Effect of sodium bicarbonate on aspirin-induced damage and potential difference changes in human gastric mucosa

Two aspirin tablets in 100 ml fluid will produce microscopical damage to the human stomach. A study was performed to determine whether a small amount of sodium bicarbonate (equivalent to one-third of a teaspoonful of baking soda) could protect against this damage. Sequential gastric biopsy specimens were taken from 15 healthy subjects before, during, and after intragastric instillation of one of the following isotonic solutions: saline; sodium bicarbonate; 600 mg aspirin suspended in sodium bicarbonate; and aspirin suspended in saline. On a separate day the same solutions were instilled, but gastric transmucosal potential differences were monitored. Light microscopy and scanning electron microscopy of the biopsy specimens showed occasional mucous degranulation of mucosal surface cells, but no cell damage during instillation of sodium bicarbonate. Light microscopy studies 10 minutes after aspirin in saline showed damage in 20% of surface cells, with focal areas of cellular disruption and microscopic erosions, but only 3·4% of cells were damaged after aspirin in bicarbonate and there were no erosions. Electron microscopy showed a damaged honeycombed appearance of surface epithelium after aspirin in saline and a normal cobblestone appearance after aspirin in bicarbonate. Aspirin dissolved in bicarbonate failed to induce the usual fall in potential difference.These findings indicate that sodium bicarbonate in amounts equivalent to one-third of a teaspoonful of baking soda protects the gastric mucosa against aspirin-induced damage and prevents the usual fall in potential difference after aspirin.     

Aspirin, but not NO-releasing aspirin (NCX-4016), interacts with selective COX-2 inhibitors to aggravate gastric damage and inflammation

Aceylation of cyclooxygenase (COX)-2 by aspirin can trigger the formation of 15(R)-epilipoxin A4, or aspirin-triggered lipoxin (ATL). ATL exerts protective effects in the stomach. Selective COX-2 inhibitors block ATL synthesis and exacerbate aspirin-induced gastric damage. Nitric oxide-releasing aspirins, including NCX-4016, have antiplatelet effects similar to aspirin but do not cause gastric damage. In the present study, we examined whether or not NCX-4016 triggers ATL synthesis and/or upregulates gastric COX-2 expression and the effects of coadministration of NCX-4016 with a selective COX-2 inhibitor on gastric mucosal injury and inflammation. Rats were given aspirin or NCX-4016 orally and either vehicle or a selective COX-2 inhibitor (celecoxib) intraperitoneally. Gastric damage was blindly scored, and granulocyte infiltration into gastric tissue was monitored through measurement of myeloperoxidase activity. Gastric PG and ATL synthesis was measured as was COX-2 expression. Whereas celecoxib inhibited gastric ATL synthesis and increased the severity of aspirin-induced gastric damage and inflammation, coadministration of celecoxib and NCX-4016 did not result in damage or inflammation. NCX-4016 did not upregulate gastric COX-2 expression nor did it trigger ATL synthesis (in contrast to aspirin). Daily administration of aspirin for 5 days resulted in significantly less gastric damage than that seen with a single dose, as well as augmented ATL synthesis. Celecoxib reversed this effect. In contrast, repeated administration of NCX-4016 failed to cause gastric damage, whether given alone or with celecoxib. These studies support the notion that NCX-4016 may be an attractive alternative to aspirin for indications such as cardioprotection, including in individuals also taking selective COX-2 inhibitors.     

Gastritis increases resistance to aspirin-induced mucosal injury via COX-2-mediated lipoxin synthesis

Products of cyclooxygenase (COX)-2 contribute to mucosal defense. Acetylation of COX-2 by aspirin has been shown to result in the generation of 15(R)-epi-lipoxin A4, which exerts protective effects in the stomach. In gastritis, it is possible that lipoxin A4 makes a greater contribution to mucosal defense. We tested this hypothesis in the rat, by using the iodoacetamide-induced gastritis model. Iodoacetamide was added to the drinking water for 5 days. Rats were then given aspirin, and the extent of gastric damage was blindly assessed 3 h later. Gastric 15(R)-epi-lipoxin A4 and PGE2 levels were determined. The effects of pretreatment with a selective COX-2 inhibitor, rofecoxib, and of a lipoxin receptor antagonist were assessed. Effects of aspirin and the other test drugs on leukocyte adherence within mesenteric venules were assessed by intravital microscopy. Aspirin elicited greater lipoxin synthesis in the inflamed than in the normal stomach, and there was reduced gastric damage. Rofecoxib inhibited lipoxin synthesis and exacerbated aspirin-induced damage. The lipoxin antagonist also exacerbated aspirin-induced damage. In rats with gastritis, aspirin reduced leukocyte adherence (in contrast to an increase in normal rats), and this effect was reversed by rofecoxib or by the lipoxin antagonist. These results support the notion that aspirin-triggered lipoxin synthesis via COX-2 makes an important contribution to mucosal defense in both the normal and inflamed stomach.     

Effects of pectin-induced passive linkage of gastric H+ on the gastric acid secretion 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 x 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 x kg(-1) increased the number of gastric mucosal lesions in both models, while no increase was produced by the application of 25-mg x 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.     

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.     

Aspirin-induced gastric injury in the rat: histologic changes and sucralfate cytoprotection

The effect of pretreatment with intragastric sucralfate on aspirin acid-induced gastric mucosal lesions in the rat was studied. The finding by others that sucralfate is cytoprotective and that this cytoprotective effect probably is mediated, at least in part, by stimulation of endogenous prostaglandin synthesis was confirmed. In addition, a time course study revealed that the maximum cytoprotective effect was present 1 min after sucralfate administration and persisted for at least 6 hr. Microscopic evaluation of histologic sections revealed that sucralfate significantly decreased aspirin-induced deep mucosal erosions (those extending into the parietal cell area) but not superficial mucosal damage. Superficial mucosal damage (surface cell injury and erosions involving the mucous neck cell area) could not be detected grossly. The lesions seen grossly were deeper erosions involving the parietal cell area of the mucosa.     

Aggravation of nonsteroidal antiinflammatory drug gastropathy by glucocorticoid deficiency or blockade of glucocorticoid receptors in rats

Our previous investigations suggest that the reduction of stress-induced corticosterone release, or inhibition of corticosterone actions, promotes stress-induced gastric erosions in rats. In this study the effect of glucocorticoid deficiency on susceptibility to gastric mucosal injury by nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated in rats. Gastric erosions induced in male rats by indomethacin (25 mg/kg sc) or acidified aspirin (40 mM po) were studied one week after adrenalectomy with or without corticosterone replacement or after occupation of glucocorticoid receptors by the antagonist RU-38486 during the period of erosion formation. Corticosterone for replacement (4 mg/kg sc) was injected 15 min before the administration of indomethacin or acidified aspirin to adrenalectomized rats. The antagonist RU-38486 (10 mg/kg po) was administered twice, 20 min before and 60 min after NSAID administration. Plasma corticosterone levels were measured by fluorometry. Gastric erosions were quantitated by measuring the area of damage. Indomethacin or acidified aspirin induced both plasma corticosterone rise and gastric erosions. Adrenalectomy decreased both basal and NSAID-induced corticosterone levels and markedly promoted gastric erosion formation caused by the NSAID. An acute corticosterone replacement mimicking indomethacin-and aspirin-induced corticosterone rise prevented the effect of adrenalectomy on the gastric erosions. The administration of the glucocorticoid/progesterone antagonist RU-38486 significantly potentiated the formation of gastric erosions induced by indomethacin as well as aspirin. These observations suggest a gastroprotective action of glucocorticoids released in response to NSAID treatment against NSAID-induced injury.     

Gastroprotective and vasodilatory effects of epidermal growth factor: the role of sensory afferent neurons

Epidermal growth factor (EGF) has been shown to exert gastric hyperemic and gastroprotective effects via capsaicin-sensitive afferent neurons, including the release of calcitonin gene-related peptide (CGRP). We examined the protective and vasodilatory effects of EGF on the gastric mucosa and its interaction with sensory nerves, CGRP, and nitric oxide (NO) in anesthetized rats. Intragastric EGF (10 or 30 microg) significantly reduced gastric mucosal lesions induced by intragastric 60% ethanol (50.6% by 10 microg EGF and 70.0% by 30 microg EGF). The protective effect of EGF was significantly inhibited by pretreatment with capsaicin desensitization, human CGRP1 antagonist hCGRP-(8-37), or N(omega)-nitro-L-arginine methyl ester (L-NAME). Intravital microscopy showed that topically applied EGF (10-1,000 microg/ml) dilated the gastric mucosal arterioles dose dependently and that this vasodilatory effect was significantly inhibited by equivalent pretreatments. These findings suggest that EGF plays a protective role against ethanol-induced gastric mucosal injury, possibly by dilating the gastric mucosal arterioles via capsaicin-sensitive afferent neurons involving CGRP and NO mechanisms.     

Picomole doses of platelet-activating factor predispose the gastric mucosa to damage by topical irritants

The ability of the endogenous pro-inflammatory phospholipid, platelet-activating factor (Paf), to increase the susceptibility of the rat gastric mucosa to damage induced by a topical irritant was studied in an ex vivo gastric chamber model. Intravenous infusion of Paf (1-100 ng/kg/min) for 5 minutes dose-dependently increased the haemorrhagic damage induced by topically applied 20% ethanol. The pro-ulcerogenic actions of Paf were not solely due to its hypotensive actions, since a significant augmentation of damage was observed with doses of Paf (1 ng/kg/min) which did not affect systemic arterial blood pressure. These pro-ulcerogenic actions were not shared by the structurally similar precursor/breakdown product, lyso-Paf (100 ng/kg/min). Paf (100 ng/kg/min) also significantly increased the gastric damage induced by topically applied 2 mM sodium taurocholate. Infusion of Paf for 5 minutes without topical irritation only caused significant gastric damage at the highest dose tested (100 ng/kg/min). Histologically, this damage was characterized by extensive vasocongestion, deep mucosal necrosis, swelling of the gastric glands and accumulations of neutrophils in the mucosal and submucosal venules. Paf is thus a potent pro-ulcerogenic agent in the gastric mucosa. The endogenous release of Paf during septic shock or inflammatory diseases of the gastrointestinal tract could contribute to the mucosal injury associated with these disorders.     

Picomole doses of platelet-activating factor predispose the gastric mucosa to damage by topical irritants

The ability of the endogenous pro-inflammatory phospholipid, platelet-activating factor (Paf), to increase the susceptibility of the rat gastric mucosa to damage induced by a topical irritant was studied in an gastric chamber model. Intravenous infusion of Paf (1–100 ng/kg/min) for 5 minutes dose-dependently increased the haemorrhagic damage induced by topically applied 20% ethanol. The pro-ulcerogenic actions of Paf were not solely due to its hypotensive actions, since a significant augmentation of damage was observed with doses of Paf (1 ng/kg/min) which did not affect systemic arterial blood pressure. These pro-ulcerogenic actions were not shared by the structurally similar precursor/breakdown product, lyso-Paf (100 ng/kg/min). Paf (100 ng/kg/min) also significantly increased the gastric damage induced by topically applied 2 mM sodium taurocholate. Infusion of Paf for 5 minutes without topical irritation only caused significant gastric damage at the highest dose tested (100 ng/kg/min). Histologically, this damage was characterized by extensive vasocongestion, deep mucosal necrosis, swelling of the gastric glands and accumulations of neutrophils in the mucosal and submucosal venules. Paf is thus a potent pro-ulcerogenic agent in the gastric mucosa. The endogenous release of Paf during septic shock or inflammatory diseases of the gastrointestinal tract could contribute to the mucosal injury associated with these disorders.     

Gastroprotective action of orexin-A against stress-induced gastric damage is mediated by endogenous prostaglandins, sensory afferent neuropeptides and nitric oxide

Orexin-A, identified in the neurons and endocrine cells in the gut, has been implicated in control of food intake and sleep behavior but little is known about its influence on gastric secretion and mucosal integrity. The effects of orexin-A on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and restraint stress (WRS) or 75% ethanol were determined. Orexin-A (5-80 microg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by WRS and this was accompanied by the significant rise in plasma orexin-A, CGRP and gastrin levels, the gastric mucosal blood flow (GBF), luminal NO concentration and an increase in mRNA for CGRP and overexpression of COX-2 protein and the generation of PGE(2) in the gastric mucosa. Orexin-A-induced protection was abolished by selective OX-1 receptor antagonist, vagotomy and attenuated by suppression of COX-1 and COX-2, deactivation of afferent nerves with neurotoxic dose of capsaicin, pretreatment with CCK(2)/gastrin antagonist, CGRP(8-37) or capsazepine and by inhibition of NOS with L-NNA. This study shows for the first time that orexin-A exerts a potent protective action on the stomach of rats exposed to non-topical ulcerogens such as WRS or topical noxious agents such as ethanol and these effects depend upon hyperemia mediated by COX-PG and NOS-NO systems, activation of vagal nerves and sensory neuropeptides such as CGRP released from sensory nerves probably triggered by an increase in gastric acid secretion induced by this peptide.     

Complement plays an important role in gastric mucosal damage induced by ischemia-reperfusion in rats.

Ischemia-reperfusion (I/R) of stomach causes gastric mucosal injury. Complement can also cause tissue damage, however its role in gastric I/R injury has not been thoroughly investigated. We evaluated the effect of complement suppression in reducing damage to the gastric epithelium caused by local I/R. Local gastric ischemia was induced by clamping the left gastric artery. The blood-to-lumen clearance of 51Cr-labeled EDTA (51Cr-EDTA) served as an index of epithelial damage. 51Cr-EDTA clearance increased shortly after reperfusion with peak values at 10 min. Intraperitoneal administration of cobra venom factor (CVF; 50 units) prior to I/R, which reduced the serum complement value (CH50) to an undetectable level, remarkably suppressed the 51Cr-EDTA clearance following reperfusion. A monocarboxylic acid derivative of K-76 (K-76 COOH) reduced the CH50 by more than 30% (100 mg/kg) and 60% (200 mg/kg). Rats pretreated with K-76 significantly attenuated the increase in 51Cr-EDTA clearance produced by I/R. These results suggest that complement inhibitor could be used to protect gastric mucosal injury induced by local I/R stress.     

The effect of nitric oxide donors and L-arginine on the gastric electrolyte barrier.

The potential difference across the stomach wall (PD) is determined by the gastric mucosal barrier. The decrease in the PD evoked by "the barrier breakers", e.g. aspirin, ethanol or bile acids is believed as a sensitive index of the mucosal damage. The effect of glyceryl trinitrate (GTN), isosorbide dinitrate (IDN) and molsidomine (MOL)--all exogenous donors of nitric oxide (NO), as well as L-arginine (L-ARG), which is a substrate for NO-synthase and Nomega-nitro-L-arginine (L-NNA), a non-selective NO synthase inhibitor on the gastric electrolyte barrier were studied against the gastric damage induced by ethanol. All NO donors given intragastrically alone caused only moderate, not significant changes in the PD and failed to affect the mucosal barrier, while L-NNA slightly decreased the PD. The NO donors and L-arginine applied as pretreatment prior to ethanol resulted in diminishing of its damaging action that was similar for all these drugs, while L-NNA intensified both the injury and the drop in the PD values caused by ethanol. In summary, our results showed the protective effect of endogenous nitric oxide from L-ARG and that originating from GTN, MOL and IDN on the gastric electrolyte barrier, supporting involvement of nitric oxide in the mechanism of gastric protection in the stomach.     

Endothelium-derived relaxing factor (nitric oxide) has protective actions in the stomach

The role that nitric oxide, an endothelium-derived relaxing factor, may play in the regulation of gastric mucosal defence was investigated by assessing the potential protective actions of this factor against the damage caused by ethanol in an ex vivo chamber preparation of the rat stomach. Topical application of glyceryl trinitrate and sodium nitroprusside, which have been shown to release nitric oxide, markedly reduced the area of 70% ethanol-induced hemorrhagic damage. Topical application of a 0.01% solution of authentic nitric oxide also significantly reduced the severity of mucosal damage. Pretreatment with indomethacin precluded the involvement of endogenous prostaglandins in the protective effects of these agents. The protective effects of NO were transient, since a delay of 5 minutes between NO administration and ethanol administration resulted in a complete loss of the protective activity. The protection against ethanol afforded by 10 micrograms/ml nitroprusside could be completely reversed by intravenous infusion of either 1% methylene blue or 1 mM hemoglobin, both of which inhibit vasodilation induced by nitric oxide. Intravenous infusion of 1% methylene blue significantly increased the susceptibility of the mucosa to damage induced by topical 20% ethanol. These results indicate that ethanol-induced gastric damage can be significantly reduced by nitric oxide. The mechanisms underlying the protective actions of nitric oxide are unclear, but may be related to its vasodilator or anti-aggregatory properties.     

Effects of ethanol on gastric acid secretion and gastric mucosal cyclic AMP in the rat.

The effect of ethanol on the secretion of gastric acid and the content of cyclic AMP of the gastric mucosa was studied in rats. Intravenously, ethanol (10 to 800 mg/kg) had no effect on the output of acid. Upon local application into the stomach, ethanol (1 to 10%) caused a concentration-dependent inhibition of the output of gastric acid. The effect was evident within 5 min. At the concentration of 1 %,ethanol decreased the rate of acid secretion maximally by about 30%. At the concentration of 3 %, the maximal inhibition was about 70 %. At the concentration of 10 %, ethanol caused a total cessation of the output of acid within 20 to 60 min.Five and 25 min after the administration of 10 % ethanol into the stomach, the gastric mucosal content of cyclic AMP was decreased by approximately 50 %. Also in vitro, the mucosal content of cyclic AMP was decreased by ethanol within 5 min. The decrease was about 30 % with 2.5 % ethanol, approximately 60 % with 10 % ethanol, and approximately 45 % with 20 % ethanol. Alcohol inhibited the activity of the cyclic AMP phosphodiesterase of the gastric mucosa in a competitive manner. The K_i-value was 0.16 M which would correspond to an alcohol concentration of 9.1 % (v/v). Ethanol caused a concentration-dependent inhibition of the activity of the gastric mucosal adenyl cyclase. By 0.166 M (9.4 %) alcohol the inhibition was nearly 100 %.It is concluded that the ethanol-induced decrease of cyclic AMP in the gastric mucosa is due to a decreased formation of the nucleotide. The accompanying inhibition of the output of acid by ethanol is consistent with the view that cyclic AMP is an intracellular regulator of the gastric acid secretion. In view of the role of cyclic AMP in the control of the integrity of the cells, it is suggested that the ethanol-induced damage of gastric mucosa might also be, at least partly, due to the decreased mucosal content of cyclic AMP.     

Enhancement of gastric mucosal integrity by Lactobacillus rhamnosus GG

The gastric mucosa is frequently exposed to different exogenous and endogenous ulcerative agents. Alcoholism is one of the risk factors for the development of mucosal damage in the stomach. This study aimed to assess if a probiotic strain Lactobacillus rhamnosus GG (LGG) is capable of protecting the gastric mucosa from acute damage induced by intragastric administration of ethanol. Pre-treatment of rats with LGG at 10(9) cfu/ml twice daily for three consecutive days markedly reduced ethanol-induced mucosal lesion area by 45%. LGG pre-treatment also significantly increased the basal mucosal prostaglandin E(2) (PGE(2)) level. In addition, LGG attenuated the suppressive actions of ethanol on mucus-secreting layer and transmucosal resistance and reduced cellular apoptosis in the gastric mucosa. It is suggested that the protective action of LGG on ethanol-induced gastric mucosal lesions is likely attributed to the up-regulation of PGE(2), which could stimulate the mucus secretion and increase the transmucosal resistance in the gastric mucosa. All these would protect mucosal cells from apoptosis in the stomach.     

Calcitonin gene-related peptide can attenuate or augment pancreatic damage in caerulein-induced pancreatitis in rats.

We have recently shown that treatment with calcitonin gene-related peptide (CGRP) before and during induction of acute pancreatitis exhibits a protective effect against pancreatic damage evoked by overdose of caerulein. Studies in the stomach have shown that administration of CGRP exhibits dual action on gastric mucosa, CGRP administration before induction of gastric lesions, protects gastric mucosa against damage, whereas treatment with this peptide after development of gastric ulcer exacerbates mucosal injury. These observations prompt us to determine the influence of CGRP administrated before and after induction of pancreatitis on development and evolution of pancreatic tissue damage. METHODS: Acute pancreatitis was induced by s.c. infusion of caerulein (10 microg/kg/h) for 5 h. CGRP was administrated (10 microg/kg s.c. per dose) 30 min prior to caerulein infusion and 3 h later during caerulein infusion or at the time 1 h, 4 h and 7 h after the end of caerulein infusion. Rats were sacrificed at the time 0 h, 3 h or 9 h after cessation of caerulein administration. The pancreatic blood flow (PBF), plasma activity of amylase, plasma interleukin-1beta concentration, cell proliferation, biochemical and morphological signs of pancreatitis were examined. RESULTS: Caerulein-induced pancreatitis (CIP) led to 42% decrease in DNA synthesis, 30% inhibition of PBF, as well as, a significant increase in pancreatic weight, plasma amylase activity, plasma interleukin-1beta concentration, and development of the histological signs of pancreatic damage (edema, leukocyte infiltration and vacuolization). Treatment with CGRP prior and during induction of CIP attenuated the pancreatic damage what was manifested by partial reversion of the drop in DNA synthesis (40.9+1.7 v. 34.2+2.0 dpm/microg DNA) and PBF (83+3% v. 70+3%). Increases in pancreatic weight and plasma interleukin-1beta were reduced. Morphology showed improvement of pancreatic integrity. Administration of CGRP after induction of CIP aggravated pancreatic damage what was manifested by additional decrease in PBF and DNA synthesis. Also pancreatic weight as well as histological signs of pancreatic damage were increased. CONCLUSIONS: (1) Administration of CGRP before and during induction of pancreatitis protects pancreas against pancreatic damage. (2) Treatment with CGRP after development of CIP aggravates pancreatic damage.     

Peripheral GLP-1 gastroprotection against ethanol: the role of exendin, NO, CGRP, prostaglandins and blood flow

The aim of this study was to investigate the effects of peripherally injected glucagon like peptide-1 (GLP-1) on ethanol-induced gastric mucosal damage and the mechanisms included in the effect. Absolute ethanol was administered through an orogastric cannula right after the injection of GLP-1 (1, 10, 100, 1000 or 10,000 ng/kg; i.p.). The rats were decapitated an hour later, the stomachs removed and the gastric mucosal damage scored. 1000 ng GLP-1 inhibited gastric mucosal damage by 45% and 10,000 ng GLP-1 by 60%. The specific receptor antagonist exendin-(9-39) (2500 ng/kg; i.p.), calcitonin gene related peptide (CGRP) receptor antagonist CGRP-(8-37) (10 microg/kg; i.p.), nitric oxide (NO) synthase inhibitor l-NAME (30 mg/kg; s.c.) and cyclooxygenase inhibitor indomethacin (5 mg/kg; i.p.) inhibited the preventive effect of GLP-1 on ethanol-induced gastric mucosal damage. GLP-1 also prevented the decrease in gastric mucosal blood flow caused by ethanol when administered at gastroprotective doses (1000 and 10,000 ng/kg; i.p.). In conclusion, GLP-1 administered peripherally prevents the gastric mucosal damage caused by ethanol in rats. CGRP, NO, prostaglandin and gastric mucosal blood flow are thought to play a role in this effect, mediated through receptors specific to GLP-1.     

Exogenous and endogenous ghrelin in gastroprotection against stress-induced gastric damage

Ghrelin, identified in the gastric mucosa has been involved in control of food intake and growth hormone (GH) release but little is known about its influence on gastric secretion and mucosal integrity. The effects of ghrelin on gastric secretion, plasma gastrin and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) were determined. Exogenous ghrelin (5, 10, 20, 40 and 80 microg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS and this was accompanied by the significant rise in plasma ghrelin level, gastric mucosal blood flow (GBF) and luminal NO concentrations. Ghrelin-induced protection was abolished by vagotomy and attenuated by suppression of COX, deactivation of afferent nerves with neurotoxic dose of capsaicin or CGRP(8-37) and by inhibition of NOS with L-NNA but not influenced by medullectomy and administration of 6-hydroxydopamine. We conclude that ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol and WRS, and these effects depend upon vagal activity, sensory nerves and hyperemia mediated by NOS-NO and COX-PG systems.