Secretion In Pylorus-ligated Rats Research Articles

Gastric antisecretory and cytoprotective effects of leaf extracts of Amaranthus tricolor Linn. in rats

The present study was aimed to evaluate the antiulcer activity of leaf extracts of Amaranthus tricolor Linn. (Amaranthaceae) in rats. The effects of A. tricolor leaves on gastric secretion and the effect of gastric cytoprotection were evaluated using five different models of gastric ulcers: acetic acid-induced, pylorus ligation-induced, ethanol-induced, indomethacin-induced and ischemia-reperfusion-induced gastric ulcers. The different extracts, namely, ethanolic extract (EAT), petroleum ether extract (PEAT), chloroform extract (CAT) and ethyl acetate extract (EAAT) of A. tricolor leaves were administered at a dose of 200 mg/kg per oral (p.o.). The acute oral toxicity study revealed that all the extracts were safe up to 2 000 mg/kg, p.o; hence one-tenth of this dose was selected for evaluation of antiulcer activity. The EAT and EAAT (200 mg/kg, p.o.) showed gastric ulcer-healing effect in acetic acid-induced chronic gastric ulcers. The EAT and EAAT inhibited gastric secretion in pylorus-ligated rats and showed gastric cytoprotective effect in ethanol-induced and indomethacin-induced gastric ulcers, while PEAT and CAT showed no significant antiulcer effect. The leaf extracts of A. tricolor are found to possess very good antiulcer property in the experimental animal models of gastric ulcers which is consistent with the literature report in folk medicine.

Characterization of the mechanisms involved in the gastric antisecretory effect of TLQP-21, a vgf-derived peptide, in rats

TLQP-21, a vgf-derived peptide modulates gastric emptying and prevents ethanol-induced gastric lesions in rats. However, it remains to be studied whether or not TLQP-21 affects gastric acid secretion. In this study, we evaluated the effects of central (0.8-8 nmol/rat) or peripheral (48-240 nmol/kg, intraperitoneally) TLQP-21 administration on gastric acid secretion in pylorus-ligated rats. The mechanisms involved in such activity were also examined. Central TLQP-21 injection significantly reduced gastric acid volume and dose-dependently inhibited total acid output (ED(50) = 2.71 nmol), while peripheral TLQP-21 administration had no effect. The TLQP-21 antisecretory activity was prevented by cysteamine (300 mg/kg, subcutaneously), a depletor of somatostatin, by indomethacin (0.25 mg/rat, intracerebroventricularly), a non-selective cyclooxygenase inhibitor, and by functional ablation of sensory nerves by capsaicin. We conclude that TLQP-21 could be considered a new member of the large group of regulatory peptides affecting gastric acid secretion. The central inhibitory effect of TLQP-21 on gastric acid secretion is mediated by endogenous somatostatin and prostaglandins and requires the integrity of sensory nerve fibres.

Protective effect of a cysteine prodrug and antioxidant, L-2-oxothiazolidine-4-carboxylate, against ethanol-induced gastric lesions in rats

Earlier studies have suggested an important role of glutathione (GSH) in cytoprotection against free radicals induced oxidative damage. This study reports gastroprotective effects of a cysteine precursor, L-2-oxothiazolidine-4-carboxylate (OTC), in experimental models of gastric secretion and ulceration. Acid secretion studies (volume and acidity) were undertaken in pylorus-ligated rats whereas the gastric lesions were induced by ethanol. Different groups of animals were treated with OTC (0, 100, 200 and 400 mg/kg). The levels of gastric wall mucus, nonprotein sulfhydryls (NP-SH) and myeloperoxidase (MPO) were measured in the glandular stomach of rats following ethanol-induced gastric lesions. Both medium and high doses of OTC significantly reduced the volume and acidity of gastric secretion in pylorus-ligated rats. Pretreatment with OTC significantly and dose-dependently attenuated the formation of ethanol-induced gastric lesion. OTC significantly protected the gastric mucosa against ethanol-induced depletion of gastric wall mucus, NP-SH and MPO. The gastroprotective effects of OTC may be attributed to its ability to inhibit neutrophils activity and replenish GSH demand.

Comparative antiulcer effect of Bisdemethoxycurcumin and Curcumin in a gastric ulcer model system

The antiulcer effect of bisdemethoxycurcumin, a yellow pigment found mainly in rhizomes of Curcuma longa, was compared with curcumin in gastric ulcer model systems to validate its clinical application as a remedy for peptic ulcer. Western blot analysis of mouse macrophage cell line RAW 264.7 activated with lipopolysaccharide showed that bisdemethoxycurcumin inhibited inducible nitric oxide synthase (iNOS) production significantly but had no effect on tumor necrosis factor-alpha (TNF-alpha) production, whereas curcumin showed stronger suppression of iNOS protein production and inhibited TNF-alpha protein production significantly. However, bisdemethoxycurcumin and curcumin possessed similar potency in scavenging nitric oxide generated from mouse macrophage cell line RAW 264.7. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed that both curcuminoids inhibited the induction of iNOS dose-dependently at the transcriptional level and curcumin also appeared to inhibit the induction of TNF-alpha at post-transcriptional level. In an animal model, intraduodenal administration of bisdemethoxycurcumin (5-80 mg/kg body wt.) showed a strong inhibitory effect on gastric acid secretion in pylorus-ligated rats whereas curcumin (5-20 mg/kg body wt.) showed a less inhibitory effect, with maximum potency at a dose of 20mg/kg body wt. Moreover, oral administration of bisdemethoxycurcumin at doses of 20-80 mg/kg body wt. twice daily for 10 days showed a significant curative efficacy in accelerating the healing of acetic acid-induced chronic gastric ulcer and promotion of mucosal regeneration in the ulcerated portion in a dose-related manner with potency equal to curcumin. In contrast, the curative potency of curcumin tended to decrease at doses over 160 mg/kg body wt./day. Western blot analysis in ulcerated gastric mucosa showed that bisdemethoxycurcumin dose-dependently reduced the increased protein expression level of iNOS but not TNF-alpha. These results indicated that bisdemethoxycurcumin directly accelerates gastric ulcer healing with potency equal to curcumin. Its antiulcer effect might be due to its properties of decreasing gastric acid secretion and enhancing the mucosal defensive mechanism through suppression of iNOS-mediated inflammation.

Preventive and curative effects of curcumin on the development of gastric inflammatory diseases in rats.

Preventive and curative effects of curcumin on experimental acute and chronic gastric ulcers were investigated to validate its clinical application on a remedy for peptic ulcer. Intraduodenal administration of curcumin, 5-20mg/kg, inhibited gastric acid secretion in pylorus-ligated rats, and oral administration prevented ethanol-induced acute gastric mucosal lesions. Curcumin (20-80mg/kg, p.o.) dose-dependently prevented both serotonin-induced gastric mucosal lesions and compound 48/80-induced gastric mucosal lesions in rats. Furthermore, oral administration of curcumin, 10-80mg/kg, twice daily for 10days, significantly accelerated the healing of acetic acid-induced chronic gastric ulcer and promoted mucosal regeneration in the ulcerated portion in a dose-related manner. Cimetidine prevented the formation of ethanol-induced gastric mucosal lesions, but not of serotonin-induced and compound 48/80-induced gastric mucosal lesions. Consecutive administration of cimetidine showed a marked acceleration in the healing of acetic acid-induced ulcer. Aminoguanidine, an inducible nitric oxide synthase (iNOS) inhibitor, showed anti-ulcerogenic effects similar to those oberved for curcumin. The present results indicate that curcumin exhibits gastric cytoprotection in the acute lesion models and ulcer healing promotion in the chronic ulcer model. The preventive and curative effects of curcumin might be due to an increase in the mucosal defensive mechanism through its antioxidant property and inhibition of NO or cytokine-mediated inflammation.

Essential Role of Pepsin in Pathogenesis of Acid Reflux Esophagitis in Rats

Pepsin, a protease activated by gastric acid, is a component of the refluxate, yet the role of pepsin in the pathogenesis of reflux esophagitis has not been well studied. In the present study, we examined the effect of pepstatin, a specific inhibitor of pepsin, on acid reflux esophagitis. Acid reflux esophagitis was induced in rats by ligating both the pylorus and the forestomach for 3 or 4 hr. Pepstatin, ecabet Na (the anti-ulcer drug), and L-glutamine were administered intragastrically after the ligation. Pepstatin or ecabet Na, given intragastrically, significantly prevented esophageal lesions, even though they did not affect basal acid secretion in pylorus-ligated rats. Pepstatin significantly inhibited pepsin activity in vivo and in vitro, while ecabet Na inhibited this activity in vitro. By contrast, L-glutamine given intragastrically aggravated the lesions in a dose-dependent manner, but even in the presence of L-glutamine the development of esophageal lesions was totally prevented by coadministration of pepstatin or ecabet Na. L-Glutamine increased the pH of gastric contents to approximately 2.0, the optimal pH for the proteolytic activity of pepsin in vitro. In addition, intragastric administration of exogenous pepsin worsened the severity of esophageal damage. These results suggest that pepstatin is highly effective against acid reflux esophagitis, without influencing acid secretion, while L-glutamine aggravated these lesions by increasing the pepsin activity by shifting the intraluminal pH to the optimal pH range for proteolytic action. It is assumed that pepsin plays a major pathogenic role in the development of acid reflux esophagitis.

Evidence for a Role of the GHS‐R1a Receptors in Ghrelin Inhibition of Gastric Acid Secretion in the Rat

Ghrelin, the endogenous ligand of the GH secretagogue receptor (GHS-R) has been previously shown to inhibit gastric acid secretion in pylorus-ligated rats. Two isoforms of GHS-R have been identified: GHS-R(1a) and GHS-R(1b). The present study aimed: (i) to characterise the type of GHS-R involved in the central gastric inhibitory activity of ghrelin by using des-octanoyl ghrelin, and synthetic GHS-R(1a) agonist (EP1572) and antagonist (D-Lys(3)-GHRP-6) and (ii) to investigate the relationship between ghrelin and cortistatin (CST) in the control of gastric acid secretion by using the natural neuropeptide CST-14 and the synthetic octapeptide CST-8. The specific interactions of all the compounds with GHS-R(1a) were determined by comparing their ability to displace labelled ghrelin or somatostatin from its receptors on rat hypothalamic membranes or on rat cardiomyocyte, respectively. Intracerebroventricular administration of 0.01 and 1 nmol/rat des-octanoyl ghrelin did not affect gastric acid secretion in pylorus-ligated rats, whereas EP1572 either i.c.v. (0.01-1 nmol/rat) or i.p. (10 and 20 nmol/kg) inhibited acid gastric secretion. Preteatment with D-Lys(3)GHRP-6 (3 nmol/rat, i.c.v.) was able to remove the inhibitory action of ghrelin (0.01 nmol/rat, i.c.v.) on gastric acid volume and acid output, thus indicating that the type 1a GHS-R likely mediates the gastric inhibitory action of ghrelin. This is supported by binding data showing that D-Lys(3)GHRP-6, but not des-octanoyl ghrelin, binds to hypothalamic GHS-R. CST-14 (1 nmol/rat, i.c.v.) did not affect either basal or ghrelin inhibition of gastric acid secretion. CST-8 (1 nmol/rat, i.c.v.) was able to counteract the gastric ghrelin response. The observation that CST-14 binds both GHR-S and somatostatin receptors, whereas CST-8 specifically displaces only ghrelin binding, indicates that CST-8 behaves as a GHS-R(1a) antagonist.

Antisecretory and antiulcer effects of diphenyl diselenide

The antisecretory and antiulcer effects of diphenyl diselenide were studied in vivo and in vitro. Diphenyl diselenide, administered intraperitoneally prevented the development of gastric lesions induced by ethanol and indomethacin. There was no difference in plasma uric acid concentrations in diphenyl diselenide-treated rats with gastric lesions induced by 70% ethanol. There were no changes in TBARS levels in diphenyl diselenide-treated rats with gastric lesions induced by indomethacin and ethanol. Diphenyl diselenide (5, 10 and 50 mg/kg) inhibited gastric acid secretion in pylorus-ligated rats. In vitro results demonstrated that diphenyl diselenide inhibited lipid peroxidation induced by Fe 2+/ascorbate/H 2O 2 and reduced K +-dependent ATPase activity. The mechanisms by which pre-administered diselenide protects the damaged area in the gastric mucosa are not clear but it appears that the antiulcer activity of diphenyl diselenide is the result of antisecretory activity, via inhibition of gastric K +-ATPase activity.

Mechanisms of protection by pantoprazole against NSAID-induced gastric mucosal damage

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) can be associated with severe adverse digestive effects. In clinical settings, proton pump inhibitors have proven to be effective in preventing and healing NSAID-induced gastroduodenal lesions. The present study investigates the mechanisms of protection afforded by pantoprazole against gastric injury induced by different NSAIDs in rats. Animals were orally treated with indomethacin (100 micromol/kg), diclofenac (60 micromol/kg), piroxicam (150 micromol/kg) or ketoprofen (150 micromol/kg). Thirty minutes before NSAIDs, animals received pantoprazole 6 or 60 micromol/kg orally. Four hours after NSAIDs, the following parameters were assessed: histomorphometric evaluation of gastric mucosal damage; gastric mucosal levels of myeloperoxidase (MPO), malondialdehyde (MDA), reduced glutathione as an index of non-proteic sulfhydryl compounds (GSH), and prostaglandin E2 (PGE2); mucosal cyclooxygenase-1 and -2 (COX-1, COX-2) mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). Separate experiments were carried out to assay the effects of pantoprazole on gastric acid secretion in pylorus-ligated rats. The in vitro influence of pantoprazole (1-10 microM) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate was also examined. All NSAIDs elicited mucosal necrotic lesions associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels, were detected in the gastric mucosa of indomethacin-, piroxicam- or ketoprofen-treated animals. Indomethacin enhanced mucosal COX-2 expression, while not affecting COX-1. At the oral dose of 6 micromol/kg pantoprazole did not affect NSAID-induced mucosal damage, whereas at 60 micromol/kg it markedly reduced injuries provoked by all test NSAIDs. Pantoprazole 60 micromol/kg also reversed the effects of NSAIDs on MPO, MDA, and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced COX-2 expression. However, at both doses, pantoprazole inhibited acid secretion in pylorus-ligated rats. Furthermore, pantoprazole concentration dependently reduced the in vitro oxidation of LDLs. Our results suggest that besides inhibiting acid secretion, the protection afforded by pantoprazole against NSAID-induced gastric damage depends on a reduction in mucosal oxidative injury, which may also account for an increment of sulfhydryl radical mucosal bioavailability. It is also suggested that pantoprazole does not influence the down-regulation of gastric prostaglandin production associated with NSAID treatment.

Lansoprazole prevents experimental gastric injury induced by non-steroidal anti-inflammatory drugs through a reduction of mucosal oxidative damage

This study investigated the mechanisms of protection afforded by the proton pump inhibitor lansoprazole against gastric injury induced by different non-steroidal anti-inflammatory drugs (NSAIDs) in rats. Male Sprague-Dawley rats were orally treated with indomethacin (100 micromol/kg), diclofenac (60 micromol/kg), piroxicam (150 micromol/kg) or ketoprofen (150 micromol/kg). Thirty minutes before NSAIDs, animals were orally treated with lansoprazole 18 or 90 micromol/kg. Four hours after the end of treatments, the following parameters were assessed: gastric mucosal PGE2, malondialdehyde (MDA), myeloperoxidase (MPO) or non-proteic sulfhydryl compounds (GSH) levels; reverse transcription-polymerase chain reaction (RT-PCR) of mucosal COX-2 mRNA; gastric acid secretion in pylorus-ligated animals; in vitro effects of lansoprazole (1-300 micromol/L) on the oxidation of low density lipoproteins (LDLs) induced by copper sulphate. All NSAIDs elicited mucosal necrotic lesions which were associated with neutrophil infiltration and reduction of PGE2 levels. Increments of MPO and MDA contents, as well as a decrease in GSH levels were detected in the gastric mucosa of indomethacin- or piroxicam-treated animals. Indomethacin enhanced mucosal cyclooxygenase-2 expression, while not affecting cyclooxygenase-1. At the oral dose of 18 micromol/kg lansoprazole partly counteracted diclofenac-induced mucosal damage, whereas at 90 micromol/kg it markedly prevented injuries evoked by all test NSAIDs. Lansoprazole at 90 micromol/kg reversed also the effects of NSAIDs on MPO, MDA and GSH mucosal contents, without interfering with the decrease in PGE2 levels or indomethacin-induced cyclooxygenase-2 expression. However, both lansoprazole doses markedly inhibited acid secretion in pylorus-ligated rats. Lansoprazole concentration-dependently reduced the oxidation of LDLs in vitro. These results suggest that, besides the inhibition of acid secretion, lansoprazole protection against NSAID-induced gastric damage depends on a reduction in mucosal oxidative injury, which is also responsible for an increment of sulfhydryl radical bioavailability. It is also suggested that lansoprazole does not influence the down-regulation of gastric prostaglandin production associated with NSAID treatment.

Pharmacological study of Stachytarpheta cayennensis Vahl in rodents

Freeze-dried aqueous extracts (AEs, 0.1-1g/kg body wt., p.o.) obtained from entire or selected parts of Stachytarpheta cayennensis were tested for their effects on gastric secretion, gastric motility, inflammation and pain in rodents, with the purpose of validating the plant's ethnomedical uses. The AE-Total, AE-Flowers and AE-Leaves but not AE-Stems inhibited the gastric acid secretion in pylorus-ligated rats with varying potency. Purification of AEs yielded the semipurifed fractions EtFs rich in iridoids. All the EtFs with exception of EtF-Stems inhibited gastric acid secretion of pylorus ligated mice. While AE-Total stimulated the intestinal transit of mice by 43%, AE-Leaves delayed it by 38%. These effects on intestinal transit were not observed when the EtFs were tested. Only AE-Leaves and AE-Flowers altered the gastric emptying of semisolids, increasing it by 45% and 69%, respectively. These results indicate that the compounds related to inhibition of gastric acid secretion and gastrointestinal motility are different. The AE-Total reduced abdominal writhing induced by acetic acid potently (ED50 value = 700 mg/kg, p. o.) without altering the writhes induced by acetylcholine. Attempts to identify the mechanism of analgesia were unsuccessful since the AE-Total did not show analgesic effects when tested in different models of pain such as formalin and capsaicin or the tail-flick test. Pretreatment of animals with AE-Total did not show antiinflammatory activity in any of the acute (paw edema induced by carrageenin, dextran or histamine, pleurisy induced by carrageenin and capsaicin-induced mouse ear edema) or chronic (air pouch) models used. No toxic signs were observed after administration of the different extracts up to 2 g/kg body wt., p.o. Collectively, the results confirmed folk information indicating presence of analgesic, mild laxative and potent inhibition of gastric secretion activities in the aqueous extracts of S. cayennensis. The results do not, however confirm the folk use of the plant as an antiinflammatory medicine.

Effects of centrally injected GLP-1 in various experimental models of gastric mucosal damage

Glucagon-like peptide-1 (GLP-1) is accepted to be a peptide involved in the central regulation of gastrointestinal function, but its potential gastroprotective effect is not clear. The aim of this study was to investigate whether intracerebroventricularly injected GLP-1 has protective effects on gastric mucosal lesions induced by several models, and if yes, whether these effects are due to the gastric antisecretory effect of the peptide. GLP-1 which was injected in three different doses (1, 10, 100 ng/10 μl; i.c.v.) to conscious rats prevented the mucosal lesions induced by reserpine and ethanol, but did not prevent the gastric mucosal lesions induced by pyloric ligation. In addition, 1 ng/10 μl dose of centrally injected GLP-1 inhibited gastric acid secretion in pylorus-ligated rats. As a result, we conclude that intracerebroventricularly injected GLP-1 may play a role in the prevention of gastric mucosal lesions induced by certain experimental models and this gastroprotective effect may be independent from its antisecretory effect.

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

The plants belonging to Pfaffia genus are used in folk medicine to treat gastric disturbances. This study examined the effects of an aqueous extract of Pfaffia glomerata (Spreng) Pedersen (AEP) on the gastrointestinal tract. Wistar rats were pretreated orally (p.o.) with the AEP (125, 250, 500 and 1000 mg.kg −1) before induction of ulcers by hypothermic restraint stress (HRS, 3 h restraint stress at 4 °C), ethanol (ET, 70%; 0.5 ml/animal; p.o.) or indomethacin (IND, 20 mg.kg −1; s.c.). Control animals received water (C) or ranitidine (60 mg.kg −1) p.o. The AEP protected rats against HRS and ET-induced ulcers, but was not able to protect the gastric mucosa against IND-induced ulcers. When injected into the duodenal lumen, the AEP reduced total acidity and both basal and histamine-stimulated acid secretion in pylorus-ligated rats. In addition, gastric secretion from AEP-treated animals exhibited increased concentrations of nitrite and nitrate. Treatment of animals with L-NAME (120 mg.kg −1, p.o.) prevented both the reduction of total acidity and the increase in NO x levels promoted by AEP treatment. In conclusion, AEP effectively protected the gastric mucosa and inhibited gastric acid secretion in rats, probably by involving the histaminergic pathway and an enhanced production of nitric oxide in the stomach.

Actions of crude hydroalcoholic extract of Pfaffia sp on gastrointestinal tract

The plants that compound the Pfaffia genus are used in folk medicine to treat gastric disturbances. This study examined the effects of a crude hydroalcoholic extract of Pfaffia sp on the gastrointestinal tract. Female Wistar rats were pretreated orally (p.o.) with the hydroalcoholic extract of Pfaffia (0.5, 1 and 2 g.kg-1) before the induction of ulcer with hypothermic restraint stress (HRS), ethanol (ET) or indomethacin (IND). Control animals received water (C) or ranitidine (60mg/kg) p.o. The hydroalcoholic extract of Pfaffia (0.5, 1 and 2 mg.kg-1) protected rats against HRS and ET - induced ulcers, but was not able to protect the gastric mucosa against IND - induced ulcers. When injected into the duodenal lumen, the hydroalcoholic extract of Pfaffia inhibited basal and stimulated acid secretion in pylorus-ligated rats. These results indicate that this plant has a protective action against gastric lesions of the mucosa involving the reduction of gastric acid secretion.

Gastroprotective effects of a crude extract of Baccharis illinita DC in rats

Baccharis illinita DC (Compositae) is used in folk medicine to treat gastric disorders. The crude hydroalcoholic extract of leaves and stems tested on mice at doses from 1.0 to 6.0 g/kg, PO, did not produce signs of toxicity. Only the aqueous extract of leaves (0.1 g/kg, PO) increased intestinal motility in mice. The crude hydroalcoholic extract of stems and leaves (HESL) protected rats against lesions induced by ethanol or restraint-in-cold. The crude aqueous extract of roots protected against ulcers induced by ethanol, indomethacin or restraint-in-cold, and the crude aqueous extract of flowers only protected against lesions induced by ethanol. When injected into the duodenal lumen, the aqueous root extract inhibited basal acid secretion in pylorus-ligated rats. The results obtained in the present pharmacological assays indicate that this plant has a protective action against gastric lesions of the mucosa involving the maintenance of protective factors such as mucus, bicarbonate and blood flow, besides the reduction of gastric acid secretion.

Inhibition of CN (protein phosphatase-2B) suppresses Ca2+-mediated acid secretion in rats.

It has been suggested that CN (calcineurin, protein phosphatase-2B) regulates signal transduction, particularly in various secretory cells. In this study, we examined whether CN plays a role in stimulus-secretion coupling of gastric parietal cells. Localization of CN in gastric epithelial cells was examined immunohistochemically. The role of CN in the acid secretion pathway of gastric parietal cells was assessed by evaluating the effect of FK506, a specific inhibitor of CN, on gastric acid secretion in pylorus-ligated rats. In addition, the effect of FK506 on secretagogue (carbachol, tetragastrin and histamine)-stimulated acid secretion was investigated in lumen-perfused rats. CN was specifically expressed in gastric parietal cells and chief cells of the gastric mucosal epithelium immunohistochemically. FK506 dose-dependently inhibited gastric acid secretion in pylorus-ligated rats. In lumen-perfused rats, FK506 completely inhibited acid secretion prestimulated by carbachol and tetragastrin, agonists known to increase cytosolic Ca2+, but did not affect acid secretion prestimulated by histamine. Our findings demonstrate that FK506 has a potent antisecretory effect in parietal cells through inhibition of only Ca2+-mediated acid secretion pathways. As FK506 is known to specifically inhibit CN, which plays an important role in signal transduction in various secretory cells, protein dephosphorylation signalling might also be crucial for gastrin and M3 muscarine receptor-mediated stimulation of proton pump.

Involvement of central K ATP channels in the gastric antisecretory action of α 2-adrenoceptor agonists and β-endorphin in rats

The intracerebroventricularly (i.c.v.) injected presynaptic α 2-adrenoceptor agonists, clonidine and oxymetazoline, exerted a dose-dependent inhibition on the gastric acid secretion in pylorus-ligated rats; the ED 50 values were 20 and 7.5 nmol/rat, respectively. Moreover, β-endorphin, given i.c.v., also decreased acid secretion (ED 50=0.25 nmol/rat i.c.v.). The antisecretory effect of these compounds was highly reduced by glibenclamide (10 nmol/rat i.c.v.), a selective blocker of K ATP channels. These results suggest that K ATP channels in the central nervous system are likely to be involved in the centrally initiated antisecretory action of both α 2-adrenoceptor agonists and β-endorphin.

Four response stages of capsaicin-sensitive primary afferent neurons to capsaicin and its analog: gastric acid secretion, gastric mucosal damage and protection.

Capsaicin is the active component of red hot peppers, which modifies specifically the capsaicin-sensitive sensory afferent nerves. The action of capsaicin is an initial short-lasting stimulation, which is followed by desensitization to capsaicin itself, and to other stimuli of afferent sensory nerves. Four response stages of capsaicin-sensitive primary afferents exist to capsaicin, depending on the dose and duration of exposure to the drug. These are excitation, a sensory blocking effect, long-term selective neurotoxic impairment, and irreversible cell destruction. The possible roles of four stages of capsaicin-sensitive primary afferents can be evaluated in relation to gastric acid secretion, and to the details of the defensive side of gastric mucosa against different chemicals, physical agents, drugs and other pathological stress. Capsaicin inhibited the gastric acid secretion in pylorus-ligated rats when it was given intragastrically at a dose of 0.4-1.8 microg/kg. Small doses of capsaicin (up to 800 microg, i.g.) produced a dose-dependent inhibition (ID50 = 400 microg), and its inhibitory effect was exerted for 1 h in healthy human subjects. While a small dose (5 microg/kg) of capsaicin caused inhibition, a high dose (50-100 mg/kg) enhanced the gastric mucosal lesions productivity by causing hyperacidity in pylorus-ligated animals. Capsaicin and its analog inhibited the development of different chemically induced gastric mucosal damage in various experimental models if they were given intragastric doses (microg/kg). The final effects of capsaicin depend on the dosage and timing. The different effects are excitation, a sensory-blocking effect, long-term selective neurotoxic impairment and irreversible cell destruction.

Gastroprotective effects of pantoprazole against experimental mucosal damage

The present study investigated the gastroprotective effects of the proton pump inhibitor pantoprazole on gastric mucosal damage induced by ethanol-HCl in rats. Omeprazole was used as reference drug. The morphometric analysis of gastric histological sections revealed that pantoprazole and omeprazole dose-dependently prevented the necrotic mucosal injury evoked by ethanol-HCl (ED50 = 14.1 and 21.6 micromol/kg, respectively). These effects were associated with a marked increment of Alcian blue recovery from gastric bound mucus (ED50 = 18.8 and 29.3 micromol/kg, respectively). In addition, both pantoprazole and omeprazole inhibited gastric acid secretion in pylorus-ligated rats (ED50 = 1.5 and 3.3 micromol/kg, respectively). Further experiments indicated that the protective effects of pantoprazole were not modified by L-365,260 (a gastrin receptor antagonist), suramin (a drug able to interfere with endogenous growth factors), N(G)-nitro-L-arginine (an inhibitor of nitric oxide synthase) or systemic ablation of capsaicin-sensitive sensory nerves, whereas they were partly blocked by indomethacin (an inhibitor of prostaglandin synthesis) and fully prevented by N-ethylmaleimide (a potent blocker of sulfhydryl compounds). The present data provide histomorphometric evidence that: 1) pantoprazole is endowed with gastroprotective properties and is more active than omeprazole in preventing the necrotic mucosal damage induced by ethanol-HCl; 2) according to the rank order of ED50 values, the protective effects of both drugs appear to depend mainly on the enhancement of the gastric mucosal barrier rather than on the inhibition of acid secretion; 3) an increased production of prostaglandins, as well as an increased availability of sulfhydryl radicals at the level of the gastric mucosa may account for the gastroprotective effects of pantoprazole.

Anti-ulcer Effects of Chitin and Chitosan, Healthy Foods, in Rats

In this study, we compared the effects of low molecular weight (LMW) chitosan (MW: 25,000-50,000), high molecular weight (HMW) chitosan (MW: 500,000-1000,000) and chitin on ethanol-induced gastric mucosal injury and on the healing of acetic acid-induced gastric ulcers in rats. Oral administration of LMW chitosan (250, 500 and 1000 mg/kg) dose-dependently prevented ethanol-induced gastric mucosal injury. Repeated oral administration of LMW chitosan (100, 200 and 400 mg/kg twice daily) also dose-dependently accelerated the gastric ulcer healing. However, the effects of HMW chitosan and chitin on the gastric mucosal injury formation and the gastric ulcer healing were less potent than those of LMW chitosan. LMW chitosan (250 and 500 mg/kg, orally) was ineffective in inhibiting gastric acid secretion in pylorus-ligated rats, although it had a weak acid-neutralizing action. LMW-chitosan (250, 500 and 1000 mg/kg orally) dose-dependently prevented the decrease in gastric mucus content induced by ethanol. These results indicate that of the three compounds, LMW chitosan has the most potent gastric cytoprotective and ulcer healing-promoting actions. In addition, gastric mucus-increasing action of LMW-chitosan may be, at least in part, related to the anti-ulcer effect of this compound.