Ethanol-induced Gastric Lesions In Rats Research Articles

PROTECTIVE EFFECTS OF QUERCETIN, A FLAVONOID ANTIOXIDANT, IN ABSOLUTE ETHANOL-INDUCED ACUT GASTRIC ULCER

Free radicals have been reported to be responsible for many ailments including gastroduodenal ulcers. Recent studies demonstrated that quercetin (QE) has an antioxidant effects on injuries caused by various toxic agents in different experimental models. In our study, we examined anti-ulcerogen and antioxidant effects of quercetin on ethanol-induced gastric lesions in rats. QE was administered intraperitoneally (i.p.) 50 mg/kg. It was found that pretreatment with QE significantly reduced ethanol-induced gastric damage and malondialdehyde levels, and significantly increased antioxidant enzyme activities. We conclude that QE clearly has antioxidant properties and that the protective effect of QE against ethanol-induced gastric mucosal lesion, at least in part, depends upon the reduction in the lipid peroxidation and an increase in the activity of antioxidant enzymes.

Gastroprotective effects of phenylpropanoids from the rhizomes of Alpinia galanga in rats: structural requirements and mode of action

The effects of 1′ S-1′-acetoxychavicol acetate and related phenylpropanoids isolated from the rhizomes of Alpinia galanga on ethanol-induced gastric lesions in rats were examined. Among them, 1′ S-1′-acetoxychavicol acetate and 1′ S-1′-acetoxyeugenol acetate markedly inhibited the ethanol-induced gastric mucosal lesions (ED 50=0.61 and ca. 0.90 mg/kg). In addition, 1′ S-1′-acetoxychavicol acetate inhibited the lesions induced by 0.6 M HCl (ED 50=0.73 mg/kg) and aspirin (ED 50=0.69 mg/kg) but it did not show a significant effect on indomethacin-induced gastric lesions and acid output in pylorus-ligated rats at doses of 0.5–5.0 mg/kg. From the gastroprotective effects of various related compounds, the 1′-acetoxyl group of 1′ S-1′-acetoxychavicol acetate and 1′ S-1′-acetoxyeugenol acetate was found to be essential for their strong activity. With regard to the mode of action, the gastroprotective effects of 1′ S-1′-acetoxychavicol acetate were attenuated by pretreatment with indomethacin and N-ethylmaleimide, and 1′ S-1′-acetoxychavicol acetate significantly increased the glutathione levels of gastric mucosa in rats. These findings suggest that endogenous prostaglandins and sulfhydryl compounds are involved in the protective effect of 1′ S-1′-acetoxychavicol acetate.

Protective effects of steroid saponins from paris polyphylla var. yunnanensis on ethanol- or indomethacin-induced gastric mucosal lesions in rats: structural requirement for activity and mode of action

The methanolic extract from the rhizomes of Paris polyphylla S m. var . yunnanensis (F r.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3- O-α- l-rhamnopyranosyl(1→2)-[α- l-arabinofuranosyl(1→4)]-β- d-glucopyranoside ( 1), pennogenin 3- O-α- l-rhamnopyranosyl(1→4)-α- l-rhamnopyranosyl(1→4)-[α- l-rhamnopyranosyl(1→2)]-β- d-glucopyranoside ( 2), diosgenin 3- O-α- l-rhamnopyranosyl(1→2)-[α- l-arabinofuranosyl(1→4)]-β- d-glucopyranoside ( 3), and diosgenin 3- O-α- l-rhamnopyranosyl(1→4)-α- l-rhamnopyranosyl(1→4)-[α- l-rhamnopyranosyl(1→2)]-β- d-glucopyranoside ( 4), and a new furostanol-type steroid saponin, parisaponin I ( 5), together with two known furostanol-type steroid saponins, trigofoenoside A ( 6) and protogracillin ( 7), were isolated from the active fraction. Compounds 1– 4 (1.25–10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3- O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.

Protective effect of a plant formula on ethanol-induced gastric lesions in rats.

A plant formula and its five components were evaluated independently for their gastric protective effect against ethanol-induced stomach lesions in rats. Aqueous extracts of the plant formula (0.25-2g crude drug/kg orally) and its individual components (at the same dose) all showed significant stomach protective effects dose dependently. However, when these extracts were given to rats at a dose of 0.25 g/kg, the five single-herb preparations did not show any activity, but the formula-extract still exhibited a strong protective effect. These findings suggest the presence of a synergistic effect among the plant components. Chemical examination of the extracts indicated that the major ingredients of the five plants were essential oils, terpenoids, flavonoids, glycosides and saccharides and these may contribute to the stomach protective activity observed.

Mechanism of the beneficial effects of dantrolene sodium on ethanol-induced acute gastric mucosal injury in rats

In our study, we examined anti-ulcerogen and antioxidant effects of dantrolene sodium on ethanol-induced gastric lesions in rats. Dantrolene sodium was administered intraperitoneally (i.p.) in several doses, and famotidine was used at a dose of 20 mg kg −1. It was found that pretreatment with dantrolene sodium at doses of 1, 5 and 10 mg kg−1 significantly reduced ethanol-induced gastric damage and malondialdehyde levels, and significantly increased antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities. We conclude that dantrolene sodium clearly has antioxidant properties and that the protective effect of dantrolene sodium against ethanol-induced gastric mucosal lesion, at least in part, depends upon the reduction in the lipid peroxidation and an increase in the activity of antioxidant enzymes SOD and GSH-Px.

Protective effects of polygodial and related compounds on ethanol-induced gastric mucosal lesions in rats: structural requirements and mode of action

The methanolic extract from the leaves of Tasmannia lanceolata was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, three known sesquiterpenes, polygodial, polygodial 12α-acetal, and polygodial 12β-acetal, and a new sesquiterpene, methyl isodrimeninol, were isolated as the active constituents. Among them, polygodial showed very potent gastroprotective effects (ED 50=0.028 mg/kg, po). From the gastroprotective effects of various reduction and oxidation derivatives of polygodial, the dialdehyde or diacetal structure was found to be essential for the strong activity. Since the gastroprotection of polygodial was attenuated by pretreatment with indomethacin, N-ethylmaleimide, N G-nitro- l-arginine methyl ester and ruthenium red, endogenous prostaglandins, sulfhydryl compounds, nitric oxide and vanilloid receptors may be involved in the protective activity.

Monochloramine impairs mucosal blood flow response and healing of gastric lesions in rats: relation to capsaicin-sensitive sensory neurons.

We examined the effects of monochloramine (NH2Cl) on the gastric mucosal blood flow (GMBF) response and the healing of ethanol-induced gastric lesions in rats. Rats fasted for 18 h were given the 99% ethanol p.o. for induction of gastric lesions, and were fed normally from 1 h later onwards. Monochloramine, at non-ulcerogenic doses (5 to approximately 20 mmol/L), was given p.o. twice daily for 7 days, starting 2 h after ethanol treatment. Gastric lesions caused by ethanol healed almost completely within 7 days with re-epithelialization. The repeated administration of NH2Cl significantly delayed the healing of ethanol-induced gastric lesions in a dose-dependent manner. The damaged mucosa showed a marked rise in H+ permeability, resulting in luminal acid loss, but this process was accompanied by an increase of mucosal blood flow. Monochloramine did not affect the increased mucosal H+ permeability observed in the stomach after damage by ethanol, but significantly inhibited the mucosal hyperemic response associated with luminal acid loss. Prior exposure of the mucosa to NH2Cl (20 mmol/L) did not affect the gastric hyperemic response caused by mucosal application of misoprostol (a prostaglandin E1 derivative) or NOR-3 (a nitric oxide donor), but totally attenuated the increase of GMBF in response to intragastric capsaicin. Impaired healing and GMBF responses were also observed in rats following chemical ablation of capsaicin-sensitive sensory neurons. These results suggest that NH2Cl impaired the healing of acute gastric mucosal lesions at low concentrations, and this action may be attributable, at least partly, to the impairment of gastric hyperemic response caused by the dysfunction of capsaicin-sensitive sensory neurons.

The Effects of Captopril and Naloxone on Restraint–Cold-Stress- and Ethanol-Induced Gastric Lesions in Rats

1. This study was undertaken to investigate the effect of captopril (1 μg/kg or 1 mg/kg, IP) on the actions of naloxone (5 mg/kg, IP) in gastric ulceration induced by ethanol and restraint–cold-stress. 2. Neither naloxone (5 mg/kg, IP) nor captopril (1mg/kg, IP) alone induced any change in the indices of the ulcer in either group. 3. Captopril at a lower dose (1μg/kg, IP), when combined with naloxone (5 mg/kg, IP), significantly reduced cumulative ulcer length only in the ethanol-treated group (from 54.9±7.2 mm to 22.5±6.2 mm). 4. However, a high dose of captopril (1 mg/kg) plus naloxone pretreatment caused a significant reduction in both ethanol (from 54.9±7.2 mm to 24.9±6.5 mm) and restraint–cold-stress (from 19.0±3.0 mm to 5.3±1.0 mm)-induced ulcer formation. 5. Acetylsalycilic acid, when used together with captopril, increased the ulcer formation induced by stress. 6. Naloxone, by increasing the release of prostaglandins, has been shown to prevent ulcer formation induced by several noxious stimuli. 7. Therefore, the effect of the combination might be due to the synergistic interaction of both drugs on prostaglandin synthesis.

Prevention of ethanol-induced gastric lesions in rats by wu-bei-san.

The effects of Wu-Bei-San (WBS) and its components Wu-Tsi-Ku (WTK) and Bei-Mu (BM) on gastric lesions induced by necrotizing agents were investigated in rats. Oral administration of WBS or WTK, but not BM, dose-dependently prevented gastric lesions induced by ethanol. Moreover, the gastric protective action of WTK was potentiated by simultaneous administration of BM under the same experimental conditions. Pretreatment with indomethacin, which is a prostaglandin synthesis inhibitor and idoacetamide, which is a sulfhydryl blocker did not influence the inhibited ethanol lesion of WBS. Gastric lesions induced by acidified aspirin were prevented by both WBS and calcium carbonate, which is a major constituents of WTK. However, pretreatment with calcium carbonate did not affect the gastric lesions induced by ethanol. These results indicate protective action of WBS on the gastric mucosa through both acid neutralization and cytoprotection, although more work is needed to clarify the role of WBS in cytoprotection.

Gastrointestinal actions of buprenorphine: are different receptors involved?

The effects of buprenorphine on castor-oil-induced diarrhoea, gastrointestinal transit and ethanol-induced gastric lesions in rats were compared to the same effects of morphine. Like morphine, buprenorphine prevented castor-oil-induced diarrhoea. However, it has no effect on gastrointestinal transit per se but prevented the inhibitory action of morphine. While morphine protected against ethanol-induced gastric lesions, buprenorphine aggravated them. It is suggested that different types/subtypes of opioid receptors may be involved in the gastrointestinal actions of buprenorphine.

Drugs acting at central benzodiazepine receptors attenuate ethanol-induced gastric lesions in rats

The characteristics of the receptors involved in the protective action of benzodiazepines against ethanol-induced gastric lesions were investigated by studying the effect of benzodiazepine ligands on such lesions in both intact and unilaterally vagotomized rats. Clonazepam [5-(2-chlorophenyl)-1,3-dihydro-7-nitro-2 H-1,4-benzodiazepine-2-one] a specific central-type receptor agonist (0.625–2.5 mg/kg p.o. or i.p.) and CGS 9896 [2-(4-chlorophenyl)-2,5-dihydropyrazolo{4,3-c}quinoline-3(3 H)-one] a non-sedative partial agonist with anxiolytic properties (2.5–10 mg/kg p.o.) significantly reduced the gastric damage induced by ethanol (10 ml/kg of a 50% solution v/v p.o.) in non-vagotomized rats but Ro 5-4864 [7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2 H-1,4-benzodiazepine-2-one] a pure peripheral-type receptor agonist (5–20 mg/kg p.o.) failed to affect this damage. The protective action of clonazepam and CGS 9896 against ethanol-induced gastric lesions was blocked, dose dependently, by the central-type receptor antagonist, flumazenil [ethyl8-fluoro-5,6-5-methyl-6-oxo-4 H-imidazo{1,4}benzodiazepine-3-carboxylate] (1.25–20 mg/kg i.p.). In the unilaterally vagotomized rat, ethanol produced lesions in the right (vagotomized) and the left (non-vagotomized) halves of the gastric mucosa to nearly the same extent, while clonazepam and CGS 9896 uniformly decreased the lesions in both halves. It is concluded that central-type benzodiazepine receptors located in the stomach, specifically those mediating the anxiolytic effect of benzodiazepines, are involved in the protective action of benzodiazepines against ethanol-induced gastric lesions.

Studies on Antiulcer Agents. I. Synthesis and Pharmacological Properties of Ethyl 2-((1H-Benzimidazol-2-yl)sulfinylmethyl)-4-dimethylamino-5-pyrimidinecarboxylate, a New H+/K+-ATPase Inhibitor Possessing Mucosal Protective Activity.

Ethyl 2-[1H-benzimidazol-2-yl)sulfinylmethyl]-4-dimethylamino-5- pyrimidinecarboxylate (2) has been synthesized and evaluated for antiulcer properties. Compound 2 is a H+/K(+)-ATPase inhibitor that affords mucosal protection against absolute ethanol-induced gastric lesions in rats after oral and parenteral administrations. On the other hand, omeprazole, a representative H+/K(+)-ATPase inhibitor, showed mucosal protective action only after oral administration, indicating that it required gastric acid secretion to generate activity. The antiulcer activity of 2 in animal models, such as water-immersion stress-induced gastric ulcer in rats and acidified aspirin-induced gastric ulcer in rats, was three times higher than that of cimetidine.

P2-144 - Effect of diet-induced hypercholesterolemia on HCI plus ethanol-induced gastric lesions in rats

P2-144 - Effect of diet-induced hypercholesterolemia on HCI plus ethanol-induced gastric lesions in rats

Adrenalectomy, but not vagotomy, reverses the worsening effect of Ca 2+ blockers on ethanol-induced gastric lesions in rats

This study examines the influence of the adrenals and of the vagus nerve on the lesion-worsening action of nitrendipine or verapamil on 75% ethanol-induced gastric mucosal damage in rats. Bilateral adrenalectomy antagonized ethanol lesion aggravation by nitrendipine or verapamil; instead, dose-related lesion reduction was seen. Dexamethasone treatment of adrenalectomized rats restored the lesion-enhancing effects of both Ca 2+ channel blockers. Bilateral subdiaphragmatic vagotomy failed to abolish the adverse action of nitrendipine or verapamil on ethanol lesions. The findings suggest that the adrenal corticoids modulate the worsening effect of Ca 2+ channel antagonists on ethanol-induced gastric damage; when the influence of the adrenal steroids is removed, these compounds become gastroprotective.

Dual effects ofN-ethylmaleimide on ethanol-induced gastric lesions in rats

The effects of N-ethylmaleimide (NEM), a sulfhydryl (SH) blocker, on ethanol-induced gastric lesions were investigated in rats by varying the route of administration. Oral administration of acidified ethanol (60% ethanol in 150 mM HCl, 1 ml) produced hemorrhagic bandlike lesions in the gastric mucosa. Pretreatment of the animals with orally administered NEM (0.1-10 mg/kg) dose-dependently inhibited these lesions (the inhibition was over 80% at 1 mg/kg or greater), and the effects were partially reversed by indomethacin (5 mg/kg, subcutaneous). However, when NEM (10 mg/kg) was given subcutaneously, this agent significantly worsened the lesions. Intragastrically applied NEM produced a dose-dependent reduction of the transmucosal potential difference (PD) and the mucosal nonprotein SH levels, an increase of the volume of gastric contents, and an inhibition of gastric motility, while these parameters remained unaltered after subcutaneous administration of the agent. The microvascular permeability in the mucosa was significantly increased by both oral and subcutaneous administration of NEM (10 mg/kg) but remained unchanged in response to lower doses of orally administered (less than 3 mg/kg). These results suggest that NEM given orally is cytoprotective to the stomach against ethanol, probably by acting as a mild irritant and due to dilution of an irritant and inhibition of gastric motility (muscle relaxation), but when given subcutaneously it aggravates the lesions by unknown mechanisms.

Effects of Sasa Senanensis Rehder Extract (SE) on Stress or Ethanol-induced Gastric Lesions in Rats

Effects of Sasa Senanensis Rehder Extract (SE) on Stress or Ethanol-induced Gastric Lesions in Rats

Prevention of Ethanol-Induced Gastric Lesions in Rats by Natural Honey, and Its Possible Mechanism of Action

The effects and the mechanism of natural honey on absolute ethanol-induced gastric lesions were studied in rats. Drugs and/or honey were administered subcutaneously or orally to 48-h fasted animals at different time intervals before oral administration of ethanol (0.5 ml/100 g). Mucosal damage and pH were measured 1 h later. Honey afforded protection against gastric damage and reversed the changes in pH induced by ethanol. The effects of honey were dose- and time-dependent. Thus, pretreatment with honey (1.25 g/kg) 30 min before ethanol provided more than 80% protection. On the other hand, administration of honey simultaneously with or 5 min after ethanol failed to offer protection. The cyclooxygenase inhibitor indomethacin (IND) did not alter the protective effects when given before or after honey. The protective effects of honey could be reversed by treatment with the sulfhydryl (SH) blocker N-ethylmaleimide (NEM). Combined IND and NEM treatment caused greater reduction of the protective effects, but the values were not significantly different from those obtained with NEM alone. Thus, the gastroprotective effects of honey appeared to be mediated through SH-sensitive processes. Furthermore, the protective effects were supported by both macroscopic and microscopic findings. It is suggested that honey may be used clinically in preventing/reducing ethanol-induced gastric lesions in humans.

The Role of Capsaicin-Sensitive Afferent Nerves in Protective Effect of Capsaicin against Absolute Ethanol-Induced Gastric Lesions in Rats

The role of capsaicin-sensitive afferent nerves in gastroprotection by capsaicin was investigated in the absolute ethanol-induced gastric lesion model in rats. Capsaicin (0.1 and 0.5 mg/kg, p.o.) inhibited the lesion formation dose-dependently. The protective effect of capsaicin was attenuated by indomethacin-pretreatment and disappeared in capsaicin-sensitive nerve degenerated rats. Capsaicin did not induce the distension of gastric mucosal folds. These results suggested that stimulation of capsaicin-sensitive afferent nerves by capsaicin would enhance the prostaglandin formation, leading to an inhibition of gastric lesions.

The role of capsaicin-sensitive afferent nerves in protective effect of capsaicin against absolute ethanol-induced gastric lesions in rats.

The role of capsaicin-sensitive afferent nerves in gastroprotection by capsaicin was investigated in the absolute ethanol-induced gastric lesion model in rats. Capsaicin (0.1 and 0.5 mg/kg, p.o.) inhibited the lesion formation dose-dependently. The protective effect of capsaicin was attenuated by indomethacin-pretreatment and disappeared in capsaicin-sensitive nerve degenerated rats. Capsaicin did not induce the distension of gastric mucosal folds. These results suggested that stimulation of capsaicin-sensitive afferent nerves by capsaicin would enhance the prostaglandin formation, leading to an inhibition of gastric lesions.

Effect of captopril on oxyphenbutazone and ethanol-induced gastric lesions in rats

We studied the effect of the angiotensin converting enzyme inhibitor, captopril, on two models of gastric ulcers; oxyphenbutazone and ethanol-induced lesions. There was a significant protective effect against oxyphenbutazone-induced ulcers, which was prevented by prior administration of indomethacin. Captopril, however, failed to protect against ethanol-induced lesions. These findings are discussed in the light of captopril being a sulfhydryl compound with prostaglandin-releasing activity.