Protective effects of polygodial on gastric mucosal lesions induced by necrotizing agents in rats and the possible mechanisms of action

The effects of polygodial isolated from the leaves of Tasmannia lanceolata on necrotizing agents-induced gastric lesions in rats were compared with capsaicin. Polygodial markedly inhibited the gastric mucosal lesions induced by several necrotizing agents, such as ethanol (ED(50)=0.029 mg/kg, p.o.), 0.6 M HCl (ED(50)=0.26 mg/kg, p.o.), and aspirin (ED(50)=0.38 mg/kg, p.o.), and partly inhibited the gastric mucosal lesions induced by indomethacin, but showed no significant effect on acid output in pylorus-ligated rats at doses of 0.05-0.5 mg/kg. The gastroprotection of polygodial was attenuated by pretreatment with indomethacin (10 mg/kg, s.c.), N(G)-nitro-L-arginine methyl ester (70 mg/kg, i.p.), N-ethylmaleimide (10 mg/kg, s.c.) and ruthenium red (3.5 mg/kg, s.c.). Polygodial (0.2 mg/kg, p.o.) increased the amount of reduced glutathione in gastric mucosa of ethanol-treated group. These results suggested that endogenous prostaglandins, nitric oxide, sulfhydryl compounds and vanilloid receptor-mediated effects are involved in the protective effect of polygodial.     

Nitric oxide and sensory afferent neurones modulate the protective effects of low-dose endotoxin on rat gastric mucosal damage

Pretreatment (1 h) with low doses (5–40 μg/kg i.p.) of Escherichia coli endotoxin dose dependently reduced the gastric mucosal damage induced by a 10 min challenge with 1 ml ethanol (50% and 100%) in conscious rats. Treatment with the nitric oxide synthesis inhibitor, oxide synthesis inhibitor, N^G-nitro- -arginine methyl ester (L-NAME, 5 and 10 mg/kg i.p.), significantly inhibited the protective effects of endotoxin (40 μg/kg i.p.). The actions of L-NAME were reversed by the prior administration of -arginine (100 mg/kg i.p.). The protective effects of endotoxin were not influenced by pretreatment with dexamethasone (5 mg/kg s.c. twice) or indomethacin (5 mg/kg s.c.). However, ablation of sensory afferent neurones by capsaicin pretreatment (20, 30 and 50 mg/kg s.c.) abolished the mucosa protective effects of endotoxin (40 μg/kg). These findings suggest that the protection elicited by low doses of endotoxin against ethanol-induced mucosal damage involves synthesis of nitric oxide and activation of sensory neurones.     

Cytoprotective action of mast cell stabilizers against ethanol-induced gastric lesions in rats

We examined the effects of FPL-52694 and disodium cromoglycate (DSCG), mast cell stabilizers, on HCl X ethanol-induced gastric lesions in rats and investigated the factors involved in their protection. Oral (p.o.) administration of 1 ml of HCl X ethanol (60% in 150 mM HCl) induced linear hemorrhagic lesions in the gastric mucosa within 1 hr. FPL-52694 (1-30 mg/kg), given both p.o. and intraperitoneally (i.p.), prevented these lesions in a dose-related manner. DSCG (3-30 mg/kg) also dose-dependently reduced the formation of these lesions when this agent was given i.p. The protective effects of these drugs on HCl X ethanol-induced lesions were significantly attenuated by pretreatment with indomethacin (5 mg/kg, s.c.). Both gastric acid secretion and transmucosal potential difference were significantly reduced by topical application of FPL-52694 (greater than 10 mg/kg), but were not affected by i.p. administration of FPL-52694 and DSCG. On the other hand, gastric motor activity measured as intraluminal pressure recordings was significantly inhibited for 2 hr by both FPL-52694 (p.o. and i.p.) and DSCG (i.p.), and these effects were also significantly antagonized with prior administration of indomethacin. A significant relationship was found between the effects of these two drugs on the lesion index and the motility index (r: 0.9214, P less than 0.01), but not other factors. These results suggest that mast cell stabilizers such as FPL-52694 and DSCG protect the gastric mucosa against HCl X ethanol through a systemic action, probably mediated with endogenous prostaglandins. Although the mechanism of cytoprotection remains unknown, this property may be related to their inhibitory effects on gastric motor activity.     

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.     

Role of the NO/cGMP/K(ATP) pathway in the protective effects of sildenafil against ethanol-induced gastric damage in rats

BACKGROUND AND PURPOSE: Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase. Sildenafil, acting via NO-dependent mechanisms, prevents indomethacin-induced gastropathy. Activation of ATP-sensitive potassium channels (K(ATP)) is involved in gastric defence. Our objective was to evaluate the role of the NO/cGMP/K(ATP) pathway in the protective effects of sildenafil against ethanol-induced gastric damage. EXPERIMENTAL APPROACH: Rats were treated with L-NAME (1 or 3 mg kg(-1), i.p.) or with L-arginine (200 mg kg(-1), i.p.) + L-NAME (3 mg kg(-1), i.p.), the guanylate cyclase inhibitor, ODQ (10 mg kg(-1), i.p.), glibenclamide (0.1, 0.3, 1 or 3 mg kg(-1), i.p.) or with glibenclamide (1 mg kg(-1), i.p.) + diazoxide (3 mg kg(-1), i.p.). After thirty minutes, the rats received sildenafil (1 mg kg(-1), by gavage), followed by intragastric instillation of absolute ethanol (4 ml kg(-1)) to induce gastric damage. One hour later, gastric damage (haemorrhagic or ulcerative lesions) was measured with a planimetry programme. Samples of stomach were also taken for histopathological assessment and for assays of tissue glutathione and haemoglobin.KEY RESULTS: Sildenafil significantly reduced ethanol-induced gastric damage in rats. L-NAME alone, without L-arginine, significantly reversed the protection afforded by sildenafil. Inhibition of guanylate cyclase by ODQ completely abolished the gastric protective effect of sildenafil against ethanol-induced gastric damage. Glibenclamide alone reversed sildenafil's gastric protective effect. However, glibenclamide plus diazoxide did not alter the effects of sildenafil.CONCLUSIONS: Sildenafil had a protective effect against ethanol-induced gastric damage through the activation of the NO/cGMP/K(ATP) pathway.     

Anti-ulcer activity and mode of action of the polysaccharide fraction from the leaves of Panax ginseng.

The effects of a weakly acidic polysaccharide fraction, GL-4, from the leaves of Panax ginseng C. A. Meyer on various experimental gastric ulcer models in mice and rats have been studied. Oral administration of GL-4 at doses of 50 to 200 mg/kg inhibited the formation of the gastric lesions induced by necrotizing agents such as HCl/ethanol and ethanol in a dose-dependent manner. This protective effect was observed not only upon oral but also upon subcutaneous administration of GL-4 (50-100 mg/kg). GL-4 also inhibited the formation of gastric ulcers which were induced by water immersion stress, indomethacin, or pylorus-ligation. The contents of prostaglandin E2 in the gastric juice from rats were not influenced by oral administration of GL-4. The protective action of GL-4 against HCl/ethanol-induced gastric lesions was not abolished by pretreatment with indomethacin. When GL-4 (100 mg/kg, p.o.) was administered into pylorus-ligated rats, both gastric acidity and pepsin activity in the gastric juice decreased significantly.     

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.     

Preventive actions of N-(3-aminopropionyl)-L-histidinato zinc (Z-103) through increases in the activities of oxygen-derived free radical scavenging enzymes in the gastric mucosa on ethanol-induced gastric mucosal damage in rats.

Z-103 at 1 to 25 mg/kg, p.o. prevented 100% ethanol-induced gastric mucosal lesions in a dose-dependent manner. Z-103 at 3 to 25 mg/kg, p.o. significantly elevated gastric mucosal superoxide dismutase (SOD)-like activity 1 hr after its administration to normal rats. In addition, Z-103 at doses (10 and 25 mg/kg, p.o.) which prevented 100% ethanol-induced gastric lesion further increased gastric mucosal SOD-like and glutathione peroxidase (GSH-px) activities elevated by 60% ethanol. Z-103 (10 and 25 mg/kg) significantly inhibited the increase in thiobarbituric acid-reactive substances in gastric mucosa injured by 60% ethanol. The combination with cycloheximide, a protein synthesis inhibitor, completely abolished the prevention of 60% ethanol-induced gastric mucosal lesions and the elevation of both free radical scavenging enzyme activities in the mucosa by Z-103 (10 mg/kg, p.o.). These results suggest that Z-103 may partly protect rat gastric mucosa against ethanol-induced damage by scavenging oxygen-derived free radicals via increases in the synthesis of SOD-like and GSH-px enzymes in the mucosa.     

Gastroprotective mechanisms of centipedic acid, a natural diterpene from Egletes viscosa LESS

This study was aimed to clarify the mechanisms of gastroprotection by centipedic acid (CPA), a natural diterpene from Egletes viscosa LESS. (Asteraceae) using ethanol-induced gastric mucosal damage in mice and gastric secretion in 4-h pylorus-ligated rats as model systems. In mice, intragastrically administered CPA (25, 50, 100 mg/kg) greatly reduced the mucosal lesions induced by 96% ethanol (0.2 ml, p.o.) by 18, 53, and 79%, respectively, whereas N-acetylcysteine (NAC, 300 mg/kg, i.p.), the reference compound produced a 50% inhibition. In 4-h pylorus-ligated rats, CPA (50 mg/kg) applied intraduodenally decreased both gastric secretory volume and total acidity. Similar to NAC, the plant diterpene effectively prevented the ethanol associated decrease in non-proteic sulfhydryls (NP-SH) and the elevated thiobarbituric acid-reactive substances (TBARS) in gastric tissue, suggesting that these compounds exert an antioxidant effect. Pretreatment of mice with indomethacin, the cyclooxygenase inhibitor but not with capsazepine, the transient receptor potential vanilloid-1 (TRPV1)-receptor antagonist greatly suppressed the gastroprotective effect of CPA. Furthermore, CPA gastroprotection was significantly attenuated in mice pretreated with L-NAME or glibenclamide the respective inhibitors of nitric oxide synthase and K(+)(ATP) channel activation. These data suggest that CPA affords gastroprotection by different and complementary mechanisms, which include a sparing effect on NP-SH reserve, and roles for endogenous prostaglandins, nitric oxide, and TRPV1-receptor and K(+)(ATP) channel activation.     

Effects of 12-sulfodehydroabietic acid monosodium salt (TA-2711), a new anti-ulcer agent, on gastric secretion and experimental ulcers in rats

Effects of 12-sulfodehydroabietic acid monosodium salt (TA-2711), a new anti-ulcer agent, on gastric secretion and experimental ulcers were investigated in rats. Oral administration of TA-2711 at doses of 25 to 100 mg/kg immediately after pyloric ligation markedly reduced pepsin activity and slightly lowered acid concentration without affecting the volume of gastric juice. Addition of TA-2711 (0.25-16 mg/ml) directly to gastric juice also reduced pepsin activity in vitro. Oral TA-2711 dose-relatedly inhibited the formation of pylorus-ligated ulcers (50-200 mg/kg), aspirin-induced gastric erosions (25-100 mg/kg) and cysteamine-induced duodenal ulcers (100-800 mg/kg). In addition, this drug prevented both the formation of gastric lesions (6.3-100 mg/kg, p.o.) and the fall in gastric potential difference (100 mg/kg, p.o.) induced by ethanol. The preventive effect against ethanol-induced lesions was suppressed by pretreatment with indomethacin (10 mg/kg, s.c.). Intravenous dosing of TA-2711 (10-100 mg/kg) never produced such effects on ethanol-induced lesions and pepsin activity as observed by oral administration. These results indicate that TA-2711 exerts its anti-ulcer effect by a local action, and it is suggested that both reduction of pepsin activity and a mucosal prostaglandin-mediated process are involved in the anti-ulcer action of TA-2711.     

Gastroprotective effect of a flavone from Lonchocarpus araripensis Benth. (Leguminosae) and the possible mechanism

The gastroprotective effect of DDF (3,6-dimethoxy-6', 6'-dimethyl-[2', 3' : 7,8]-chromeneflavone) from Lonchocarpus araripensis Benth. (Leguminosae) on gastric damage induced by absolute ethanol (96%, 0.2 mL/mouse) and indometacin (30 mg kg(-1), p.o.) in mice was investigated. Intraperitoneally administered DDF at dose levels of 50, 100 and 200 mg kg(-1) markedly reduced the gastric lesions in the ethanol model by 62, 72 and 96%, and in the indometacin model by 34, 70 and 75%, respectively, as compared with misoprostol (50 microg kg(-1), p.o.), the reference compound that caused lesion suppression by 67% in ethanol model and by 72% against indometacin-induced ulceration. The ED50 of DDF in reducing gastric lesions induced by ethanol and indometacin (dose of the DDF that reduced the gastric lesion area by 50% in relation to the control value) was 50.87 and 61.56 mg kg(-1), respectively. Mechanistic studies were carried out at 100 mg kg(-1) DDF using the ethanol model. Compared with N-acetylcysteine (750 mg kg(-1), p.o.), a donor of sulfhydryls, DDF only partially replenished the ethanol-induced depletion of gastric mucosal NP-SH. Pretreatment with TRPV1 antagonist capsazepine (5 mg kg(-1), i.p.) or the non-selective cyclooxygenase inhibitor indometacin (10 mg kg(-1), p.o.) effectively blocked the gastroprotective effect of DDF (100 mg kg(-1)) against ethanol damage. Furthermore, the effect of DDF was significantly reduced in mice pretreated with L-NAME, or glibenclamide, the respective inhibitors of nitric oxide synthase and K+ ATP channel activation. These data provide evidence to show that DDF affords gastroprotection against gastric damage induced by ethanol and indometacin by different and complementary mechanisms, which include involvement of endogenous prostaglandins, nitric oxide release, the activation of TRPV1 receptor or K+ ATP channels, besides a sparing effect on NP-SH reserve.     

Leptin in gastroprotection induced by cholecystokinin or by a meal. Role of vagal and sensory nerves and nitric oxide.

Leptin, detected recently in the stomach, is a product of the ob gene released by cholecystokinin (CCK) and plays an important role in the control of food intake but its influence on gastroprotection against the damage caused by noxious agents has not been studied. This study was designed to compare the effects of leptin and cholecystokinin-8 (CCK-8) on gastric mucosal lesions induced by topical application of 75% ethanol or acidified aspirin. Four series of Wistar rats (A, B, C and D) were used to determine the effects of: (A) suppression of prostaglandin biosynthesis by indomethacin (5 mg/kg i.p.); (B) inhibition of nitric oxide (NO)-synthase by nitro-L-arginine methyl ester (L-NAME) (5 mg/kg i.v.); (C) blockade of sensory nerves by capsaicin (125 mg/kg s.c.) and (D) bilateral vagotomy, on the gastric lesions induced by intragastric (i.g.) application of ethanol with or without pretreatment with CCK-8, a known gastroprotective substance or leptin. CCK-8 (1-100 microg/kg i.p.) and leptin (0.1-50 microg/kg i.p.) dose dependently attenuated gastric lesions induced by 75% ethanol; the dose reducing these lesions by 50% being about 10 microg/kg and 8 microg/kg, respectively. The protective effects of CCK-8 and leptin were accompanied by a significant rise in gastric blood flow (GBF) and luminal NO concentration. Leptin was also effective to attenuate aspirin-induced damage and the accompanying fall in the GBF, whereas CCK-8 dose dependently worsened aspirin damage and failed to influence GBF. CCK (1-100 microg/kg i.p.), given in graded doses, produced a dose-dependent increase in the plasma leptin level and a rise of the expression of ob messenger RNA (mRNA) in gastric mucosa, the maximum being reached at a dose of 100 microg/kg. Pretreatment with CCK-8 (10 microg/kg i.p.) or with 8% peptone, that is known to stimulate CCK release, also produced a significant rise in plasma leptin levels and up-regulation of ob mRNA while reducing significantly the gastric lesions induced by 75% ethanol to the same extent as that induced by exogenous leptin (10 microg/kg i.p.). Indomethacin, which suppressed prostaglandin generation by approximately 90%, failed to influence leptin- or CCK-8-induced protection against ethanol, whereas L-NAME attenuated significantly CCK-8- and leptin-induced protection and hyperemia but addition to L-NAME of L-arginine, but not D-arginine, restored the protective and hyperemic effects of both hormones. The ob mRNA was detected as a weak signal in the intact gastric mucosa and in that exposed to ethanol alone but this was further enhanced after treatment with graded doses of CCK-8 or peptone meal applied prior to ethanol. We conclude that: (1) exogenous leptin or that released endogenously by CCK or meal exerts a potent gastroprotective action depending upon vagal activity, and involving hyperemia probably mediated by NO and sensory nerves but unrelated to endogenous prostaglandins; (2) leptin mimics the gastroprotective effect of CCK and probably mediates the protective and hyperemic actions of CCK in the rat stomach.     

Gastroprotective activity of ferruginol in mice and rats: effects on gastric secretion, endogenous prostaglandins and non-protein sulfhydryls

The gastroprotective mechanism of the natural diterpene ferruginol was assessed in mice and rats. The involvement of gastric prostaglandins (PGE(2)), reduced glutathione, nitric oxide or capsaicin receptors was evaluated in mice either treated or untreated with indometacin, N-ethylmaleimide (NEM), N-nitro-L-arginine methyl ester (L-NAME) or ruthenium red, respectively, and then orally treated with ferruginol or vehicle. Gastric lesions were induced by oral administration of ethanol. The effects of ferruginol on the parameters of gastric secretion were assessed in pylorus-ligated rats. Gastric PGE(2) content was determined in rats treated with ferruginol and/or indometacin. The reduction of gastric glutathione (GSH) content was determined in rats treated with ethanol after oral administration of ferruginol, lansoprazole or vehicle. Finally, the acute oral toxicity was assessed in mice. Indometacin reversed the gastroprotective effect of ferruginol (25 mg kg(-1)) but not NEM, ruthenium red or L-NAME. The diterpene (25 mg kg(-1)) increased the gastric juice volume and its pH value, and reduced the titrable acidity but was devoid of effect on the gastric mucus content. Ferruginol (25, 50 mg kg(-1)) increased gastric PGE(2) content in a dose-dependent manner and prevented the reduction in GSH observed due to ethanol-induced gastric lesions in rats. Single oral doses up to 3 g kg(-1) ferruginol did not elicit mortality or acute toxic effects in mice. Our results showed that ferruginol acted as a gastroprotective agent stimulating the gastric PGE(2) synthesis, reducing the gastric acid output and improving the antioxidant capacity of the gastric mucosa by maintaining the GSH levels.     

Effects of misoprostol, (+/-)-methyl (11 alpha, 13E)-11, 16-dihydroxy-16-methyl-9-oxoprost-13-en-l-oate, on various gastric and duodenal lesions in rats

Male Sprague-Dawley rats (230-280 g), either fasted for 15-24 hr or non-fasted prior to experiments, were used. Misoprostol (3-100 micrograms/kg, p.o.) dose-dependently inhibited the development of 150 mM HCl X aspirin (100 mg/kg)-, 150 mM HCl X 60% ethanol-, and aspirin (150 mg/kg)-induced gastric lesions. Misoprostol (30, 100 micrograms/kg, p.o.), given twice daily for 4 days, significantly inhibited prednisolone (50 mg/kg given once daily for 4 days)-induced gastric lesions. Misoprostol (30 or 2 X 300 micrograms/kg, p.o.) also significantly inhibited water-immersion stress (21 degrees C, 10 hr)-induced gastric lesions or mepirizole (200 mg/kg)-induced duodenal lesions, respectively. In contrast, misoprostol (30-300 micrograms/kg, p.o.) had no effects on indomethacin (25 mg/kg)- and mepirizole (200 mg/kg)-induced gastric lesions. Misoprostol (30 micrograms/kg, p.o.) had no effect on gastric secretion in pylorus-ligated preparations (4 hr), but it (100 or 300 micrograms/kg, p.o.) significantly increased the volume and pepsin output. Gastric motility, either normal or enhanced with indomethacin (25 mg/kg), was inhibited by misoprostol (30 or 300 micrograms/kg, p.o.). Misoprostol (30 micrograms/kg, i.d.) significantly stimulated duodenal HCO3- secretion. Mechanisms by which misoprostol inhibits various gastric lesions remain unknown. However, the stimulatory activity on duodenal HCO3- secretion appears to be involved in the preventive effect of misoprostol on the development of duodenal lesions. The effects of cimetidine and 16,16-dimethyl PGE2 were also studied and compared with those of misoprostol.     

The influence of omeprazole on the protective effects of secretagogues against ethanol-induced gastric ulceration in rats

The influence of omeprazole on the antiulcer effects of histamine, methacholine and pentagastrin on ethanol-induced gastric ulceration was studied. Histamine 5 mg/kg, methacholine 500 micrograms/kg or pentagastrin 100 micrograms/kg pretreatment s.c. markedly reduced ethanol (50%, 10 ml/kg p.o.)-induced gastric ulceration in pylorus-ligated conscious rats, but significantly elevated the gastric secretory volume and acid output. Omeprazole pretreatment 50 mg/kg s.c. reduced gastric secretion and abolished the ulcer-protecting effects of the three secretagogues. The same doses of histamine, methacholine or pentagastrin did not significantly alter the gastric secretory volume but increased the total acid output of ex-vivo stomach chamber preparations in anaesthetised animals. Histamine worsened ethanol-evoked ulceration whereas methacholine and pentagastrin had no effect on the lesions. Omeprazole pretreatment did not prevent ulcer aggravation by histamine. It is concluded that the antiulcer effects of the three secretagogues in conscious animals are probably due to the increased secretory volume which lessens the ulcerogenic action of ethanol by its dilution. Omeprazole reduces the secretory volume and thus prevents the antiulcer effect of these secretagogues. The findings with histamine and omeprazole in the ex-vivo stomach experiments support the suggestion that it is unlikely that increased gastric acid secretion affects the ulcerogenicity of ethanol in rat stomach.     

Effects of troxipide on acute gastric lesions in rats

Effects of troxipide on several acute gastric lesions in rats were investigated in comparison with those of cetraxate. Troxipide (100, 200, 300 mg/kg) and cetraxate (100, 300, 1,000 mg/kg), given orally, dose-dependently protected the gastric mucosa from damage due to ethanol. Aspirin- and 0.6 N HCl-induced gastric lesions were dose-dependently inhibited by troxipide (200, 300 mg/kg), but only significantly inhibited by cetraxate at high dose (1,000 mg/kg). Troxipide (100, 200, 300 mg/kg) dose-dependently prevented the formation of gastric lesions induced by water-immersion stress, whereas cetraxate (600, 1,000 mg/kg) also significantly prevented gastric lesions. That is, protective effects of troxipide were much more potent than those of cetraxate against aspirin-, 0.6 N HCl- and water-immersion stress-induced gastric lesions, whereas both were almost equal against ethanol-induced gastric lesions. In addition, cytoprotective effects of troxipide against ethanol-induced lesions were most remarkable at 10, 30, 60 min after administration (100, 300 mg/kg) and lasted for up to 240 min. These results suggested that troxipide might be useful for the treatment of acute gastric lesions in humans.     

Evaluation of tiquizium bromide (HSR-902) as an antiulcer agent

The effects of HSR-902, an antimuscarinic agent, on development of various gastric and duodenal lesions, gastric secretion, pupil size and salivation in rats were compared with those of pirenzepine.2HC1 (pirenzepine, antiulcer agent) and timepidium bromide (timepidium, antispasmodic). 1) HSR-902 (10-100 mg/kg), given orally, dose-dependently inhibited the developments of gastric lesions induced by water-immersion stress, aspirin, indomethacin, serotonin and reserpine and duodenal lesions induced by cysteamine and mepirizole. The activities of HSR-902 were almost equal or somewhat more potent than those of pirenzepine, and they were more potent than those of timepidium. 2) HSR-902 (30 and 100 mg/kg, p.o.), when examined using pylorus-ligated preparations, dose-dependently inhibited the gastric acid output, pepsin output, and gastric acid and pepsin concentrations, but did not inhibit the gastric volume (HSR-902, in a higher dose, slightly increased the gastric volume.). Pirenzepine (100 mg/kg, p.o.), like atropine sulfate, inhibited the gastric volume, acid output and pepsin output, but did not inhibit the gastric acid and pepsin concentrations. Timepidium (100 mg/kg, p.o.), however, hardly influenced these parameters except for increasing the gastric volume. 3) HSR-902 (100 mg/kg, p.o.) induced the mydoriasis and inhibited the pilocarpine-induced salivation, and its activities were less potent than those of pirenzepine. These results suggest that HSR-902 is a promising agent for the treatment of peptic ulcer.     

Modification of aspirin and ethanol-induced mucosal damage in rats by intragastric application of resiniferatoxin

The capsaicin analogue ‘resiniferatoxin’ (RTX) was used to investigate the role of capsaicin-sensitive sensory nerves in gastric mucosal injury caused by intragastric (ig) acidified aspirin (200 mg/kg in 2 ml of 0.15 N HCl) or ethanol (2 ml of 50% v/v or 96%) in pylorus-ligated rats. Animals were sacrificed 1, 2 and 4 h later, when gastric secretory responses, number and severity of mucosal lesions were calculated. Intragastric RTX (0.6–1.8 μg/kg) prevented mucosal injury in a dose-dependent manner induced by topical acidified aspirin. The protective effect lasted for 1h and was accompanied by inhibition of gastric acid secretion by RTX. RTX (0.6 and 1.0 μg/kg) co-administered with ethanol reduced mucosal injury caused by 50% ethanol; the protective effect of RTX being more apparent when the drug was given 15 min prior to 50% ethanol. Unexpectedly, RTX co-administered with absolute ethanol aggravated the ethanol-induced mucosal damage. It is concluded that capsaicin-sensitive sensory nerves mediated microcirculatory changes in gastroprotection and these involve inhibition of gastric acid secretion.     

The Role of Nitric Oxide and Sulphydryls in Gastric Mucosal Protection Induced by Sodium Cromoglycate in Rats

The role of endogenous nitric oxide and sulphydryls in gastric protection afforded by sodium cromoglycate against ethanol-induced gastric lesions was studied in rats. Drugs were administered either intraperitoneally (i.p.) or subcutaneously (s.c.) 30, 45 or 60 min before oral administration of ethanol. Administration of cromoglycate before ethanol dose-dependently inhibited ethanol-induced gastric lesions. Pretreatment with N^G-nitro-l -arginine methyl ester (L-NAME), an inhibitor of nitric oxide biosynthesis, dose-dependently aggravated gastric lesions and reduced cromoglycate-induced gastric protection. The attenuating effect of L-NAME on gastric protection elicited by cromoglycate was reversible by pretreatment with l -arginine but not by d -arginine. On the other hand, ethanol-induced gastric lesions were found to be associated with a reduction of nonprotein sulphydryl content of glandular stomachs. Pretreatment with cromoglycate prevented non protein sulphydryl depletion and afforded protection. Pretreatment with N-ethylmaleimide, a sulphydryl blocker, caused dose-dependent enhancement of ethanol-induced gastric lesions and further depletion of non protein-sulphydryl. Treatment with N-ethylmaleimide before cromoglycate reduced the gastric protection that was associated with depletion of nonprotein sulphydryls. Furthermore, combined N-ethylmaleimide and L-NAME pretreatment caused a greater aggravation of ethanol-induced gastric lesions and significantly produced a higher reduction of the protective effects of cromoglycate. However, pretreatment with l -arginine only partially restored the protective effects of cromoglycate. These results suggest that the protective effects of cromoglycate may be dependent on the maintenance of a critical level of both endogenous nitric oxide and nonprotein sulphydryls in the gastric mucosa.     

Prostaglandins, capsaicin-sensitive sensory nerves and neutrophil infiltration, but not nitric oxide, contribute to cold restraint stress-induced gastric adaptation in rats

The aim of the present study was to determine the role of prostaglandins (PG), nitric oxide (NO) and capsaicin-sensitive sensory nerves in neutrophil infiltration in gastric adaptation to cold restraint stress in rats. Wistar rats were exposed to single or repeated cold restraint stress for 3.5 h every other day for up to 4 days. Prior to repeated stress, rats were pretreated with NG-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg, s.c.), indomethacin (10 mg/kg, s.c.) or capsaicin (125 mg/kg, s.c.). The extent of gastric mucosal lesions was evaluated histologically and myeloproxidase (MPO) activity, PGE2, NO and calcitonin gene-related peptide (CGRP) levels were measured in gastric tissue. Cold restraint stress produced haemorrhagic lesions and reduced PGE2 and CGRP levels in the stomach, with an increase in MPO activity and NO levels. Repeated stress insults reduced stress-induced gastric damage, NO production and MPO activity, with an increase in PGE2 and CGRP levels compared with rats exposed to single cold restraint stress. Adaptation to cold restraint stress was prevented by indomethacin and capsaicin pretreatment, but not by L-NAME. We conclude that the stomach has the ability to adapt to repeated exposure to cold restraint stress and that the adaptation, via inhibition of neutrophil infiltration, is mediated, at least in part, by endogenous PG and CGRP.