Mucosal Lesions In Rats Research Articles

Roles of nocturnal melatonin and the pineal gland in modulation of water-immersion restraint stress-induced gastric mucosal lesions in rats.

The roles of melatonin and the pineal gland in the circadian variation of water-immersion restraint stress-induced gastric mucosal lesions in rats were investigated. Fasted rats were subjected to water-immersion restraint stress during both the diurnal and nocturnal phases of a light:dark cycle. Pinealectomized and sham-operated rats were also subjected to water-immersion restraint stress at night. The lesion area after 4 hr of stress during the dark phase was significantly lower than in light-phase controls. Pinealectomy increased the lesion area in the dark phase, compared to the sham operation, but this effect was counteracted by intracisternal melatonin preadministration at a dose of 100 ng/rat. Melatonin concentrations in control rats during the light phase were significantly increased 4 hr after water-immersion restraint stress. In contrast, melatonin concentrations 4 hr after water-immersion restraint stress in the dark phase were significantly depressed compared with the control levels at the corresponding time. Melatonin levels after stress exposure were markedly decreased in pinealectomized rats as compared with sham-operated rats. These results suggest that circadian rhythm has an important role in the formation of stress-induced gastric mucosal lesions in rats and that melatonin responses to water-immersion restraint stress differ between day and night. The pineal gland modulates the stress response and melatonin contributes to gastric protection via a mechanism involving the central nervous system.

Preventive effect of ebselen on acute gastric mucosal lesion development in rats treated with compound 48/80

The preventive effect of ebselen, a seleno-organic compound, which is known to possess glutathione peroxidase-like activity and antioxidative and anti-inflammatory properties, on the development of acute gastric mucosal lesions was examined in rats with a single injection of compound 48/80 (0.75 mg/kg, i.p.), a mast cell degranulator. Pre-administration of ebselen (p.o.) at a dose of 50 or 100 mg/kg, but not 10 mg/kg, prevented gastric mucosal lesion development at 3 h, but not gastric mucosal lesion formation at 0.5 h, after compound 48/80 injection, although any dose of pre-administered ebselen did not affect decreased gastric mucosal blood flow and increased serum serotonin and histamine concentrations found at 0.5 and 3 h after compound 48/80 injection. A decrease in Se-glutathione peroxidase activity and increases in the activities of myeloperoxidase, an index of tissue neutrophil infiltration, and xanthine oxidase and the concentration of thiobarbituric acid reactive substances, an index of lipid peroxidation, were found in gastric mucosal tissues at 0.5 h after compound 48/80 injection and these changes were further enhanced at 3 h. Pre-administration of ebselen (p.o.) at a dose of 50 or 100 mg/kg, but not 10 mg/kg, attenuated all these changes found at 3 h after compound 48/80 injection. These preventive effects of ebselen occurred in a dose-dependent manner. The present results indicate that pre-administered ebselen prevents the development of compound 48/80-induced acute gastric mucosal lesions in rats, and suggest that this preventive effect of ebselen could be due to its glutathione peroxidase-like activity and antioxidative and anti-inflammatory properties.

Nitric Oxide Donating Compounds Inhibit HCl-Induced Gastric Mucosal Lesions Mainly via Prostaglandin

Prostaglandin (PG) and nitric oxide (NO) have been known to inhibit the lesion formation induced by necrotic agents. However, no clear correlation between PG and NO has been shown in the gastro-protective action against necrotic agent-induced gastric mucosal lesions in rats. Thus, the present study was performed to clarify this correlation. Gastric mucosal lesions were induced by the oral administration of 0.6 M HCl in rats. 16,16-Dimethyl PGE2 (0.3 - 3 μ g /kg, p.o.; dim-PGE2), sodium nitrite (0.3 and 1 mg /kg, s.c.) and sodium nitroprusside (30 and 100 mg /kg, i.v.; SNP) dose-dependently inhibited the lesion formation. Orally administered sodium nitrite or SNP (3 mg/kg) also significantly inhibited the lesion formation. The gastroprotective action by dim-PGE2 was not affected by the pre-treatment with NG-nitro-L-arginine methylester (10 mg/kg, i.v.). The gastroprotective effect by sodium nitrite or SNP was markedly attenuated by the pre-treatment with indomethacin (10 mg/kg, s.c.). These findings suggest that NO donating compounds inhibit the HCl-induced mucosal lesions mainly through prostaglandin, but dim-PGE2 directly inhibits the lesions without involvement of NO in rats.

Neutrophil chemoattractant 2β regulates expression of the Reg gene in injured gastric mucosa in rats

Background & Aims: Regenerating (Reg) protein has a trophic effect on gastric mucosal cells. We have shown that Reg gene expression is increased in enterochromaffin-like (ECL) cells during the healing of damaged gastric mucosa around mucosal erosion. This study was designed to explore the stimulants of Reg expression during the healing of gastric mucosal damage. Methods: Time course changes of the expression of genes for various proinflammatory cytokines and Reg were investigated after induction of gastric mucosal lesions in rats. The direct effect of proinflammatory cytokines on Reg gene expression and Reg protein production were investigated in vitro using counterflow elutriation–enriched rat ECL cells. CXC receptor 2 (CXCR-2) expression was investigated in ECL cells by reverse-transcription polymerase chain reaction. Reg gene expression was also investigated in rats treated by the neutralizing antibody of cytokine-induced neutrophil chemoattractant (CINC-2β). Results: During healing, the gene expression of several proinflammatory cytokines and Reg was markedly augmented. Among the proinflammatory cytokines, CINC-2β is the only cytokine in which augmented expression preceded the increase of Reg gene expression. In rats treated with CINC-2β neutralizing antibody, the augmentation of Reg gene expression was significantly inhibited. When ECL cells were incubated with these proinflammatory cytokines, CINC-2β dose-dependently increased Reg messenger RNA and Reg protein in ECL cells. CXCR-2 was identified in isolated ECL cells. Conclusions: CINC-2β, expressed in damaged gastric mucosa, stimulates the production of Reg protein in ECL cells via CXCR-2 and may be involved in the accelerated healing of injured gastric mucosa.GASTROENTEROLOGY 2000;119:1610-1622

Effects of Centella asiatica on ethanol induced gastric mucosal lesions in rats

Centella asiatica is a herbal medicine widely used in China and India for wound healing. The aim of this study was to examine its effects on the prevention of ethanol induced gastric lesions in rats. Gastric transmucosal potential difference (PD) was reduced by the application of 50% ethanol in the gastric ex-vivo chamber model and Centella extract (CE) accelerated its recovery. Oral administration of CE (0.05g/kg, 0.25g/kg and 0.50g/kg) before ethanol administration significantly inhibited gastric lesions formation (58% to 82% reduction) and decreased mucosal myeloperoxidase (MPO) activity in a dose dependent manner. These results suggested that CE prevented ethanol induced gastric mucosal lesions by strengthening the mucosal barrier and reducing the damaging effects of free radicals.

Absolute Stereostructures and Syntheses of Saussureamines A, B, C, D and E, Amino Acid–Sesquiterpene Conjugates with Gastroprotective Effect, from the Roots of Saussurea lappa

From the methanolic extract of the dried roots of Saussurea lappa Clarke, Saussureae Radix, five amino acid–sesquiterpene conjugates, saussureamines A, B, C, D and E, were isolated together with a lignan glycoside, (−)-massoniresinol 4″-O-β-d-glucopyranoside. Their stereostructures were determined on the basis of chemical and physicochemical evidence. In addition, saussureamines and the related amino acid–sesquiterpene conjugates were synthesized using a Michael type addition reaction of amino acid to the α-methylene-γ-lactone moiety of sesquiterpenes. Saussureamines A, B and C, costunolide and dehydrocostus lactone showed a gastroprotective effect on acidified ethanol-induced gastric mucosal lesions in rats. Saussureamines A also exhibited an inhibitory effect on gastric mucosal lesions induced by water-immersion stress in mice.

Gene expression profiles in gastric mucosa of sleep deprivation rats.

Stress has been shown to induce gastric mucosal lesions and lower the effectiveness of the mucosa as a barrier[1-6]. In rats, gastric ulcers can be produced by cold-restraint stress[7-9] and it is frequently employed as a model for the study of the mechanisms of stress on ulcer formation. Cold-restraint stress however is not normally encountered in human subjects while sleep deprivation is a common experience among city dwellers, night shift workers and medical professionals. It imposes stress on the body, and produces a variety of health problems[10-14]. Sleep deprivation may affect the epithelium linings of the gastrointestinal tract, because stress been demonstrated to produce gastric mucosal lesions in rats[15,16]. Although various factors has been proposed to account for this process, the precise mechanism of how sleep deprivation to affect the gastric mucosa barrier, especially at the molecular level, still remains unclear. In this project we observed the effect of sleep deprivation on the defensive factors of gastric mucosa, and used cDNA expression arrays to identify genes expressed abnormally in gastric mucosa of sleep deprivation rats.

Effects of pectin-induced passive linkage of gastric H + on the gastric acid secretion and on the development of ethanol- and salicylate-induced gastric mucosal lesions in rats

The aim of this study was to evaluate the effects of intragastrically given pectin-induced physicochemical properties and actions on active gastric acid secretion and on the development of ethanol- and aspirin-induced gastric mucosal lesions. The observations were carried out on CFY-strain rats, fasted for 24 h before the experiments with water ad libitum. The observations were carried out in two experimental series. A) The gastric mucosal lesions were produced by intragastrically given 96% ethanol or aspirin prepared with 0.2 M HCl. Different doses of pectin (100, 50 and 25 mg.kg –1, respectively) were administered intragastrically 30 min before giving necrotizing agents. The number of gastric lesions was noted 1 h after the administration, while the severity of gastric mucosal lesions was scored by semi-quantitative scale. B) The effects of pectin were studied on the volume and H + secretion of the stomach in 4-h pylorus-ligated rats. It has been found that: 1) the gastric mucosal lesions could be produced in 100% of rats by the application of both necrotizing agents. 2) Pectin in doses of 50–100 mg.kg –1 increased the number of gastric mucosal lesions in both models, while no increase was produced by the application of 25-mg.kg –1 dose. 3) The severity of mucosal lesions increased significantly after the administration of all doses of pectin. 4) The pectin-induced increase of gastric lesions (number) showed a dose-response effect. 5) The pectin produced a significant increase in the volume of gastric secretion and gastric H + secretion. It has been concluded that: a) pectin-induced physicochemical changes are able to enhance the aggression to gastric mucosa produced by ethanol and aspirin; b) a positive correlation exists between the linkage of H + to pectin and significant active metabolic response in the rat stomach; c) pectin alone stimulates the active metabolic process of the gastric H + secretion.

Therapeutic effect of Oren-gedoku-to extract on stress-induced acute gastric mucosal lesions in rats

Oral administration of Oren-gedoku-to extract (TJ-15), a traditional Chinese herbal medicine for the therapy of gastric ulcers and gastritis, dose-dependently prevented the progression of acute gastric mucosal lesions in rats with water immersion restraint (WIR) stress. The preventive effect of TJ-15 on the lesion progression was stronger than that of Saiko-keishi-to extract (TJ-10) or Shigyaku-san extract (TJ-35), each of which is a traditional Chinese herbal medicine for the therapy of gastric ulcers and gastritis, when compared on the basis of a single dosage of each medicine for adults. This TJ-15 administration attenuated increases in gastric mucosal lipid peroxide concentration and xanthine oxidase and myeloperoxidase activities with the gastric mucosal lesion progression and recovered the decreased gastric mucosal non-protein SH concentration found at a progressed stage of the gastric mucosal lesions. These results indicate that TJ-15 exerts a therapeutic effect on WIR stress-induced acute gastric lesions in rats more strongly than TJ-10 or TJ-35, and suggest that the therapeutic effect of TJ-15 could be due to its preventive actions on lipid peroxidation and sulphydryl oxidation via oxygen free radicals generated by the xanthine-XO system and infiltrated neutrophils in the gastric mucosa and on neutrophil infiltration into the tissue.

Therapeutic effect of Oren‐gedoku‐to extract on stress‐induced acute gastric mucosal lesions in rats

Therapeutic effect of Oren‐gedoku‐to extract on stress‐induced acute gastric mucosal lesions in rats

Preventive effect of Oren-gedoku-to (Huanglian-Jie-Du-Tang) extract on the development of stress-induced acute gastric mucosal lesions in rats

The preventive effect of Oren-gedoku-to (Huanglian-Jie-Du-Tang) extract (TJ-15), a traditional Chinese herbal medicine for the therapies of gastric ulcers and gastritis, on the development of stress-induced acute gastric mucosal lesions was examined in rats with water immersion restraint (WIR) stress. Simultaneous p.o. administration of TJ-15 at a dose of 20, 100 or 250 mg/kg prevented dose-dependently gastric mucosal lesion development in rats subjected to WIR stress over a 6-h period. In the gastric mucosa of rats with WIR stress alone, lipid peroxide concentration and xanthine oxidase (XOD) and myeloperoxidase—an index of neutrophil infiltration—activities increased with lesion development, while nonprotein SH concentration decreased. The simultaneous administration of TJ-15 attenuated all these changes with gastric mucosal lesion development in a dose-dependent manner. These results indicate that simultaneously administered TJ-15 exerts a preventive effect on the development of WIR stress-induced acute gastric lesions in rats, and suggest that the preventive effect of TJ-15 could be due to its preventive actions on enhanced sulfhydryl oxidation and lipid peroxidation via oxygen free radicals generated by the xanthine–xanthine oxidase system and infiltrated neutrophils in the gastric mucosa and on neutrophil infiltration into the tissue.

Effect of caffeine on ibuprofen-induced gastric mucosal damage in rats.

During investigations on the effect of caffeine on ibuprofen-induced gastric mucosal lesions in rats, we have found that caffeine (p.o.) inhibits the development of ibuprofen-induced gastric lesions in a dose-dependent manner (ED50 18.4 mg kg(-1)). To investigate this protective effect of caffeine, we have studied the effect of caffeine on HCl-ethanol-induced gastric mucosal lesions with or without indomethacin pretreatment. Caffeine inhibited the development of HCl-ethanol-induced gastric lesions with and without indomethacin pretreatment. These results indicate that caffeine did not act as a mild irritant but, on the contrary, had protective effects. We measured the gastric mucosal prostaglandin E2 (PGE2) concentrations and gastric mucosal blood flow, as representative protective factors for gastric mucosa. Caffeine did not affect the gastric mucosal PGE2 concentrations 4h after administration of ibuprofen. However, topical administration of caffeine resulted in an increase in gastric mucosal blood flow, as measured by laser Doppler flowmetry. We investigated the gastric acid secretion and gastric mucosal myeloperoxidase activity as representative aggressive factors for gastric mucosa. When caffeine was administered intraduodenally in pylorus-ligated rats, gastric acid secretion decreased in a dose-dependent manner, with an ED50 of 44.9 mg kg(-1). Caffeine decreased ibuprofen-induced gastric myeloperoxidase activity in a dose-dependent manner, with an ED50 of 9.1 mg kg(-1). These findings indicate that caffeine, at least in rats, may inhibit the development of acute gastric mucosal injury. The mechanisms underlying the protective actions of caffeine are unclear, but may be related in part to an increase in gastric mucosal blood flow and suppression of neutrophil activation.

Roles of capsaicin-sensitive sensory nerves, endogenous nitric oxide, sulfhydryls, and prostaglandins in gastroprotection by momordin Ic, an oleanolic acid oligoglycoside, on ethanol-induced gastric mucosal lesions in rats

The roles of capsaicin-sensitive sensory nerves (CPSN), endogenous nitric oxide (NO), sulfhydryls (SHs), prostagfandins (PGs) in the gastroprotection by momordin Ic, an oleanolic acid oligoglycoside isolated from the fruit of Kochia scoparia (L.) Schrad., on ethanol-induced gastric mucosal lesions were investigated in rats. Momordin Ic (10 mg/kg, p.o.) potentially inhibited ethanol-induced gastric mucosal lesions. The effect of momordin Ic was markedly attenuated by the pretreatment with capsaicin (125 mg/kg in total, s.c., an ablater of CPSN), N G-nitro-L-arginine methyl ester (L-NAME, 70 mg/kg, i.p., an inhibitor of NO synthase), N-ethylmaleimide (NEM, 10 mg/kg, s.c., a blocker of SHs), or indomethacin (10 mg/kg, i.e., an inhibitor of PGs biosynthesis). The attenuation of L-NAME was abolished by L-arginine (300 mg/kg, i.V., a substrate of NO synthase), but not by D-arginine (300 mg/kg, i.V., the enatiomer of L-arginine). The effect of the combination of capsaicin with indomethacin, NEM, or L-NAME was not more potent than that of capsaicin alone. The combination of indomethacin and NEM, indomethacin and L-NAME, or indomethacin and NEM and L-NAME increased the attenuation of each alone. These results suggest that CPSN play an important role in the gastroprotection by momordin Ic on ethanol-induced gastric mucosal lesions, ana endogenous PGs, NO, and SHs interactively participate, in rats.

Gastroprotections of escins Ia, Ib, IIa, and IIb on ethanol-induced gastric mucosal lesions in rats

Effects of escins Ia, Ib, IIa, and IIb isolated from horse chestnuts on ethanol-induced gastric mucosal lesions and the roles of capsaicin-sensitive afferent neurons, endogenous nitric oxide (NO), sulfhydryls, prostaglandins, as well as gastric secretion and the sympathetic nervous system, were investigated in rats. Test samples were given orally to fasted rats 1 h before ethanol (1.5 ml/rat, p.o.) treatment or ligation of the pylorus. Escins Ia–IIb (10–50 mg/kg) potently inhibited ethanol-induced gastric mucosal lesions, whereas desacylescins I and II (50 mg/kg) showed no such effect. These active saponins (10 and 20 mg/kg) did not decrease the gastric secretion. The gastroprotections of escins Ia–IIb were attenuated by the pretreatment with capsaicin, N G-nitro- l-arginine methyl ester, and indomethacin, but not by N-ethylmaleimide. The effects of escins Ia–IIb were also attenuated in streptozotocin-induced diabetic rats, in which the activity of the sympathetic nervous system was abnormal. These results suggest that the gastroprotections of escins Ia–IIb on ethanol-induced gastric mucosal lesions are acid-independent, whereas endogenous prostaglandins, NO, capsaicin-sensitive afferent neurons, and the sympathetic nervous system participate.

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

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

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

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

Protective effect of Irsogladine on monochloramine induced gastric mucosal lesions in rats:a comparative study with rebamipide.

AIM:To examine the effect of irsogladine, a novel antiulcer drug, on the mucosal ulcerogenic response to monochloramine (NH(2)Cl) in rat stomach, in comparison with rebamipide, another antiulcer drug with cytoprotective a ctivity.METHODS AND RESULTS:Oral administration of NH(2)Cl-(120mM) produced severe hemorrhagic lesions in unanesthetized rat stomachs.Both irsogladine (1mg/kg-10mg/ kg,po) and rebamipide (30mg/kg-100mg/kg, po) dose dependently prevented the development of these lesions in response to NH(2)Cl, the effect of irsogladine was significant at 3mg/kg or greater, and that of rebamipide only at 100mg/kg. The protective effect of irsogladine on NH(2)Cl induced gastric lesions was significantly reduced by N( G) nitro L arginine methyl ester (L-NAME) but not by indomethacin, while that of rebamipide was significantly mitigated by indomethacin but not by L-NAME. Topical application of NH(2)Cl-(20mM)caused a marked reduction of potential difference (PD) in exvivo stomachs. This PD reduction was not affected by mucosal application of irso-gladine, but significantly prevented by rebamipide. The mucosal exposure to NH(4)OH (120mM) also caused a marked PD reduction in the ischemic stomach (bleeding from the carotid artery), resulting in gastric lesions. These ulcerogenic and PD responses caused by NH(4)OH plus ischemia were also significantly mitigated by rebamipide, in an indomethacin sensitive manner, while irsogladine potently prevented such lesions without affecting the PD response, in a L-NAME sensitive manner.CONCLUSION:These results suggest that (1)NH(2)Cl gen-erated either exogenously or endogenously damages the gastric mucosa, (2)both irsogladine and rebamipide protect the stomach against injury caused by NH(2)Cl,and (3)the mechanism underlying the protective action of irsogladine is partly mediated by endogenous nitric oxide, while that of rebamipide is in part mediated by endogenous prostaglandins.

Participation of xanthine-xanthine oxidase system and neutrophils in development of acute gastric mucosal lesions in rats with a single treatment of compound 48/80, a mast cell degranulator.

The participation of xanthine-xanthine oxidase and neutrophils in the development of acute gastric mucosal lesions was examined in rats injected once with compound 48/80, a mast cell degranulator. Gastric mucosal lesions appeared 0.5 hr after compound 48/80 injection and developed at 3 hr. The formation of gastric mucosal lesions at 0.5 hr after compound 48/80 injection was prevented by pretreatment with anti-neutrophil antiserum and NPC 14686, an antiinflammatory agent, but not with allopurinol, a xanthine oxidase inhibitor. The development of gastric mucosal lesions at 3 hr after compound 48/80 injection was prevented by pretreatment with anti-neutrophil antiserum, NPC 14686, or allopurinol. Increases in the activities of gastric mucosal xanthine oxidase and myeloperoxidase, an index of neutrophil infiltration, and the content of lipid peroxide occurred 0.5 hr after compound 48/80 injection, and these increases were enhanced at 3 hr. The increases in gastric mucosal myeloperoxidase activity and lipid peroxide content at 0.5 hr after compound 48/80 injection were attenuated by pretreatment with anti-neutrophil antiserum and NPC 14686, while only the increase in gastric mucosal xanthine oxidase activity at the same time point was arrested by allopurinol pretreatment. The increases in gastric mucosal xanthine oxidase and myeloperoxidase activities and lipid peroxide content at 3 hr after compound 48/80 treatment were attenuated by pretreatment with anti-neutrophil antiserum, NPC 14686, or allopurinol. When compound 48/80-injected rats were treated with allopurinol at 0.5 hr after compound 48/80 injection, the progression of gastric mucosal lesions at 3 hr after the injection was almost completely prevented with inhibition of the increases in gastric mucosal xanthine oxidase and myeloperoxidase activities and lipid peroxide content. These results indicate that in rats with a single compound 48/80 treatment neutrophils infiltrated into the gastric mucosa participated in the development of acute gastric mucosal lesions and that the xanthine-xanthine oxidase system in the gastric mucosa participated in the progression rather than the formation of the gastric mucosal lesions.

Protective effects of oleanolic acid oligoglycosides on ethanol- or indomethacin-induced gastric mucosal lesions in rats

We examined the effects of various oleanolic acid oligoglycosides obtained from traditional herbs on ethanol- or indomethacin-induced gastric mucosal lesions in rats and on gastric secretion in pylorus-ligated rats. Test samples were given orally to fasted rats 1 h before absolute ethanol (1.5 ml rat , p.o.) or indomethacin (30 mg kg , s.c.) treatment, or ligation of the pylorus. Oleanolic acid 3- O-monodesmosides [oleanolic acid 3- O-glucuronide ( 1, 20–50 mg kg ), momordin Ic ( 2, 5–50 mg kg ), and 28- O-deglucosyl-chikusetsusaponins IV ( 5, 10–50 mg kg ) and V ( 7, 10–50 mg kg )] were found to show protective effects on ethanol-induced gastric mucosal lesions, whereas oleanolic acid 3,28- O-bisdesmosides [momordin IIc (3), chikusetsusaponins IV (4) and V (6)], oleanolic acid 28- O-monodesmoside [compound O (8)], and their common aglycon [oleanolic acid ( 9)] showed no such effects. Oleanolic acid 3- O-monodesmosides ( 1, 2, and 5) also showed protective effects on indomethacin-induced gastric mucosal lesions. 28- O-Deglucosyl-chikusetsu-saponin V ( 7) did not inhibit the indomethacin-induced lesions, while chikusetsusaponins V ( 6, 50 mg kg ) had the gastroprotective effect. These active saponins ( 1, 2, 4–7, 10–50 mg kg ) did not decrease the gastric secretion by oral administration in pylorus-ligated rats.

Role of Nitric Oxide and Prostaglandin in the Protective Effect of Pibutidine Hydrochloride, a Novel Histamine H 2-Receptor Antagonist, on the Gastric Mucosal Lesions in Rats

1. The role of endogenous nitric oxide (NO) and prostaglandins (PGs) in the gastric mucosal protective action of pibutidine hydrochloride (IT-066), a novel histamine H 2-receptor antagonist, was investigated in a 0.15 N hydrochloride (HCl)+60% ethanol (EtOH)-induced gastric lesion model. 2. The 0.15 N HCl + 60% EtOH-induced lesion formation was reduced significantly by IT-066 (3 mg/kg, PO), NOR3 (spontaneous NO releaser; 0.03–0.1 mg/kg, SC) or PGE2 (0.01 mg/kg, PO) but was not reduced by famotidine (1–10 mg/kg, PO). 3. Pretreatment with N G-nitro- L-arginine methyl ester ( L-NAME) (3 mg/kg, IV), an inhibitor of NO synthase, inhibited the protective action of IT-066 (3 mg/kg, PO), and the inhibitory effect of L-NAME was reversed by L-arginine (300 mg/kg, IV). The protective effect of PGE2 (0.01 mg/kg, PO) was not affected by the pretreatment with L-NAME (3 mg/kg, IV). 4. Infusion of carboxy-PTIO (1 mg/kg/min), a direct NO scavenger, inhibited the protective effect of IT-066 (3 mg/kg, SC) or NOR3 (0.1 mg/kg, SC). Pretreatment with indomethacin (5 mg/kg, SC) markedly reduced the protective effect of IT-066 (3 mg/kg, PO) or NOR3 (0.1 mg/kg, SC). 5. These results suggest that endogenous NO and PGs may be implicated in the gastric mucosal protection induced by IT-066 and that the endogenous PGs may contribute to the protective effect of NO.