Erosions In Rats Research Articles

The Protective Effect of Dapsone Against Ethanol, Stress, and Indomethacin-Induced Gastric Erosion in Rats

Several factors contribute to the development of gastric erosions, including corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs), alcohol, and stress. These factors can cause or worsen gastrointestinal ulcers by activating inflammatory pathways or by altering gastric mucosal blood flow. Dapsone is an antimicrobial compound with anti-inflammatory properties. The aim of this study was to evaluate the protective effects of dapsone against gastric erosions induced by alcohol, stress, or indomethacin. Gastric damage was induced in male rats in three different experimental models: ethanol (5 ml/kg, p.o.)-, water-immersion stress-, and indomethacin (30 mg/kg, p.o.)- induced ulcer. Rats in each of these three experimental models were divided into five groups: Normal group, 2. Control group (gastric damage+vehicle), 3. Gastric damage+dapsone 1 mg/kg, 4. Gastric damage+dapsone 3 mg/kg, 5. Gastric damage+dapsone 10 mg/kg. In this study, the J- score ulcer index and histopathological assessment were performed. In addition, inflammatory cytokines levels, NF-κB expression, and MPO activity were determined. Dapsone reduced the tissue injuries and erosion area in all three experimental groups compared to the control group. In addition, serum levels of inflammatory cytokines, TNF-alpha, and IL-1β were reduced in the dapsone treatment groups. The expression of NF-κB and tissue concentration of myeloperoxidase (a marker of neutrophil activation) was also reduced in rats given dapsone. To conclude, dapsone exhibits significant protective effects against the development of experimental gastric erosions in rats, and these effects seem to be related to its anti-inflammatory and antioxidant properties.

Corticosterone at physiological dose accelerates the healing of experimental gastric erosions in rats

The data of literature about the action of glucocorticoids on the gastric ulcer/erosion healing mainly concern the effects of lasting glucocorticoid therapy or single injection of glucocorticoids at pharmacological doses. These data clearly indicate that glucocorticoids delay the natural healing of experimental gastric injury. However, the role of endogenous glucocorticoids in the gastric mucosal healing processes remained unknown for a long time. In our previous studies we tested this question and the results obtained argue the contribution of endogenous glucocorticoids to the healing of injured gastric mucosa. In the present study we verified whether natural exogenous glucocorticoids (such as corticosterone in rodents) injected at physiological doses similar to endogenous ones may contribute to the healing of gastric erosions accelerating the healing process. For this, in experiments in male SD rats we studied the effects of corticosterone injected at physiological dose 4 mg/kg or dexamethasone injected at the dose 1 mg/kg on the healing of injured gastric mucosa. The glucocorticoid receptor antagonist RU‐38486 (20 mg/kg) was injected to one half of each group 2 h before the glucocorticoid administration. Glucocorticoid or RU‐38486 vehicle (propylene glycol) was injected as a control. Indomethacin (IM) at the dose 35 mg/kg and 3.5 h gastric ischemia‐reperfusion (IR, 30 min occlusion of celiac artery followed by 3 h of reperfusion) were used as ulcerogenic stimuli in preliminary fasted rats. To estimate IM‐ or IR‐induced gastric erosion formation (erosion area) two groups of rats were sacrificed in 4 h after IM injection or 3.5 h after IR. Corticosterone or dexamethasone as well as their vehicle were injected 4 h after IM administration or 3.5 h after IR (0 time point of healing) to other groups to estimate their effects on the healing of injured gastric mucosa in 6 h and 24 h after the hormonal or vehicle administration. IM‐ and IR‐induced erosions healed with time. In control (vehicle treated rats) an average area of erosions in 6 h time point did not differ from that in 0 time point. At the same time an average area of erosions in 24 h time point was significantly lower than that in 0 time point (healing). Corticosterone but not dexamethasone injection accelerated the healing: in corticosterone treated rats significant decrease in an average area of erosions was already observed in 6 h time point. The preliminary glucocorticoid receptor antagonist RU‐38486 injection prevented accelerating effect of corticosterone on the healing process. The findings suggest that natural glucocorticoid corticosterone injected at physiological dose may accelerate the healing of experimental gastric erosions in rats.Support or Funding InformationThe study was supported by grant of Russian Science Foundation (RSF) N 19‐15‐00430.

A “Histodilutional Barrier” Formed in Gastric Mucosa by VEGF Pretreatment Protects Ethanol‐Induced Hemorrhagic Gastric Erosions in Rats

Since VEGF increases vascular permeability (VP), we tested the hypothesis that it might create a perivascular “histodilutional barrier”, like histamine, hence delay the absorption of damaging chemicals.MethodsFasted Sprague‐Dawley rats were given VEGF164 (0.01, 0.04, or 0.2 ug/100g) by gavage either alone or 30 min before administration of 75% ethanol (1 ml/kg). Evans blue was injected i.v. 15 min before autopsy. Rats were euthanized 30 min after VEGF alone or 1 hr after ethanol administration. Scrapings of gastric mucosa were harvested for VP measurement spectrophotometrically (560 nm) of Evans blueextravasation in the gastric mucosa. Hemorrhagic gastric mucosal lesions were measured by an Imaging Analysis System and calculated as % of glandular stomach, and also examined by histology.Results0.04ug/100g VEGF treatment significantly increased gastric VP compared to the controls (p < 0.05). Pretreatment with 0.01, 0.04, or 0.2 ug/100g VEGF reduced ethanol‐induced lesions from 10.6±1.7% (controls) to 8.9±1.8, 0.9±0.2 (p <0.01), or 2.8±0.7% (p <0.05), respectively. Histologic examination showed mild or moderate gastric edema in lamina propria or submucosa after VEGF alone, and no or only superficial gastric erosions in the rats treated with VEGF + ethanol.Conclusions1) Pretreatment with VEGF offered dose‐dependent gastroprotection in rats exposed to ethanol. 2) The likely mechanisms might be related to a histodilutional barrier induced by VEGF. 3) Further studies are needed to elucidate the molecular mechanisms of this new form of gastroprotection.(Supported by VA Merit Review Grants to S. Szabo).

Su1944 Formation of a “Histodilutional Barrier” in Gastric Mucosa: Protective Effect of VEGF on Ethanol-Induced Hemorrhagic Gastric Erosions in Rats

acid-induced hyperemia, further declined by IND pretreatment (10 mg/kg, sc). These results suggest that although GPR43 activation enhances duodenal mucosal defenses by increased DBS via 5HT4 activation, GPR43 activation combined with COX inhibition may increase vulnerability of duodenal mucosa to gastric acid via 5HT3 activation and reduction of blood flow. Excess 5-HT release via GPR43 activation with accompanying acid exposure may be implicated in functional dyspepsia symptoms.

Preventive Effects of Curcumin against Drug and Starvation Induced Gastric Erosions in Rats

The present study was designed to investigate the gastroprotective, analgesic, and antipyretic effects of curcumin (Cur), the major constituent of turmeric. Acetylsalicylic acid (ASA) was used in this study as a standard drug for comparison. The analgesic activity was measured using the Hot-Plate Test. The antipyretic and antiulcer effects were assessed using yeast-induced pyrexia and gastric ulceration, respectively. Curcumin (100 mg/kg) injected intra-peritoneally 1 hr prior to the Hot-Plate Test showed significant analgesic activity expressed by both parameters: an increase in latency time and a reduction in paw licking as compared to the controls. In the animal model of pyrexia, curcumin (100 mg/kg injected intra-peritoneally) exhibited a significant reduction in the rectal temperature after 1 hr, 2 hrs, 4 hrs, and 5 hrs of treatment, indicating the antipyretic effect of curcumin. Rats with orally administered curcumin (200 mg/kg) did not show any lesions on the inner lining of the stomach after a 16 hr fast, indicating the gastroprotective effects of curcumin as compared to saline- and acetylsalicylic acid-administered rats. The significantly low ulcer index in curcumin-treated rats following starvation highlights the gastroprotective characteristics of curcumin.

Effect of royal jelly on experimental colitis Induced by acetic acid and alteration of mast cell distribution in the colon of rats

This study investigated the effects of royal jelly (RJ) on acetic acid-induced colitis in rats. Twenty adult female Wistar albino rats were divided into four treatment groups of 5 animals each, including a control group (Group I); Group II was treated orally with RJ (150 mg kg−1 body weight); Group III had acetic acid-induced colitis; and Group IV had acetic acid-induced colitis treated orally with RJ (150 mg kg−1 body weight) for 4 weeks. Colitis was induced by intracolonic instillation of 4% acetic acid; the control group received physiological saline (10 mL kg−1). Colon samples were obtained under deep anaesthesia from animals in all groups. Tissues were fixed in 10% formalin neutral buffer solution for 24 h and embedded in paraffin. Six-micrometre-thick sections were stained with Mallory’s triple stain and toluidine blue in 1% aqueous solution at pH 1.0 for 5 min (for Mast Cells). RJ was shown to protect the colonic mucosa against the injurious effect of acetic acid. Colitis (colonic damage) was confirmed histomorphometrically as significant increases in the number of mast cells (MC) and colonic erosions in rats with acetic acid-induced colitis. The RJ treatment significantly decreased the number of MC and reduced the area of colonic erosion in the colon of RJ-treated rats compared with rats with untreated colitis. The results suggest that oral treatment with RJ could be used to treat colitis.

Attenuation of gastric mucosal inflammation induced by aspirin through activation of A2Aadenosine receptor in rats

To determine whether a specific adenosine A(2A) receptor agonist (ATL-146e) can ameliorate aspirin-induced gastric mucosal lesions in rats, and reduce neutrophil accumulation and production of pro-inflammatory cytokines. Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 mol/L, 8.0 mL/kg). 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL-146e, 2.5-5 mug/kg, IP) was injected 30 min before the administration of aspirin. Tissue myeloperoxidase (MPO) concentration in gastric mucosa was measured as an index of neutrophil infiltration. Gastric mucosal concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined by ELISA. Also, we examined the effect of ATL-146e on tissue prostaglandin E2 (PGE2) production and gastric secretion. Intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. The total length of gastric erosions (ulcer index) in control rats was 29.8+/-7.75 mm and was reduced to 3.8+/-1.42 mm after pretreatment with 5.0 g/kg ATL-146e (P<0.01). The gastric contents of MPO and pro-inflammatory cytokines were all increased after the administration of aspirin and reduced to nearly normal levels by ATL-146e. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of ATL-146e. The specific adenosine A(2A) receptor agonist, ATL-146e, has potent anti-ulcer effects presumably mediated by its anti-inflammatory properties.

Therapeutic effect of DA-9601 on chronic reflux gastritis induced by sodium taurocholate in rats

To investigate the therapeutic effects of DA-9601 on sodium taurocholate (TCA)-induced chronic reflux gastritis in SD rats. In this study, we have investigated the therapeutic effects of DA-9601 on chronic erosive and atrophic gastritis induced by 6 mo of TCA administration (5 mmol/L in drinking water) in SD rats. Four weeks of DA-9601 administration (0.065%, 0.216% in rat chow), following the withdrawal of TCA treatment, resulted in a significant decrease in total length of erosions in rats in a dose-dependent manner. Furthermore, the indicators of atrophic gastritis, such as reduced mucosal thickness and reduction in the number of parietal cells, were improved by the administration of DA-9601 in a dose-related manner. DA-9601 also attenuated inflammatory cell infiltration and the proliferation of collagenous fiber in the gastric mucosa. The improvement in the reduction of the gastric mucus was observed in the rats receiving a high dose of DA-9601 (0.216%). The therapeutic effect of DA-9601 on experimental chronic erosive gastritis was superior to that of rebamipide (1.08% in rat chow). Biochemical analyses showed increased mucosal prostaglandin E2 and reduced glutathione levels by DA-9601 treatment. We suggest that DA-9601 is a promising agent for the treatment of chronic erosive and atrophic gastritis with an etiological factor of bile reflux. Increased mucosal prostaglandin E2 and reduced glutathione by DA-9601 treatment may be therapeutic mechanisms for chronic erosive and atrophic gastritis.

Effect of Adrenalectomy on Healing of Indomethacin-Induced Gastric Erosions in Rats

We studied the effects of adrenalectomy and replacement therapy on healing of gastric erosions in adult Sprague-Dawley rats developed 4 h after subcutaneous injection of indomethacin in a dose of 25 or 35 mg/kg. Adrenalectomy was performed 1 week before or 4 h after indomethacin administration. Healing was evaluated by changes in the area of erosions over 24 h after indomethacin administration at fixed time intervals. Plasma corticosterone was measured. Adrenalectomy (irrespective of the time of intervention) decelerated healing of gastric injuries. Injection of corticosterone in a physiological dose of 4 mg/kg at the initial stage of healing (4 h after indomethacin administration) improved healing of erosions.

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.

Gastroprotective action of glucocorticoids during the formation and the healing of indomethacin-induced gastric erosions in rats

The aim of the present study consisted of the investigation of glucocorticoid role in the formation and the healing of indomethacin-induced (25 mg/kg, sc) gastric erosions in rats. The effect of deficiency of glucocorticoid production followed by corticosterone replacement on the formation and the healing of the gastric erosions was evaluated. Glucocorticoid production was decreased by adrenalectomy or by delayed inhibitory action after a single pharmacological dose of cortisol (300 mg/kg ip) injected 1 week before the onset of ulcerogenic stimulus. Indomethacin induced corticosterone rise and caused gastric erosions. The loss of indomethacin-induced plasma corticosterone rise potentiated the formation of indomethacin-induced erosions in both models. The area of gastric erosions in rats with glucocorticoid deficiency was considerably larger than that in control animals 4 h after indomethacin administration as well as during 48 h after the drug administration (period of erosion healing). Injecting corticosterone in rats with glucocorticoid deficiency significantly decreased the formation of indomethacin-induced gastric erosions and promoted their healing. Thus, the present data support the gastroprotective action of glucocorticoids in the formation and in the healing of indomethacin-induced mucosal injury.

Dietary cod liver oil decreases arachidonic acid in rat gastric mucosa and increases stress‐induced gastric erosions

The purpose of this study was to examine the influence of long-term feeding of dietary fat rich in either n-3 or n-6 fatty acids on the availability of arachidonic acid (20:4n-6) in major phospholipids of gastric mucosa in rats. Three groups of male Wistar rats were fed either a standard diet, a cod liver oil-enriched diet (10% by weight), or a corn oil-enriched diet (10% by weight) for 8 mon. Dietary cod liver oil significantly reduced the level of 20:4n-6 in phosphatidylcholine (PC) and in phosphatidylethanolamine (PE) of gastric mucosa. The loss of 20:4n-6 was compensated for by eicosapentaenoic acid (20:5n-3) in PC, whereas the decrease in 20:4n-6 in PE corresponded to the increase in three n-3 fatty acids: 20:5n-3, docosapentaenoic acid (22:5n-3), and docosahexaenoic acid (22:6n-3). The level of 20:5n-3 was higher than the level of 22:6n-3 both in PC and PE of mucosa in rats fed cod liver oil. Diets supplemented with corn oil increased the level of 18:2n-6 but decreased the monoene fatty acids 16:1 and 18:1n-7 in PC but not in PE of gastric mucosa. The 20:4n-6 levels of both PC and PE were markedly reduced by dietary cod liver oil, to about one-third of control levels. Similar changes were also observed in the stomach wall. Gastric erosions were observed in all rats exposed to restriction stress, but this form of stress induced twice the number of erosions in rats fed fish oil compared to control rats or rats fed corn oil. We conclude that a diet rich in fish oil altered the balance between n-6 and n-3 fatty acids in major gastric mucosal phospholipids, markedly reduced the availability of 20:4n-6, and increased the incidence of gastric erosions induced by restriction or emotional stress.

Gastric mucosal erosion produced by NMDA microinfusions in the lateral hypothalamus: effect of selective knife cuts

Bilateral infusions of N-methyl- d-aspartate (NMDA) into the lateral hypothalamus (LH) produce gastric erosions in rats. The present study attempted to determine the neural pathways that mediate this effect. In order to interrupt axonal transmission, knife cuts (KC) were made in different planes adjacent to the LH. In separate groups of rats, KC were made anterior, posterior or lateral to the LH just prior to bilateral NMDA infusions (20 μg/μl). The incidence of gastric erosions was measured 24 h after NMDA infusions. Animals receiving sham KC and infused with NMDA exhibited significantly more gastric erosions than those infused with vehicle. Lateral parasagittal KC blocked the occurrence of gastric erosions produced by NMDA, whereas anterior coronal KC significantly increased the incidence of erosions produced by NMDA. Posterior coronal KC did not alter the incidence of gastric erosions produced by NMDA infusions into the LH. These results suggest that intrinsic LH neurons with gastric function project axons laterally and probably descend through the internal capsule to brainstem medullary nuclei. The results of the anterior KC suggest that the LH sends and/or receives inhibitory projections from neural structures (possibly the amygdaloid complex) anterior to the plane of the KC.

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.

Intracerebroventricular CRF inhibits cold restraint-induced c-fos expression in the dorsal motor nucleus of the vagus and gastric erosions in rats

Acute exposure to cold-restraint induces vagal-dependent gastric erosions associated with activation of neurons in the dorsal motor nucleus of the vagus (DMN) in rats. The influence of intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF) (10 μg) on c-fos expression in the brain and gastric erosions induced by 3 h cold-restraint was investigated in conscious rats. In cold-restraint exposed rats, CRF injected i.c.v. inhibited gastric erosions and the number of Fos positive neurons in the DMN by 93 and 72%, respectively, while Fos labelling in the nucleus tractus solitarius (NTS) was increased by 5-fold compared with vehicle group. c-fos expression was also induced in the central amygdala by i.c.v. CRF, unlike the vehicle-injected group exposed to cold-restraint. c-fos expression induced by cold-restraint in the raphe pallidus (Rpa) and paraventricular nucleus of the hypothalamus was not altered by i.c.v. CRF. These data indicate that central CRF-induced gastric protection results from the inhibition of DMN neuronal activity enhanced by cold-restraint. CRF action on DMN neurons may be related to the increase in the NTS and central amygdala inputs leading to inhibition of DMN neurons rather than to the decrease in the excitatory input from the caudal raphe projections to the DMN.

Intracerebroventricular CRF inhibits cold restraint-induced c- fos expression in the dorsal motor nucleus of the vagus and gastric erosions in rats

Acute exposure to cold-restraint induces vagal-dependent gastric erosions associated with activation of neurons in the dorsal motor nucleus of the vagus (DMN) in rats. The influence of intracerebroventricular (i.c.v.) injection of corticotropin-releasing factor (CRF) (10 μg) on c- fos expression in the brain and gastric erosions induced by 3 h cold-restraint was investigated in conscious rats. In cold-restraint exposed rats, CRF injected i.c.v. inhibited gastric erosions and the number of Fos positive neurons in the DMN by 93 and 72%, respectively, while Fos labelling in the nucleus tractus solitarius (NTS) was increased by 5-fold compared with vehicle group. c- fos expression was also induced in the central amygdala by i.c.v. CRF, unlike the vehicle-injected group exposed to cold-restraint. c- fos expression induced by cold-restraint in the raphe pallidus (Rpa) and paraventricular nucleus of the hypothalamus was not altered by i.c.v. CRF. These data indicate that central CRF-induced gastric protection results from the inhibition of DMN neuronal activity enhanced by cold-restraint. CRF action on DMN neurons may be related to the increase in the NTS and central amygdala inputs leading to inhibition of DMN neurons rather than to the decrease in the excitatory input from the caudal raphe projections to the DMN.

Potentiating interactions between medullary serotonin and thyrotropin-releasing hormone-induced gastric erosions in rats

The central interaction between 5-HT and exogenous and endogenous thyrotropin-releasing hormone (TRH)-induced gastric lesions was investigated in conscious rats. Intracisternal injection (i.c.) of the TRH analog, RX 77368, (2.5 nmol) in indomethacin (2 mg/kg, i.p.)-treated rats produced 1.4 ± 0.1% of gastric corpus mucosal lesions which were aggravated by 30 and 208% by simultaneous i.c. injection 5-HT at 10 and 100 nmol, respectively, whereas i.v. 5-HT (100 nmol) had no effect. The 5- HT 2 1 c antagonist, ketanserin, given i.c. at 10 or 100 nmol reduced by 44 and 76%, respectively, cold restraint stress-induced 3.4 ± 0.6% gastric lesions in indomethacin-pretreated rats whereas, when given i.v. (100 nmol), it was inactive. Ketanserin or 5-HT (100 nmol, i.c.) alone did not modify the gastric mucosa. The present data suggest a potentiating interaction between endogenous 5-HT and TRH which has implication in the understanding of medullary mechanisms involved in gastric lesion formation induced by cold restraint.

The effect of CV‐3988 and CV‐6209 on the acute gastric erosions of rats due to water‐immersion and restraint stress

CV-3988 and CV-6209 inhibited gastric erosions in rats due to water-immersion and restraint stress in a dose-dependent manner. The above inhibitory effects of CV-3988 were observed in the presence of indomethacin, which may indicate that the inhibition is not prostaglandin dependent. The studies indicate that platelet-activating factor may be involved in the formation of erosions in rats under water-immersion and restraint stress.

The role of vasopressin in the pathogenesis of ethanol-induced gastric hemorrhagic erosions in rats: Is vasopressin an endogenous aggressor toward the gastric mucosa?

The role of vasopressin in the development of gastric hemorrhagic erosions induced by the oral administration of 1 mL of 75% ethanol in rats was studied. The area of the lesions in homozygous Brattleboro rats, having a defective vasopressin synthesis, was only 20% of that found in Wistar and heterozygous Brattleboro rats, which have normal vasopressin production. It is well known that vasopressin acts via the V1 (presser) and V2 (antidiuretic) receptors. Administration of V1 and V2 vasopressin-receptor agonists and antagonists in this model showed that pressor-receptor activity is needed for the generation of all lesions in Wistar and heterozygous Brattleboro rats. Ethanol damage to the gastric mucosa was diminished by the V1 antagonist with similar efficacy as in the case of a vasopressin deficiency. Administration of the V1 antagonist and the absence of endogenous vasopressin were shown to protect the deeper layer of the gastric mucosa (assessed by histology) and to reduce significantly the ethanol-induced vascular injury and increase in vascular permeability (assessed by the monastral blue technique). Thus, endogenous vasopressin is clearly of great importance in the pathogenesis of gastric hemorrhagic lesions induced by ethanol. These results strongly suggest that vasopressin is an endogenous aggressor toward the gastric mucosa.

Effects of the Proton Pump Inhibitor, E3810, on Gastric Secretion and Gastric and Duodenal Ulcers or Erosions in Rats

The effects of E3810, a potent proton pump inhibitor, on gastric secretion and gastric or duodenal ulcers or erosions were studied in rats. Intraduodenal administration of E3810 dose dependently inhibited gastric secretion (volume and acid outputs) in pylorus-ligated rats. The effective dose required to inhibit volume output by 50% (ED50) was 12 mg/kg and that for acid output was 3.4 mg/kg. Acutely induced gastric ulcers or erosions, such as cold-restraint stress erosions, Shay ulcers and mercaptamine (cysteamine)-induced duodenal ulcers, were significantly inhibited by oral, intraduodenal or subcutaneous administration of E3810 at 1 to 100 mg/kg. The protective effects of E3810 in these acute models were compared with those of omeprazole at the same doses. At low doses, 10 mg/kg (intraduodenally) in Shay ulcers and 3 mg/kg (subcutaneously) in mercaptamine-induced ulcers, E3810 was significantly more effective than omeprazole. But at high doses, there was no significant difference between the 2 drugs in efficacy. In the cold stress erosion model, the drugs were equally effective.