inhibition), absolute ethanol (46-53% inhibition) and pylorus ligation (38-62% inhibition). The prophylactic actions were associated with significant increases in gastric mucus production compared with the controls. The significant inhibition of pylorus-ligated ulcers occurred at gastric acid concentrations (83 mEq/l) previously known to induce severe gastric ulceration in rats. The ulcer-healing test showed significant macromorphological and histological acceleration of healing following 10-day treatment with 1 (40 - 80 mg/kg). The results show that 1 has no anti-secretory effects. The prophylactic anti-ulcer effects are associated with enhanced mucus production, which is an important factor in the mechanism of the local healing process of chronic gastric ulcers.     

Tryptamine, a Substrate for the Serotonin Transporter in Human Platelets, Modifies the Dissociation Kinetics of [3H]Imipramine Binding: Possible Allosteric Interaction

Tricyclic antidepressants and nontricyclic serotonin (5-hydroxytryptamine) uptake blockers monophasically inhibit [3H]imipramine binding in human platelets. Similarly, serotonin and tryptamine inhibit the binding of [3H]imipramine in the low micromolar range and with a pseudo-Hill coefficient near unity. Dissociation of the [3H]imipramine receptor complex in the presence of uptake inhibitors follows first-order kinetics with a half-life of approximately 60 min. Although serotonin and tryptamine do not decrease [3H]imipramine binding when added under equilibrium conditions, simultaneous addition of serotonin or tryptamine with serotonin uptake inhibitors decreases the rate of ligand-receptor dissociation in a concentration-dependent manner. These data suggest a common site of action for serotonin, which is the substrate of the transporter system, and of tryptamine, its nonhydroxylated analog. This hypothesis is supported by the identification of a high-affinity (Km = 0.55 microM), saturable, and temperature-dependent uptake of [3H]tryptamine in human platelets. Uptake of [3H]tryptamine was inhibited potently by imipramine and nontricyclic serotonin uptake inhibitors with a potency similar to that observed for [3H]serotonin uptake. These data support the hypothesis that in platelets, [3H]imipramine, tricyclic, and nontricyclic serotonin uptake inhibitors bind to a common recognition site that is associated with the serotonin transporter but that differs from the substrate recognition site of the carrier through which serotonin and tryptamine exert a heterotropic allosteric modulation on [3H]imipramine binding.     

Inhibitors of reverse serotonin uptake and of specific imipramine binding in human blood plasma

Human blood plasma contains low-molecular substances that inhibit in a dose-dependent manner both high-affinity specific binding of imipramine and reverse serotonin uptake by platelets. Incubation of human blood plasma with alumina was made use of to extract and study these imipramine-like inhibitors. The extract obtained from human blood plasma inhibited imipramine binding and reverse uptake of serotonin with median inhibitory concentrations of 0.18 +/- 0.1 and 0.36 +/- 0.15 mg/ml, respectively. After gel chromatography on Biogel P-2 the elution profile of the extract showed 2 major peaks of reverse serotonin uptake and imipramine binding inhibition and 3 additional peaks of reverse serotonin uptake inhibition, which did not have any considerable effect on imipramine specific binding. It is assumed that endogenous inhibitors of imipramine binding and reverse serotonin uptake are involved in the development of affective disorders.     

Involvement of nitric oxide in the gastroprotective effects of an aqueous extract of Pfaffia glomerata (Spreng) Pedersen, Amaranthaceae, in rats

The plants belonging to Pfaffia genus are used in folk medicine to treat gastric disturbances. This study examined the effects of an aqueous extract of Pfaffia glomerata (Spreng) Pedersen (AEP) on the gastrointestinal tract. Wistar rats were pretreated orally (p.o.) with the AEP (125, 250, 500 and 1000 mg.kg(-1)) before induction of ulcers by hypothermic restraint stress (HRS, 3 h restraint stress at 4 degrees C), ethanol (ET, 70%; 0.5 ml/animal; p.o.) or indomethacin (IND, 20 mg.kg(-1); s.c.). Control animals received water (C) or ranitidine (60 mg.kg(-1)) p.o. The AEP protected rats against HRS and ET-induced ulcers, but was not able to protect the gastric mucosa against IND-induced ulcers. When injected into the duodenal lumen, the AEP reduced total acidity and both basal and histamine-stimulated acid secretion in pylorus-ligated rats. In addition, gastric secretion from AEP-treated animals exhibited increased concentrations of nitrite and nitrate. Treatment of animals with L-NAME (120 mg.kg(-1), p.o.) prevented both the reduction of total acidity and the increase in NOx levels promoted by AEP treatment. In conclusion, AEP effectively protected the gastric mucosa and inhibited gastric acid secretion in rats, probably by involving the histaminergic pathway and an enhanced production of nitric oxide in the stomach.     

Development and Significance of Cysteamine and Propionitrile Models of Duodenal Ulcer

Cysteamine is widely used in rodents to induce duodenal ulcer. Herein, the pathogenesis of duodenal ulceration in its earliest stages was reviewed using findings from cysteamine-and propionitrile-induced duodenal ulcer in rodent models, especially taking into account changes in the secretion of gastric acid, duodenal and pancreatic bicarbonate as well asgastroduodenal motility. The effect of cysteamine-HCl in inducing ulcers in rats is circadian rhythm-dependent. The effect is greatest from just before the end of diurnal rest to just after the start of nocturnal activity. The chronobiologic effect may be in part due to the circadian rhythm-dependent increased gastric acid production from cysteamine. Titratable acidity was found to be twice as great in the gastric juice of rodents when cysteamine was given by injection at 2000 (just after the start of nocturnal activity) in comparison to when given at 0800 or 1200 (at the beginning or middle span of daily rest). Further studies have shown that adrenalectomy of rats 7 days before cysteamine administration obliterated the observed circadian susceptibility to ulcer formation. Duodenal ulceration, at least in the cysteamine model, appears to be under chronobiologic neuroendocrine control or influence, seemingly mediated by the adrenal glands.     

Vagus-mediated activation of mucosal mast cells in the stomach: effect of ketotifen on gastric mucosal lesion formation and acid secretion induced by a high dose of intracisternal TRH analogue.

TRH analogue, RX 77368, injected intracisternally (i.c.) at high dose (3 microg/rat) produces gastric mucosal lesion formation through vagal-dependent pathway. The gastric mucosal hyperemia induced by i.c. RX 77368 was shown to be mediated by muscarinic vagal efferent fibres and mast cells. Furthermore, electrical vagal stimulation was observed to induce gastric mucosal mast cell degranulation. The aim of the study was to assess the influence of ketotifen, a mast cell stabilizer, on RX 77368-induced gastric lesion formation and gastric acid secretion. RX 77368 (3 microg, i.c.) or vehicle (10 microL, i.c.) was delivered 240 min prior to the sacrifice of the animals. Ketotifen or vehicle (0.9% NaCl, 0.5 mL) was injected intraperitoneally (i.p.) at a dose of 10 mg x kg(-1) 30 min before RX 77368 injection. The extent of mucosal damage was planimetrically measured by a video image analyzer (ASK Ltd., Budapest) device. In the gastric acid secretion studies, the rats were pretreated with ketotifen (10 mg x kg(-1), i.p.) or vehicle (0.9% NaCl, 0.5 mL, i.p.), 30 min later pylorus-ligation was performed and RX 77368 (3 microg, i.c.) or vehicle (0.9% NaCl, 10 microL, i.c.) was injected. The rats were killed 240 min after i.c. injection, and the gastric acid secretion was measured through the titration of gastric contents with 0.1 N NaOH to pH 7.0. RX 77368 (3 microg, i.c.) resulted in a gastric mucosal lesion formation involving 8.2% of the corpus mucosa (n = 7). Ketotifen elicited an 85% inhibition on the development of mucosal lesions (n = 7, P < 0.001) whereas ketotifen alone had no effect on the lesion formation in the mucosa (n = 7). The RX 77368 induced increase of gastric acid secretion was not influenced by ketotifen pretreatment in 4-h pylorus-ligated animals. Central vagal activation induced mucosal lesion formation is mediated by the activation of mucosal mast cells in the stomach. Mast cell inhibition by ketotifen does not influence gastric acid secretion induced by i.c. TRH analogue in 4-h pylorus-ligated rats.     

Lung damage and pulmonary uptake of serotonin in intact dogs

We examined the influence of glass bead embolization and oleic acid, dextran, and imipramine infusion on the pulmonary uptake of trace doses of [3H]serotonin and the extravascular volume accessible to [14C]antipyrine in anesthetized dogs. Embolization and imipramine decreased serotonin uptake by 53 and 61%, respectively, but no change was observed with oleic acid or dextran infusion. The extravascular volume accessible to the antipyrine was reduced by 77% after embolization and increased by 177 and approximately 44% after oleic acid and dextran infusion, respectively. The results suggest that when the perfused endothelial surface is sufficiently reduced, as with embolization, the uptake of trace doses of serotonin will be depressed. In addition, decreases in serotonin uptake in response to imipramine in this study and in response to certain endothelial toxins in other studies suggest that serotonin uptake can reveal certain kinds of changes in endothelial function. However, the lack of a response to oleic acid-induced damage in the present study suggests that serotonin uptake is not sensitive to all forms of endothelial damage.     

An explanation of gastric hypersecretion in the pylorus-ligated rat

The hypersecretion of gastric acid in the pylorus-ligated rat has been shown to be of vagal origin. The present series of experiments were performed to identify the stimulus. The pyloric sphincter was ligated in a series of Sprague Dawley rats. Along with pylorus ligation, various other surgical manipulations were performed. Intestinal obstruction by ligation approximately 20 cm aboral to the cecum reduced unstimulated gastric secretion in the pylorus-ligated rat. However, perfusion of the lower small intestine with bicarbonate (143 mEq/L) stimulated secretion. Perfusion with either saline or deoxycholic acid (20 mEq/L) did not alter secretion. This supports a role for bicarbonate in the hypersecretion of gastric acid in the pylorus-ligated rat. The reflex appears to involve the myenteric plexus, since section of the pylorus seemed to attenuate gastric secretion. Plasma from animals with pylorus ligation, either alone or with intestinal ligation, equally inhibited gastric secretion. This suggests that while some factor inhibiting gastric secretion may be present, it appears to be unrelated to pylorus ligation.     

A novel method to produce extensive gastric antral ulcer in rats: pharmacological factors involved in the etiology of antral ulceration.

Gastric antral area is the most susceptible region to gastric ulceration in man. However, only limited information is available on animal models. In the present paper, we have developed an improved method for inducing gastric antral ulcers by the administration of 1.0 M HCl after refeeding for 1 h in rats. On day 4, the severe ulcer was found covering extensively the whole area of the antrum, and penetrated through the muscularis mucosae. The incidence of ulceration was 100% and the mean ulcer index was 37.1 +/- 16.6 mm2. In contrast, none of the erosive lesions were observed in the corpus area. Before 24 h, only slight hyperemia was observed in the antral region, suggesting that some submucosal mechanisms are involved in the ulceration processes other than the direct erosive action of HCl on the mucosal surface. Additional treatment with diethyldithiocarbamate (125 mg x kg(-1), s.c.), superoxide dismutase inhibitor, significantly aggravated this antral ulcer, and the ulcer index was 66.0 +/- 13.6 mm2. Allopurinol (50 mg x kg(-1), p.o.) significantly prevented ulcer formation induced by HCl plus DDC. GSH (150 mg x kg(-1), i.p.) also markedly prevented the ulceration. However, DMSO (0.5%, 5 mL x kg(-1), p.o.) was found not to affect ulcer formation. Famotidine (20 mg x kg(-1), p.o.) almost completely inhibited ulcer formation. From the above results, it was concluded that gastric antral ulcer can be induced by the simple treatment of 1.0 M HCl in refed rats, and the antrum has a different defensive mechanism from that in the corpus area. In addition. oxygen derived radicals, especially superoxide anion and endogenous acid secretion were found to be involved in the etiology of the aggravation of the gastric antral ulcer induced by DDC.     

Adenosine: a novel ulcer modulator in stomachs.

Adenosine has been demonstrated for its actions on gastric secretion and stress-induced gastric ulceration in animals. We examined the pharmacological actions of adenosine on ethanol-evoked gastric lesions and gastric mucosal blood flow (GMBF) in rats, because both of them are closely related. Adenosine pretreatment, in dose of 7.5 mg/kg increased GMBF and protected against ethanol-evoked gastric lesion formation. However, this antiulcer action was followed by an aggravation of gastric lesions and reduction in GMBF. We further investigated whether these actions could act through the adenosine A1 or A2 receptors, therefore L-phenylisopropyladenosine (L-PIA) or N-ethylcarboxamidoadenosine (NECA), the adenosine A1 or A2 receptor agonists, respectively, were used. The drugs given in doses of 10 or 50 micrograms/kg for L-PIA and 1 or 5 micrograms/kg for NECA, dose-dependently inhibited GMBF and potentiated ethanol-induced gastric damage. When the two drugs were given together to animals, they did not further aggravate the severity of ulceration and reduction of GMBF. These findings indicate that the antiulcer action of adenosine is not mediated via the adenosine A1 and A2 receptors but if acts through different adenosine receptor subtypes. It was because the lesion worsening effects of adenosine at the second stage of the biphasic responses were similar to the actions of L-PIA and NECA, the ulcer potentiating effect is probably acting through adenosine A1 and A2 receptors in anaesthetised rats.     

Sodium-dependent [3H]imipramine binding in rat hippocampus and its relationship to serotonin uptake

The relationship of [3H]imipramine recognition sites and serotonergic function was investigated by simultaneously determining the desipramine-defined and sodium-dependent components of [3H]imipramine binding and the serotonin levels and uptake in hippocampus of rats without and with selective lesion of serotonergic neurons with 5,7-dihydroxytryptamine. In control rats, the desipramine-defined [3H]imipramine binding to hippocampal membranes showed a high affinity (Kd = 2 nM) and low affinity (Kd = 31 nM) component. In contrast, the Scatchard analysis of sodium-dependent binding revealed a single class of sites of high affinity (Kd = 1.5 nM). Displacement of sodium-dependent [3H]imipramine binding by cold imipramine resulted in a steep curve best fitted to a one-site model. Sodium-dependent binding of [3H]imipramine at 4 nM concentration represented only about 38% of desipramine-defined binding. 5,7-Dihydroxytryptamine treatment resulted in marked reduction of hippocampal serotonin concentration and uptake without any changes in norepinephrine levels. Virtually only the low affinity component of desipramine-defined [3H]imipramine binding was detected by Scatchard analysis in 5,7-dihydroxytryptamine lesioned rats. The desipramine-defined "specific" [3H]imipramine binding in hippocampi of lesioned rats was decreased by 46%, whereas the sodium-dependent binding was only 18% of that seen in controls. Desipramine-defined specific binding in absence of sodium was not altered by lesion to serotonergic neurons. The results suggest that desipramine-defined specific [3H]imipramine binding may not be appropriate for studying the role of imipramine sites in relation to serotonin neuronal uptake and that determination of sodium-dependent binding components of both [3H]imipramine binding and serotonin uptake should be used in future studies.     

Effects of dopamine agonists and antagonists on gastric acid secretion and stress responses in rats

The dopamine agonists and promoters bromocriptine, bupropion, and p-hydroxymethylphenidate (a peripherally acting methylphenidate analog) reduced basal gastric acid secretion in rats, while the dopamine antagonists haloperidol, pimozide and metoclopramide augmented gastric acid output. Stress ulcer formation and plasma corticosterone levels were markedly reduced by l-dopa given either intraperitoneally or intracerebroventricularly as well as by intraperitoneally administered p-hydroxymethylphenidate. Domperidone, a peripheral dopamine receptor blocker, produced variable effects on stress responses, indicating a wider spectrum of action than hitherto realized for this compound. The results strongly support a role for both central and peripheral dopaminergic activity in reducing the pathological consequences of exposure to stress.     

Antigastrolesive, gastric antisecretory, diarrheagenic and mucus-stimulating effects in rats following topically applied rioprostil, a synthetic prostaglandin E1 analog

Prostaglandins may have many biological actions including hypotensive and antipeptic ulcer activity. The purpose of this investigation was to determine if the primary alcohol prostaglandin E1 analog rioprostil1 prevents ethanol-induced gastric lesions (antigastrolesive activity), inhibits gastric acid secretion (antisecretory activity), or causes diarrhea in rats when administered topically, and to compare these responses to the effect of rioprostil following enteral (oral or intraduodenal) administration. Rioprostil exhibited antigastrolesive activity in rats when administered either orally or when applied topically. The topical antigastrolesive potency of rioprostil against ethanol-induced lesions [ED50 = 3.7 (0.5-12) micrograms/kg] was similar to its oral potency [ED50 = 1.9 (1.7-2.2) micrograms/kg]. In 4 hr pylorus-ligated rats, topically administered rioprostil inhibited total gastric acid output with a potency [ED50 = 5.1 (2.6-24) mg/kg] similar to intraduodenal administration [ED50 = 3.7 (2.8-5.3) mg/kg]. In addition, in these rats rioprostil increased mucin levels and did not cause dermal irritation. Finally, the incidence of diarrhea was lower when rioprostil was applied topically than when given orally with a 16-fold difference in potency between these two routes of administration. These data show that when rioprostil is applied via the skin it has antigastrolesive, gastric antisecretory and mucus stimulatory effects in rats equal to enteral administration, and a diarrheagenic potency lower than following oral administration. This profile suggests that topical administration of rioprostil may be a useful means of delivery for clinical treatment of peptic ulcer disease.     

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

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

An inhibitor of dopamine uptake,LR5182, CIS-3-(3,4-dichlorophenyl)-2-N,N-dimethylaminomethyl-bicyclo-[2,2,2]-octane,hydrochloride

LR5182 inhibited the uptake of dopamine in rat striatal synaptosomes and the uptake of norepinephrine in cortical synaptosomes with inhibitor constants, Ki values, of 3nM and 58nM, respectively. It was only a week inhibitor of serotonin uptake in cortical synaptosomes with a Ki value of 1.7μM. The uptake of dopamine and norepinephrine were significantly lowered within an hour after an intraperitoneal injection of LR5182. Among known inhibitors of dopamine uptake in synaptosomes of rat brain, LR5182 is most effective and selective. The rigid structure of LR5182 (Figure 1) suggested a gauche conformation of dopamine to be favored by the striatal uptake of dopamine.     

Serotonergic conversion of MPTP and dopaminergic accumulation of MPP+

[3H]MPP+ had lower Km and higher Vmax values for its accumulation in rat brain synaptosomes than did [3H]MPTP. The kinetic parameters favored the uptake of [3H]MPP+ in the striatum to that in hypothalamus, whereas they were equally favorable for the uptake of [3H]MPTP in both regions. Hypothalamic uptake of [3H]MPTP and [3H]MPP+ was inhibited by desipramine, imipramine, norepinephrine, and serotonin. Striatal uptake of [3H]MPP+ and [3H]MPTP was blocked by nomifensine and dopamine. These results support the concept that MPTP accumulates in serotonergic neurons where it is oxidized by monoamine oxidase B to MPP+, which is released and then is selectively accumulated in dopaminergic neurons via the dopamine uptake system.     

Dexamethasone makes the gastric mucosa susceptible to ulceration by inhibiting prostaglandin synthetase and peroxidase - two important gastroprotective enzymes

The plausible mechanism by which dexamethasone makes the gastric mucosa susceptible to ulceration has been studied. As acid aggravates ulcer, the role of dexamethasone on acid secretion was first investigated. Dexamethasone stimulates both basal and drug (mercaptomethylimidazole)-induced gastric acid secretion by 100 and 50% respectively in male Wister rats 24 h after intramuscular administration at the dose of 1 mg/kg body wt. This stimulated acid secretion is 93% blocked by cimetidine indicating increased liberation of histamine in the process. Pretreatment of dexamethasone before 24 h produces ulcer in 30% of the pylorus- ligated rats and aggravates the ulcer index by 82% in both pylorus and esophagus ligated rats. The incidence of ulceration in the latter cases is also increased by 25%. As mucosal prostaglandin synthetase and peroxidase play an important role in gastroprotection through biosynthesis of prostaglandin and by scavenging endogenous H₂O₂ respectively, the effect of dexamethasone on the activities of these gastroprotective enzymes were studied. Prostaglandin synthetase and peroxidase activities of the mucosa are significantly inhibited by 87 and 83% respectively by 24-h pretreatment with dexamethasone. The results indicate that dexamethasone makes the mucosa prone to ulceration by inhibiting the activity of prostaglandin synthetase to block the gastroprotective action of prostaglandin and also by inhibiting the peroxidase, thereby elevating the endogenous H₂O₂ level to generate more reactive hydroxyl radical responsible for the mucosal damage.