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Background The aim of this study is to provide a morphometric description of the left-sided septal pouch (LSSP), left atrial accessory appendages, and diverticula using cardiac multi-slice computed tomography (MSCT) and to compare results between patient subgroups. Methods Two hundred and ninety four patients (42.9% females) with a mean of 69.4±13.1years of age were investigated using MSCT. The presence of the LSSP, left atrial accessory appendages, and diverticula was evaluated. Multiple logistic regression analysis was performed to check whether the presence of additional left atrial structures is associated with increased risk of atrial fibrillation and cerebrovascular accidents. Results At least one additional left atrial structure was present in 51.7% of patients. A single LSSP, left atrial diverticulum, and accessory appendage were present in 35.7%, 16.0%, and 4.1% of patients, respectively. After adjusting for other risk factors via multiple logistic regression, patients with LSSP are more likely to have atrial fibrillation (OR=2.00, 95% CI=1.14–3.48, p =0.01). The presence of a LSSP was found to be associated with an increased risk of transient ischemic attack using multiple logistic regression analysis after adjustment for other risk factors (OR=3.88, 95% CI=1.10–13.69, p =0.03). Conclusions In conclusion LSSPs, accessory appendages, and diverticula are highly prevalent anatomic structures within the left atrium, which could be easily identified by MSCT. The presence of LSSP is associated with increased risk for atrial fibrillation and transient ischemic attack.

The term cytoprotection pioneered by Robert and colleagues has been introduced to describe the remarkable ability of endogenous and exogenous prostaglandins (PGs) to prevent acute gastric hemorrhagic lesions induced by noxious stimuli such as ethanol, bile acids, hiperosmolar solutions and nonsteroidal anti-inflammatory agents such as aspirin. Since that time many factors were implicated to possess gastroprotective properties such as growth factors including epidermal growth factor (EGF) and transforming factor alpha (TGFα), vasodilatory mediators such as nitric oxide (NO) and calcitonin gene related peptide (CGRP) as well as appetite gut hormones including gastrin and cholecystokinin (CCK), leptin and recently ghrelin. This protective action of gut peptides has been attributed to the release of PG but question remains whether another peptide angiotensin, the classic component of the systemic and local renin-angiotensin system (RAS) could be involved in the mechanism of gastric integrity and gastroprotection. After renin stimulation, the circulating angiotensin I is converted to angiotensin II (ANG II) by the activity of the Angiotensin Converting Enzyme (ACE). The ANG II acting via its binding to two major receptor subtypes the ANG type 1 (AT1) and type 2 (AT2) has been shown be activated during stress and to contribute to the pathogenesis of cold stress- and ischemia-reperfusion-induced gastric lesions. All bioactive angiotensin peptides can be generated not only in systemic circulation, but also locally in several tissues and organs. Recently the new functional components of RAS, such as Ang-(1-7), Ang IV, Ang-(1-12) and novel pathways ACE2 have been described suggesting the gastroprotective role for the novel ANG II metabolite, Ang-(1-7). The fact that Ang-(1-7) is produced in excessive amounts in the gastric mucosa of rodents and that pretreatment by Ang-(1-7) exhibits a potent gastroprotective activity against the gastric lesions induced by cold-restraint stress suggests that this and possibly other vasoactive metabolites of ANG II pathway could be involved in the mechanism of gastric integrity and gastroprotection. This review summarizes the novel gastroprotective factors and mechanisms associated with metabolic fate of systemic and local RAS activation with major focus to recent advancement in the angiotensin pathways in the gut integrity.

Some recent studies indicate that cannabis may induce acute pancreatitis in humans and administration of anandamide increases the severity of acute pancreatitis; whereas another study exhibits some therapeutic effects in acute pancreatitis. Aim of the present study was to discover what is the reason for these opposite confusing results and to determine the role of sensory nerves in this effect. Acute pancreatitis was induced in rats by cerulein. Anandamide, an endogenous cannabinoid, was administered i.p. (1.5 micromol/kg) before or 2 h after cerulein administration. Stimulation of sensory nerves was performed by capsaicin (0.5 mg/kg s.c.). In rats treated with combination of anandamide plus capsaicin, capsaicin was given 10 min after each dose of anandamide. After the last injection of cerulein or 4 h later, the study was terminated. In our study we observed that stimulation of sensory nerves by capsaicin, before administration of cerulein, reduced the severity of acute pancreatitis. Anandamide, administered alone before cerulein, increased pancreatic damage in acute pancreatitis. Anandamide administered in combination with capsaicin, before cerulein, abolished the capsaicin-induced protective effect on the pancreas. Opposite effects were observed when capsaicin and anandamide were administered after injection of cerulein. Capsaicin increased the severity of acute pancreatitis, whereas anandamide reduced pancreatic damage and reversed the deleterious effect of capsaicin. We conclude that the effect of anandamide on the severity of acute pancreatitis depends on the phase of this disease. Administration of anandamide, before induction of pancreatitis, aggravates pancreatic damage; whereas anandamide administered after induction of pancreatitis, reduces the severity of acute pancreatitis. Sensory nerves are involved in the mechanism of this biphasic effect of anandamide.

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.

Hormonal fluctuations are known to predispose ulceration of the upper gastrointestinal tract, but to date no comparative study of their effects on the healing of pre-existing ulcers in the oral cavity and stomach has been made. We studied the effects of depletion of testosterone and of EGF on the healing of acetic acid-induced ulcers using rats having undergone bilateral orchidectomy and/or salivectomy respectively. We measured alterations in gastric acid secretion and blood flow at ulcer margins, as well as plasma levels of testosterone, gastrin and the proinflammatory cytokines IL-1 beta and TNF-alpha. Testosterone (0.01-10 mg/kg/day i. m.) dose-dependently delayed oral and gastric ulcer healing. When applied in an optimal dose of 1 mg/kg/day, this hormone significantly raised gastric acid secretion and plasma IL-1 beta and TNF-alpha levels. Attenuation of plasma testosterone levels via bilateral orchidectomy inhibited gastric acid secretion and accelerated the healing of oral and gastric ulcers, while increasing plasma gastrin levels and these effects were reversed by testosterone. Salivectomy raised plasma testosterone levels, and delayed oral and gastric ulcer healing. Treatment of salivectomised animals with testosterone further inhibited ulcer healing, and this effect was counteracted by EGF. We propose that testosterone delays ulcer healing via a fall in blood flow at the ulcer margin, a rise in plasma levels of IL-1 beta and TNF-alpha and, in the case of gastric ulcers, an increase in gastric acid secretion. EGF released from the salivary glands plays an important role in limitation of the deleterious effects of testosterone on ulcer healing.

Ghrelin, a 28-amino-acid peptide produced predominantly by oxyntic mucosa has been reported to affect the pancreatic exocrine function but the mechanism of its secretory action is not clear. The effects of intraduodenal (i.d.) infusion of ghrelin on pancreatic amylase outputs under basal conditions and following the stimulation of pancreatic secretion with diversion of pancreato-biliary juice (DPBJ) as well as the role of vagal nerve, sensory fibers and CCK in this process were determined. Ghrelin given into the duodenum of healthy rats at doses of 1.0 or 10.0 microg/kg increased pancreatic amylase outputs under basal conditions or following the stimulation of pancreatic secretion with DPBJ. Bilateral vagotomy as well as capsaicin deactivation of sensory fibers completely abolished all stimulatory effects of luminal ghrelin on pancreatic exocrine function. Pretreatment with lorglumide, a CCK(1) receptor blocker, reversed the stimulation of amylase release produced by intraduodenal application of ghrelin. Intraduodenal ghrelin at doses of 1.0 or 10.0 microg/kg increased plasma concentrations of CCK and ghrelin. In conclusion, ghrelin given into the duodenum stimulates pancreatic enzyme secretion. Activation of vagal reflexes and CCK release as well as central mechanisms could be implicated in the stimulatory effect of luminal ghrelin on the pancreatic exocrine functions.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, has been shown to exhibit gastroprotective properties. The aim of present study was to determine whether ghrelin administration protects the pancreas against ischemia/reperfusion-induced pancreatitis and, if so, what is the role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in this effect. In sham-operated or hypophysectomized rats, acute pancreatitis was induced by pancreatic ischemia followed by reperfusion. Ghrelin (4, 8 or 16 nmol/kg/dose) or IGF-1 (20 nmol/kg/dose) were administered intraperitoneally twice before and during induction of acute pancreatitis. In pituitary-intact rats, treatment with ghrelin attenuated the development of ischemia/reperfusion-induced pancreatitis and this effect was associated with partial reversion of the pancreatitis-evoked decrease in serum concentration of GH and IGF-1. Hypophysectomy eliminated GH from the serum, reduced serum IGF-1 concentration by 90% and increased in the severity of ischemia/reperfusion-induced pancreatitis. Administration of ghrelin was without any beneficial effect in this group of rats. In contrast, administration of IGF-1 in hypophysectomized rats reduced the severity of ischemia/reperfusion-induced pancreatitis in hypophysectomized rats. We conclude that administration of ghrelin inhibits the development of ischemia/reperfusion-induced pancreatitis and this effect is mediated by its influence on the release of GH and IGF-1.

Ghrelin is involved in the control of food intake, but its role in gastroprotection against the formation of gastric mucosal injury has been little elucidated. We studied the effects of peripheral (i.p.) and central (i.c.v.) administration of ghrelin on gastric secretion and gastric mucosal lesions induced by 3 h of ischemia/reperfusion (I/R) with or without inhibition of ghrelin growth hormone secretagogue type 1a receptor (GHS-R1a) by using ghrelin antagonist, d-Lys(3)-GHRP-6; blockade of cyclooxygenase (COX)-1 (indomethacin, SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole]) and COX-2 (rofecoxib); and bilateral vagotomy or capsaicin denervation. I/R produced typical gastric erosions, a significant fall in the gastric blood flow (GBF), an increase in gastric myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) content, and the up-regulation of mucosal ghrelin mRNA. Ghrelin dose-dependently increased gastric acid secretion and significantly reduced I/R-induced gastric erosions, while producing a significant rise in the GBF and mucosal PGE(2) generation and a significant fall in MPO activity and MDA content. The protective and hyperemic activities of ghrelin were significantly attenuated in rats pretreated with d-Lys(3)-GHRP-6 and capsaicin denervation and completely abolished by vagotomy. Indomethacin, SC560, and rofecoxib, selective COX-1 and COX-2 inhibitors, attenuated ghrelin-induced protection that was restored by supplying the methyl analog of prostaglandin (PG) E(2). The expression of mRNA for COX-1 was unaffected by ghrelin, but COX-2 mRNA and COX-2 protein were detectable in I/R injured mucosa and further up-regulated by exogenous ghrelin. We conclude that ghrelin exhibits gastroprotective and hyperemic activities against I/R-induced erosions, the effects that are mediated by hormone activation of GHS-R1a receptors, COX-PG system, and vagal-sensory nerves.

Ghrelin, identified in the gastric mucosa, has been involved in the control of food intake and growth hormone (GH) release, but whether this hormone influences the gastric secretion and gastric mucosal integrity has been little elucidated. We compared the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of ghrelin on gastric secretion and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) with or without suppression of nitric oxide (NO)-synthase or functional ablation of afferent sensory nerves by capsaicin. The number and the area of gastric lesions was measured by planimetry, the GBF was assessed by the H2-gas clearance method and blood was withdrawn for the determination of the plasma ghrelin and gastrin levels. In addition, the gastric mucosal expression of mRNA for CGRP, the most potent neuropeptide released from the sensory afferent nerves, was analyzed in rats exposed to WRS with or without ghrelin pre-treatment. Ghrelin (5-80 microg/kg i.p. or 0.6-5 microg/kg i.c.v.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS. This protective effect was accompanied by a significant rise in the gastric mucosal blood flow (GBF), luminal NO concentration and plasma ghrelin and gastrin levels. Ghrelin-induced protection was abolished by vagotomy and significantly attenuated by L-NNA and deactivation of afferent nerves with neurotoxic dose of capsaicin. The signal for CGRP mRNA was significantly increased in gastric mucosa exposed to WRS as compared to that in the intact gastric mucosa and this was further enhanced in animals treated with ghrelin. We conclude that central and peripheral ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol or WRS, and these effects depend upon vagal activity and hyperemia mediated by the NOS-NO system and CGRP released from sensory afferent nerves.

Candida albicans frequently inhabits the gastrointestinal tract of humans leading to gastrointestinal candidiasis, especially following suppression of gastric acidity, but studies on the relation between this fungal infection and gastric pathology are limited due to lack of convenient animal models resembling Candida infection in humans. MATERIAL AND METHODS. We compared the effects of C. albicans and vehicle inoculation on gastric secretion and healing of gastric ulcers induced by acetic acid in rats treated with 1) ranitidine (30 mg kg(-1) day(-1) s.c.) and 2) aspirin (ASA) (60 mg kg(-1) day(-1) i.g.) with or without probiotic bacteria Lactobacillus acidophillus. At day 0 and at 4, 15 and 25 days after ulcer induction, the ulcer area, the gastric blood flow (GBF), the quantitative gastric cultures of Candida and the expression of mRNAs for pro-inflammatory cytokines IL-1beta and TNF-alpha and growth factors EGF and TGFalpha were assessed in the gastric mucosa.Gastric acid output was reduced by over 40% soon after Candida inoculation and this effect persisted during all time intervals tested. The area of ulcers in control rats significantly decreased at day 15 and the ulcers disappeared almost completely after 25 days of their induction. In contrast, the ulcers were present until day 25 in Candida-inoculated rats followed by a fall in GBF and a rise in plasma gastrin levels, these effects being significantly attenuated by the co-treatment with Lactobacillus. Candidiasis was accompanied by up-regulation of mRNA for IL-1beta, TNF-alpha, EGF and TGFalpha and a significant increment in plasma IL-1beta and TNF-alpha levels.1) Persistent colonization with Candida could be achieved in rats treated with antisecretory agents or non-steroidal anti-inflammatory drugs (NSAIDs) such as ASA; 2) candidiasis reduces gastric acid secretion, while delaying ulcer healing possibly due to the impairment in GBF in the ulcer area and enhanced expression and release of IL-1beta and TNFalpha and 3) probiotic therapy could be useful in the treatment against the deleterious action of fungal infection on the healing of pre-existing gastric ulcers.

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 μg/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 CGRP8–37 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.

Melatonin, an antioxidant, protects the pancreas against acute inflammation but, although this indole is released mainly at night, no study has been undertaken to determine circadian changes of plasma melatonin levels and the severity of acute pancreatitis. The aims of this study were: (a) to compare the severity of caerulein-induced pancreatitis (CIP) produced in the rat during the day and at the night, and (b) to assess the changes of plasma melatonin level and the activity of an antioxidative enzyme; superoxide dismutase (SOD), in the pancreas subjected to CIP during the day time and at night without or with administration of exogenous melatonin or its precursor; l-tryptophan. Rats were kept in 12 hr light/dark cycle. CIP was induced by subcutaneous infusion of caerulein (5 μg/kg/hr for 5 hr). Melatonin (5 or 25 mg/kg) or l-tryptophan (50 or 250 mg/kg) was given intraperitoneally 30 min prior to the start of CIP. CIP induced during the day time was confirmed by histological examination and manifested by pancreatic edema, and rises of amylase and lipase plasma activities (by 400 and 500%, respectively), whereas pancreatic SOD, pancreatic blood flow (PBF) and oxygen consumption by pancreatic tissue (VO2) were decreased by 70, 40 and 45%, respectively, as compared with the appropriate controls. All morphological and biochemical parameters of CIP induced at night were significantly less severe, compared with those recorded during the light phase. Plasma melatonin immunoreactivity was significantly higher during the night, than during the day, especially following administration of melatonin or its precursor, which reversed all manifestations of CIP. In conclusion, a circadian rhythm modulates the severity of CIP with a decrease of pancreatitis severity during the night compared with that at the day time and this may be due to the increased plasma level of melatonin and higher activity of SOD in the pancreas.

Melatonin, considered as a main pineal product, may be also synthetized in the gastrointestinal tract from L-tryptophan. Melatonin has been recently shown to affect insulin release and its receptors have been characterized in the pancreas however, the effects of melatonin on the pancreatic enzyme secretion have not been examined. The aim of this study was to investigate the effects of melatonin or L-tryptophan on amylase secretion in vivo in anaesthetized rats with pancreato-biliary fistulas, and in vitro using isolated pancreatic acini. Melatonin (1, 5 or 25 mg/kg) or L-tryptophan (10, 50 or 250 mg/kg) given to the rats as a intraperitoneal (i.p.) bolus injection produced significant and dose-dependent increases in pancreatic amylase secretion under basal conditions or following stimulation of enzyme secretion by diversion of bile-pancreatic juice. This was accompanied by a dose-dependent rise in melatonin plasma level. Stimulation of pancreatic enzyme secretion caused by melatonin or L-tryptophan was completely abolished by vagotomy, deactivation of sensory nerves with capsaicin or pretreatment with CCK 1 receptor antagonists (tarazepide or L-364,718). Pretreatment with luzindole, an antagonist of melatonin MT 2 receptor failed to affect melatonin- or L-tryptophan-induced amylase secretion. Administration of melatonin (1, 5 or 25 mg/kg i.p.) or L-tryptophan (10, 50 or 250 mg/kg i.p.) to the rats resulted in the dose-dependent increase of cholecystokinin (CCK) plasma immunoreactivity. Enzyme secretion from isolated pancreatic acini was not significantly affected by melatonin or L-tryptophan used at doses of 10 -8 -10 -5 M. We conclude that exogenous melatonin, as well as that produced endogenously from L-tryptophan, stimulates pancreatic enzyme secretion in vivo while increasing CCK release. Stimulatory effect of melatonin or L-tryptophan on the exocrine pancreas involves vagal sensory nerves and the CCK release by these substances.

Melatonin, a pineal secretory product, synthesized from l-tryptophan, has received increased attention because of its antioxidative and immunomodulatory properties. It has been detected in the gut and shown to protect the gastric mucosa, and liver from acute damage, but the role of melatonin in the protection of the pancreas against acute inflammation is not clear. The aim of this study was to investigate the effects of melatonin and its precursor, l-tryptophan, on caerulein-induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)-provoked pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to the rats (25 microg/kg). I/R was induced by clamping of the inferior splenic artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr) or l-tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were confirmed by histologic examination and manifested by typical pancreatic edema, by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and the pro-inflammatory tumor necrosis factor alpha (TNFalpha) (by 500%). Lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood flow (PBF) was significantly reduced in these animals. Pretreatment of rats subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l-tryptophan (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of amylase and TNFalpha and diminished pancreatic MDA + 4-HNE contents, while enhancing PBF, pancreatic integrity and plasma levels of the anti-inflammatory interleukin 10 (IL-10). This was accompanied by a marked and dose-dependent rise of plasma melatonin immunoreactivity. Gene expression of N-acetyl transferase, an enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal rats and was significantly enhanced in the rats with CIP. We conclude that exogenous melatonin, and that produced from l-tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFalpha release combined with an increase of plasma anti-inflammatory IL-10 in rats with acute pancreatitis.

Recent identification of specific leptin receptors in the pancreas suggests that this peptide may also play some role in this gland.To examine the effect of intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of leptin in rats on caerulein-induced pancreatitis (CIP), pancreatic gene expression of leptin and inflammatory cytokine production.Caerulein (25 micrograms/kg) was infused subcutaneously into conscious rats over 5 h to produce CIP. Leptin (1, 5, or 10 micrograms/kg) was injected i.p. or i.c.v. 30 min prior to the CIP induction. The plasma level of TNF alpha and IL-4 was determined by ELISA, while plasma leptin was measured by RIA and leptin gene expression in pancreas by RT-PCR.CIP was characterized by the usual pancreatic edema, reduction in pancreatic blood flow (PBF) and an increase in serum levels of amylase, TNF alpha and IL-4. Pretreatment with i.p. or i.c.v. leptin of the CIP rats partially reversed the harmful effects of CIP on the pancreas, and reduced pancreatic inflammation and the fall in PBF. This was accompanied by a dose-dependent reduction in serum levels of amylase and TNF alpha, while serum IL-4 in the CIP rats pretreated with leptin rose dose-dependently as compared to control rats with CIP alone. Pretreatment with leptin resulted in the dose-dependent rise in plasma leptin level over that observed in vehicle-treated controls. Leptin mRNA expression in the pancreas was dose-dependently increased after infusion of caerulein. Leptin content in isolated pancreatic acini was also increased dose-dependently by caerulein added to the incubation medium bathing these acini.(1) Exogenous leptin protects the pancreas against damage by CIP; (2) endogenous leptin seems to limit the extend of pancreatic damage, and (3) these protective effects of leptin could be attributed to the reduction in TNF alpha and to the increase in IL-4 production.

Lipopolysaccharides (LPS), the component of the cell wall of gram-negative bacteria, have been implicated in the pathogenesis of acute pancreatitis, but the mechanism of their action on the pancreas has not been fully explored. The aim of this study was to investigate the effects of various doses of LPS on the integrity of intact pancreas and that involved in acute caerulein-induced pancreatitis (CIP) in the rat and to compare these effects with those of nitric oxide (NO) donor, S-nitrose-acetylpenicillamine (SNAP). The expression of constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) mRNA was also examined in the isolated pancreatic acini obtained from the inflamed pancreas of rats treated with LPS. CIP was produced by subcutaneous (s.c.) infusion of caerulein (5 μg/kg·h for 5 h) to conscious rats. Bolus injections of various doses of LPS (0.1, 1, 10, 20 or 40 mg/kg) or SNAP (1.5, 3 or 6 mg/kg) were made intraperitoneally (i.p.) either alone or 30 min prior to s.c. infusion of caerulein to induce CIP. Infusion of caerulein produced acute pancreatitis confirmed by histological examination and manifested by an increase of pancreatic mass (by about 200%). Blood levels of amylase and lipase were augmented by 400 and 800% respectively, whereas the pancreatic blood flow (PBF) was decreased by 50% in rats with CIP. Injection of low doses of LPS (0.1–1 mg/kg i.p.) or SNAP (1.5–3 mg/kg i.p.) 30 min prior to caerulein infusion reversed the harmful effects of pancreatic overstimulation with caerulein and reduced significantly the histological manifestations of CIP such as edema, neutrophil infiltration and vacuolization of the acinar cells. These protective effects of low doses of LPS pretreatment on the pancreas were completely antagonized by the suppression of the activity of NO synthase (NOS) with NG-nitro-L-arginine (L-NNA) applied (20 mg/kg i.p.) 15 min prior to the LPS injection. Combination of L-arginine (100 mg/kg i.p.), a substrate for NOS, with L-NNA given prior to low doses of LPS, restored the LPS-induced protection of the pancreas in rats with CIP. In contrast, higher doses of LPS (20–40 mg/kg i.p.) or SNAP (6 mg/kg i.p.), which produced a significant fall of the PBF, did not protect the pancreas against CIP. Administration of various doses of LPS to rats with CIP resulted in significant and dose-dependent stimulation of NO biosynthesis in the isolated acini obtained from the pancreas of these animals. LPS enhanced the expression of both cNOS and iNOS in the pancreatic acini obtained from rats subjected to CIP. The signal for cNOS mRNA was detected in all samples, reaching peak at the protective dose of LPS (1 mg/kg i.p.), while iNOS was overexpressed only at the highest doses of LPS that failed to exhibit the protective activity. We conclude that the pretreatment with low doses of LPS protects the pancreas against the damage provoked by CIP and this effect could be attributed, at least in part, to the activation of L-arginine-NO system in the pancreas.

The renin-angiotensin system (RAS) plays an important role in the maintenance of blood pressure, cardiovascular functions, body fluids homeostasis and kidney reabsorption process but little is known w

The regulation of appetite is regulated by complex mechanism involving brain-gut axis and hormonal and non-hormonal factors acting through the activity of satiety and hunger centers located in the hypothalamus [Wren & Bloom, 2007]. Among hormones controlling appetite are gastrointestinal hormones such as cholecystokinin, PYY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomedulin, the endocrine pancreatic hormones including insulin and glucagon and endocannabinoids [Wren B Tomasetto et al., 2000]. This peptide was also shown to enhance the gastric motility and gastric secretion [Tschop et al., 2000; Date et al., 2001]. Ghrelin is considered as an orexigenic peptide produced by the stomach, acting as a meal initiator [Masuda et al., 2000; Ariyasu et al., 2001]. Little is known about other factors that might affect ghrelin secretion in the stomach and its influence on gastrointestinal integrity has not been fully elucidated. A recent study in humans revealed that stomach is a major source of circulating ghrelin and that gastrectomy produced dramatic fall in the plasma ghrelin levels, whereas fasting and anorexia nervosa was accompanied by elevated plasma ghrelin levels [Ariyasu et al., 2001]. The orexins also called hypocretins, are neuropeptides novel originally discovered in a small group of neurons in the hypothalamic area (LHA) [Sakurai et al., 1998; de Lecea et al., 1998]. identified two peptides that were endogenous ligands to orphan receptor HFGAN72 [Sakurai et al., 1998]. They found that these peptides after i.c.v. injection stimulated food

Orexigenic peptides are group of endocrine hormones exerting a pleiotropic influence on many physiological functions including regulation of the feeding behaviour and energy expenditure, release of growth hormone (GH) and inotropic effects on the heart. Some of these peptides such as ghrelin, originally identified in the gastric mucosa, has been involved not only in control of food intake and growth hormone release but also exerts the immunomodulatory and anti-inflammatory properties. This review summarizes the recent attempts to prove the concept that orexigenic peptides such as ghrelin, orexin-A and obestatin besides playing an important role in the mechanism of food intake, exhibit a potent gastroprotective action against the formation of acute gastric mucosal injury induced by various ulcerogens. This protective effect depends upon vagal activity and hyperemia mediated by NOS/NO and COX/PG systems and CGRP released from sensory afferent nerves. In addition, the appetite peptides such as ghrelin and orexin-A are implicated in the mechanism of the healing of preexisting gastric ulcers due to an activation of specific GHS-R1a and OX-R1 receptors and PG/COX system.

Growth hormone (GH) has been shown to protect the intestinal barrier integrity and to stimulate the production of insulin-like growth factor 1 (IGF-1), which inhibits the development of acute pancreatitis. Sensory nerves are implicated in the protection of pancreatic tissue against acute inflammation. The aim of this study was to investigate the influence of exogenous GH on acute pancreatitis (AP) and to assess the involvement of sensory nerves and IGF-1 in above effect. Studies were performed on Wistar rats. AP was induced by subcutaneous administration of caerulein (25μg/kg) to the conscious animals. GH (1 or 2mg/kg) was administered to the rats as an intraperitoneal injection 30min prior to the start of AP. To deactivate sensory nerves capsaicin was given at total dose of 100mg/kg 10days before the experiments. AP was confirmed by histological examination and manifested by the significant rises of pancreatic weight, and serum activities of lipase, TNFα and IL-10 (by 550%, 300% and 50%, respectively), whereas IGF-1 blood concentration was markedly reduced. Administration of GH prior to the caerulein infusion significantly increased GH, IGF-1 and IL-10 blood levels, attenuated harmful effects of AP and reduced histological manifestations of pancreatitis in the rats with intact sensory nerves. This was accompanied by the reduction of serum lipase, and TNFα activities. In the AP rats with capsaicin-deactivated sensory nerves GH failed to protect the pancreas against acute damage and, as a consequence of above deactivation, IGF-1 was low. Conclusion GH modulates the development of acute pancreatitis in the presence of active sensory nerves probably via stimulation of IGF-1 release.

1-Methylnicotinamide (MNA) is one of the major derivatives of nicotinamide, which was recently shown to exhibit antithrombotic and antiinflammatory actions. However, it is not yet known whether MNA affects gastric mucosal defense. The effects of exogenous MNA were studied on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and water restraint stress (WRS) or in rats administered 75% ethanol. MNA [6.25-100 mg/kg intragastrically (i.g.)] led to a dose-dependent rise in the plasma MNA level, inhibited gastric acid secretion, and attenuated these gastric lesions induced by WRS or ethanol. The gastroprotective effect of MNA was accompanied by an increase in the gastric mucosal blood flow and plasma calcitonin gene-related peptide (CGRP) levels, the preservation of prostacyclin (PGI(2)) generation (measured as 6-keto-PGF1alpha), and an overexpression of mRNAs for cyclooxygenase (COX)-2 and CGRP in the gastric mucosa. R-3-(4-Fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO 324479), which is the selective antagonist of IP/PGI(2) receptors, reversed the effects of MNA on gastric lesions and GBF. MNA-induced gastroprotection was attenuated by suppression of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; SC-560] and COX-2 [4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one; rofecoxib] activity, capsaicin denervation, and by the pretreatment with CGRP(8-37) or capsazepine. Addition of exogenous PGI(2) or CGRP restored the MNA-induced gastroprotection in rats treated with COX-1 and COX-2 inhibitors or in those with capsaicin denervation. WRS enhanced MDA content while decreasing superoxide dismutase (SOD) activity in the gastric mucosa, but pretreatment with MNA reversed these changes. MNA exerts potent gastroprotection against WRS damage via mechanisms involving cooperative action of PGI(2) and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity, and reduction in lipid peroxidation.

Epidermal growth factor (EGF), which was originally identified in salivary glands and saliva, has been also found in the kidney and urine, suggesting that the kidney may be an alternate source of this peptide. Liver was considered as the major site of the degradation of EGF but the involvement of other organs has been little studied. Therefore, we carried out comparative studies on the organ uptake and the disappearance half-time of EGF and insulin (having similar molecular size) in the same model of anesthetized dog with arterial (from aorta) and venous (from mesenteric, portal, hepatic, renal, femoral and jugular veins) blood sampling from various organs. Basal plasma level of EGF (1.32 +/- 0.33 pmol/l) and insulin (62.1 +/- 13.8 pmol/l) in the aorta was not significantly different from that recorded at various sampling sites. During i.v. infusion of EGF at 41.6 and 166.6 pmol/kg/h, the respective arterial EGF concentrations averaged 103 +/- 21 and 240 +/- 49 pmol/kg/h and the percent reduction in plasma EGF after passage through the head, leg, intestines and liver was about 30-50% and that after passage through the kidney was about 95%. During insulin (6.9 pmol/kg/h) infusion, the arterial hormone level averaged 227 +/- 21 pmol/l and this level was significantly reduced (by 23-42%) after passage through the head, leg, intestine, liver and kidney but no significant difference was found between various venous sampling sites. EGF and insulin appearing in the urine during EGF or insulin infusion accounted for about 40 and 7% of the difference between the entering and leaving renal masses of the peptide. Mean disappearance half time on stopping of EGF and insulin infusion was, respectively, 2.32 +/- 0.58 and 6.88 +/- 1.25 min. We conclude that unlike insulin, which is removed to similar extent by various organs including the kidney and the liver, EGF is taken up mainly by kidney and EGF present in urine originates mainly from renal clearance of peptide.

Epidermal growth factor (EGF) is widely distributed in the gastrointestinal tissues and released into the gut lumen but its physiological role is questionable because of the postulated high uptake and degradation of this peptide in the liver. This study was designed to examine the action of EGF administered intraduodenally (i.d.), intravenously (i.v.) or intraportally (i.p.) on pentagastrin-stimulated gastric and pancreatic secretion and to determine the role of liver in the EGF uptake. In conscious dogs with gastric and pancreatic fistulas, EGF infused i.v. or i.p. in graded doses (0.12-1.0 microgram/kg.h) caused a dose-dependent inhibition of pentagastrin-induced gastric H+ secretion without alteration in pancreatic protein secretion. EGF infused i.v. and i.p. raised significantly plasma levels of the peptide but these increments were significantly lower with i.p. than with i.v. infusion. EGF given i.d. did not affect gastric or pancreatic secretion and failed to raise significantly plasma EGF level. In anesthetized dogs, no difference was found in the basal plasma EGF levels between arterial and portal or hepatic blood. during i.v. infusion of EGF, plasma EGF level in hepatic venous blood was about 40% lower and that in the portal blood was about 30% lower than that in arterial blood indicating a marked uptake of peptide during the passage through the liver and the intestines, respectively. EGF was present in negligible amounts in gastric secretion but appeared in nanogram concentrations in the pancreatic secretion and increased after pentagastrin stimulation. We conclude that (1) the liver and the intestines are almost equally involved in partial degradation of EGF and that the kidneys may also contribute to the elimination of circulating EGF; (2) the uptake of EGF by these organs is limited and can be overcome by increasing doses of infused EGF, and (3) absorption of EGF from the intestinal lumen does not contribute to its circulating concentrations.

Ghrelin, identified in the gastric mucosa, is involved in control of food intake and growth hormone (GH) release. Besides being an appetite hormone, central and peripheral ghrelin exerts a potent protective action against gastric mucosal experimental injury induced by stress, an effect dependant on vagal activity and hyperemia mediated by nitric oxide synthase (NOS)-nitric acid (NO) and cyclo-oxygenase (COX)-prostaglandin (PG) systems and calcitonin gene related peptide (CGRP) released from sensory afferent nerves.

Pioglitazone, a specific ligand for peroxisome proliferator-activated receptor gamma (PPAR-gamma), was recently implicated in the control of inflammatory processes and in the modulation of the expression of various cytokines such as tumor necrosis factor alpha (TNF-alpha), but its role in the mechanism of gastric mucosal integrity has not been studied extensively. This study was designed to determine the effect of pioglitazone on gastric mucosal lesions induced in rats by topical application of 100% ethanol and by 3.5 h of water immersion and restraint stress (WRS) with or without pretreatment with indomethacin (5 mg/kg i.p.) to inhibit cyclooxygenase-1 (COX-1) and COX-2 enzyme activities and L-NNA (20 mg/kg i.p.) to suppress nitric oxide (NO)-synthase. In addition, the effect of pioglitazone on ulcer healing in rats with chronic acetic acid ulcers (ulcer area 28 mm2) was determined. Rats were killed 1 h and 3.5 h after ethanol administration or WRS exposure or at day 9 upon ulcer induction, and the number and area of gastric lesions were measured by planimetry, the gastric blood flow (GBF) was determined by H2-gas clearance technique and the mucosal PGE2 generation and gene expression and plasma concentration of TNF-alpha and IL-1beta were also evaluated. Pre-treatment with pioglitazone dose-dependently attenuated gastric lesions induced by 100% ethanol and WRS; the dose reducing these lesions by 50% (ID50) being 10 mg/kg and 7 mg/kg, respectively. The protective effect of pioglitazone was accompanied by the significant rise in the GBF, an increase in PGE2 generation and the significant fall in the plasma TNF-alpha and IL-1beta levels. Strong signals for IL-1beta- and TNF-alpha mRNA were recorded in gastric mucosa exposed to ethanol or WRS, and these effects were significantly decreased by pioglitazone. Indomethacin which suppressed PG generation by about 90%, while augmenting WRS damage, and L-NNA, that suppressed NO-synthase activity, significantly attenuated the protective and hyperaemic activity of this PPAR-gamma ligand. In the chronic study, pioglitazone significantly reduced the area of gastric ulcers on day 9 and significantly raised the GBF at the ulcer margin. The acceleration of ulcer healing by PPAR-gamma ligand was accompanied by a significant increase in the expression of PECAM-1 protein, a marker of angiogenesis. We conclude that (1) pioglitazone exerts a potent gastroprotective and hyperaemic actions on the stomach involving endogenous PG and NO and attenuation of the expression and release of proinflammatory cytokines TNF-alpha and IL-1beta, and (2) PPAR-gamma ligand accelerates ulcer healing, possibly due to the enhancement in angiogenesis at ulcer margin.

Melatonin attenuates acute gastric lesions induced by topical strong irritants because of scavenging of free radicals, but its role in the pathogenesis of stress-induced gastric lesions has been sparingly investigated. In this study we compared the effects of intragastric (i.g.) or intracerebroventricular (i.c.v.) administration of melatonin and its precursor, L-tryptophan, with or without concurrent treatment with luzindole, a selective antagonist of melatonin MT 2 receptors, on gastric lesions induced by water immersion and restraint stress (WRS). The involvement of pineal gland, endogenous prostaglandins (PG) and sensory nerves in gastroprotective action of melatonin and L-tryptophan against WRS was studied in intact or pinealectomized rats or those treated with indomethacin or rofecoxib to suppress cyclooxygenase (COX)-1 and COX-2, respectively, and with capsaicin to induce functional ablation of the sensory nerves. In addition, the influence of i.c.v. and i.g. melatonin on gastric secretion was tested in a separate group of rats equipped with gastric fistulas. At 3.5 hr after the end of WRS, the number of gastric lesions was counted, the gastric blood flow (GBF) was determined by H 2 -gas clearance technique and plasma melatonin and gastrin levels were measured by specific radioimmunoassay (RIA). Biopsy mucosal samples were taken for determination of expression of mRNA for COX-1 and COX-2 by reverse transcriptase-polymerase chain reaction (RT-PCR) and of the mucosal generation of prostaglandin E 2 (PGE 2 ) by RIA. Melatonin applied i.g. (1.25-10 mg/kg) or i.c.v. (1.25-10 μg/kg) dose-dependently inhibited gastric acid secretion and significantly attenuated the WRS-induced gastric damage. This protective effect of melatonin was accompanied by a significant rise in the GBF and plasma melatonin and gastrin levels and in mucosal generation of PGE 2 . Pinealectomy, which suppressed plasma melatonin levels, aggravated the gastric lesions induced by WRS and these effects were counteracted by i.g. or i.c.v. application of melatonin. Luzindole abolished completely the gastroprotective effects of melatonin and L-tryptophan and attenuated significantly the rise in GBF evoked by the indoleamine and its precursor. Indomethacin and rofecoxib, which diminished PGE 2 biosynthesis by c. 90 and 75% or capsaicin denervation, attenuated significantly melatonin- and L-tryptophan-induced protection and the rise in the GBF. Both the protection and the hyperemia were restored by addition of exogenous CGRP to capsaicin-denervated animals. COX-1 mRNA was detected by RT-PCR in the intact and melatonin-treated gastric mucosa, while COX-2 mRNA, which was undetectable in the intact gastric mucosa, appeared in WRS-exposed mucosa, especially in the melatonin-treated animals and this was accompanied by increased generation of PGE 2 in gastric mucosa. Pinealectomy downregulated COX-2 mRNA and this effect was reversed by supplementation of pinealectomized animals with melatonin. We conclude that, (a) exogenous melatonin and its precursor, L-tryptophan, attenuates WRS-induced gastric lesions via interaction with MT 2 receptors, (b) this protective action of melatonin is because of an enhancement of gastric microcirculation, probably mediated by PGE 2 derived from COX-2 overexpression and activity, the activation of brain-gut axis involving CGRP released from sensory nerves, and the release of gastrin and (c) the pineal plays an important role in the limitation of WRS-induced gastric lesions via releasing melatonin, which exerts gastroprotective and hyperemic activities against stress ulcerogenesis.

Background Ghrelin is a novel peptide involved in the control of appetite, but its role in vascular pathologies remains to be elucidated. Ghrelin was shown to decrease blood pressure (BP) and improve endothelial function. Its plasma levels are correlated with BP in humans. Mechanisms of these effects are unknown. Because oxidative stress and increased superoxide production by NAD(P)H oxidases (Nox) are critical in the pathogenesis of hypertension, we aimed to study the effects of ghrelin on vascular superoxide production and NAD(P)H oxidase activity in spontaneously hypertensive rats (SHR). Methods Aortic superoxide production and NAD(P)H oxidase activity were measured using lucigenin (5 μmol/L) chemiluminescence. Aortas from Wistar-Kyoto rats (WKY) were used as control. Direct superoxide scavenging properties of ghrelin were tested using xanthine–xanthine oxidase system. Results Both basal superoxide production and vascular NADPH oxidase activity were significantly higher in aortas from SHR, than from WKY. Preincubation of aortic segments from SHR or WKY with ghrelin caused concentration-dependent (from 50 pg/mL to 5 ng/mL) decrease of basal superoxide production. Vascular NAD(P)H oxidase activity was inhibited by ghrelin, abolishing the difference between SHR and basal WKY. Ghrelin did not affect superoxide release from the in vitro xanthine–xanthine oxidase system, indicating lack of direct superoxide scavenging properties or inhibitory effects on xanthine oxidase in vitro. Nitric oxide synthase (NOS) inhibition, using N ω -nitro- L -arginine methyl ester (L-NAME), partially blunted the effects of ghrelin on NADPH oxidase activity indicating potential role of nitric oxide. Conclusions Ghrelin inhibits vascular oxidative stress in SHR. This effect is likely related to the inhibition of vascular NAD(P)H oxidases.

It is assumed that an overproduction of gastric acid is the most important factor in the development of peptic ulcer. However, it has been also demonstrated that gastric defense mechanisms, which prevent mucosal injury, are enhanced by the same factors that increase acid secretion. The aim of this study was to examine the role of capsaicin-sensitive sensory nerves and histamine H1, H2, and H3 receptors in histamine-induced gastroprotection against stress ulcers. Studies were performed on rats with intact or ablated sensory nerves. Ablation of sensory nerves was induced by neurotoxic doses of capsaicin. Gastric ulcers were induced by water immersion and restrain stress. Before exposure to stress, rats were pretreated with saline (control), histamine (10 micromol/kg), histamine H1 receptor antagonist pyrilamine (100 micromol/kg), histamine H2 receptor antagonist ranitidine (100 micromol/kg), histamine H3 receptor antagonist thioperamide (100 micromol/kg), or a combination of histamine with these histamine receptor antagonists.Histamine alone reduced ulcer area evoked by stress and this effect was accompanied by an increase in gastric mucosal blood flow and mucosal DNA synthesis, as well as a decrease in serum pro-inflammatory interleukin-1beta concentration. Treatment with combination of pyrilamine plus histamine caused an increase in gastric ulcer area and serum interleukin-1beta above the value observed in animals treated with saline, and this effect was accompanied by a decrease in gastric mucosal DNA synthesis. Ranitidine, in combination with histamine, reduced the ulcer area and serum interleukin-1beta to a minimal value, whereas gastric mucosal blood flow and DNA synthesis reached a maximal value. Pretreatment with thioperamide before histamine administration abolished the histamine-evoked reduction in gastric ulcer area. Ablation of sensory nerves increased the ulcer area in animals treated with saline or histamine, or histamine in combination with pyrilamine or ranitidine. In animals with sensory nerves ablation combined with administration of thioperamide plus histamine, the ulcer area was similar to that in saline-treated animals with intact sensory nerves. We conclude that: (1) histamine exhibits protective effect against stress-induced gastric ulcer and that this gastroprotection is related to stimulation of histamine H1 and H3 receptors; (2) blockade of histamine H2 receptors exhibited beneficial effect on gastric mucosa against stress-induced gastric ulcers; and (3) ablation of sensory nerves aggravates stress-induced gastric ulcer and reduces histamine-evoked gastroprotection related to stimulation of histamine H3 receptors.

Lipopolysaccharide (LPS) is one of the virulence factors in the Helicobacter pylori (Hp)-infected stomach, but it remains unknown whether single and prolonged pretreatment with Hp-LPS can affect the course of gastric damage induced by aspirin (ASA). We compared the effects of Hp-LPS with those induced by LPSs isolated from intestinal Bacteroides fragilis, Yersinia enterocolitica, and Campylobacter jejuni applied for 4 days on acute ASA-induced gastric lesions in rats. The area of ASA-induced gastric lesions, gastric blood flow (GBF), expression of mRNA and protein of leptin and plasma leptin, gastrin, interleukin-1beta, and tumor necrosis factor-alpha levels were examined. Single (once) or repeated (five times) i.p. injections of Hp-LPS (1 mg/kg) or intestinal LPSs failed to produce macroscopic gastric damage and did not affect the GBF when compared with vehicle. Hp-LPS injected repeatedly suppressed the gastric acid secretion, up-regulated leptin mRNA and protein, and increased plasma leptin and gastrin levels. Hp-LPS significantly reduced the ASA-induced gastric damage and the accompanying decline in the GBF, and these effects were significantly attenuated by capsaicin denervation and selective antagonism of cholecystokinin-B (CCK2) receptors by RPR-102681 [N-(metoxy-3 phenyl) N-(N-methyl N-phenyl-carbamylmethyl) carbamoylmethyl]-3 ureido]-3 phenyl]-2 propronique] but not by loxiglumide, an antagonist of CCK1 receptors. We conclude that 1) daily application of Hp-LPS enhances gastric mucosal resistance against ASA damage due to the increase of GBF and the expression and release of leptin and gastrin exerting trophic and gastroprotective effects, and 2) this enhanced resistance to ASA damage in Hp-LPS-adapted stomach is mediated by the sensory afferents and specific CCK2/gastrin receptors.

Helicobacter pylori (Hp) infection is involved in various gastroduodenal pathologies. Also, the potential role of Hp infection has been proposed in several extragastroduodenal disorders, such as cardiovascular, skin or immunological diseases. The role of Hp infection in acute pancreatitis has not been tested. The aim of this study was to determine the influence of Hp infection on the course of acute ischemia/reperfusion-induced pancreatitis in rats.Inoculation with CagA- and VacA-positive Hp or administration of vehicle were performed after visceral ischemia. Visceral ischemia was evoked by clamping of the celiac artery for 30 min. Four weeks later, after full recovery from primary ischemia-induced damage, acute pancreatitis was evoked by limitation of pancreatic blood flow (PBF) in the splenic artery for 30 min using microvascular clips. Rats were sacrificed 1 h or 1, 3, 5, 10, and 21 days after removal of the vascular clips. Hp infection was assessed by the urease test and gastric histology.In Hp-negative rats ischemia followed by reperfusion caused acute pancreatitis as manifested by a reduction in PBF and pancreatic DNA synthesis, as well as by increases in plasma amylase, lipase, interleukin-1beta (IL-1beta) and interleukin-10 (IL-10). The morphological features of pancreatic tissue showed necrosis, strongly pronounced edema, hemorrhages and leukocyte infiltration. The maximal intensity of pancreatic damage was observed between the 1st and 3rd day of reperfusion, then pancreatic tissue underwent regeneration. Hp infection resulted in a significant reduction in PBF and an aggravation of pancreatic ischemia 1 h and 3 and 5 days after reperfusion. Plasma amylase in Hp-infected rats was significantly higher than in Hp-negative animals 1 h and 1 and 3 days after ischemia, whereas in lipase this significant difference was observed between the 1st and 3rd day. DNA synthesis in Hp-positive rats was additionally reduced 1 h and 3 and 5 days after ischemia. Also ischemia evoked an increase in serum IL-1beta and IL-10, and morphological manifestations of pancreatitis were additionally enhanced by Hp infection.(1) Hp infection increases the severity of ischemia-induced pancreatitis; (2) Hp infection increases production of pro-inflammatory IL-1beta, and (3) Hp infection aggravates disturbances in pancreatic microcirculation in acute pancreatitis.

Hydrogen sulfide (H2S) modulates a number of physiological actions including vasodilatation, inhibition of oxidant stress and apoptosis. H2S which is formed in gastric epithelium by the activity of two enzymes cysthationine γ-lyase (CSE) and cystathionine β-synthetase (CBS) has been shown to protect the gastric mucosa from ethanol-induced gastric lesions but whether its efficacy against acid-dependent stress-induced damage has been little studied. It also remains unknown how the expression of CSE and CBS contribute to the mucosal damage induced by stress in the presence or absence of H2S. We studied the effect of NaHS, a H2S-donor and L-cysteine, a H2S precursor on 1) gastric acid secretion in rats equipped with chronic gastric fistulas (GF) and water immersion restraint stress (WRS)-induced gastric lesions with intact and capsaicin-denervated sensory nerves (large dose 125 mg/kg s.c for 3 days). Rats were pretreated 30 min before the WRS with A) NaHS (5 mg/kg i.g); B) Lcysteine (10 mg/kg i.g.) with or without the combination with inhibitors of CSE activity, beta-cyano-L-alanine (BCA, 50 mg/kg i.g.) and D,L-propargylglycine (PAG 15 80 mg/kg i.g.). The number of gastric lesions was measured by planimetry, the gastric blood flow (GBF) by H2-gas clearance technique and the mRNA expression of CSE, CBS, HIF-1 α and antioxidizing enzymes SOD and GPx was assessed by RT-PCR and Western Blot. NaHS (120 mg/kg) and cysteine (5-40 mg/kg) dose-dependently inhibited basal and histaminestimulated gastric acid secretion in GF rats. Exposure to WRS caused mucosal hemorrhagic lesions accompanied by the fall in GBF and upregulation of mRNA expression of CSE and CBS. Pretreatment with NaHS and L-cysteine significantly reduced WRS-induced gastric damage and significantly raised GBF and these effects were completely lost in animals with capsaicin denervation. BCA and PAG which dose-dependently augmented the number of WRS lesions, reversed the NaHS and L-cysteine-induced protection and hyperemia against WRS-induced gastric damage. Upregulation of mRNA expression for HIF-1 α mRNA, CSE and CBS in the gastric mucosa exposed to WRS was diminished by NaHS and L-cysteine and these effects were further enhanced in capsaicin-denervated rats treated with NaHS and L-cysteine. The increased expression of SOD and GPx mRNA was observed in NaHSand L-cysteine-pretreated rats but not in those with capsaicin-denervation. We conclude that: 1) an increase in the expression of CSE and CBS, key enzymes in H2S biosynthesis, could compensate for the stress-induced impairment of gastric mucosal defense; 2) antisecretory activity of H2S donors contributes to the attenuation of acid-dependent injury caused by WRS, and 3) sensory mediators and antioxidizing enzymes SOD and GPx play an important role in H2S-induced gastroprotection against WRS-induced ulcerogenesis.

It has long been recognized that intestinal blood flow increases at mealtimes. Mesenteric hyperaemia is also evoked by activation of sensory peptidergic nerves. Our studies explored the possible role of endogenous nitric oxide (NO) in the rat intestinal vasodilator response to luminal instillation of an oleic acid plus bile mixture before and after acute intrajejunal instillation of capsaicin and after chronic pretreatment with capsaicin. In anaesthetized rats we measured jejunal blood flow (BF) with an ultrasonic Doppler flowmeter and systemic arterial pressure (AP) with a pressure transducer. Intestinal perfusion with 80 mM oleic acid in bile increased BF by 98 +/- 12%. Instillation of 4 mg of capsaicin into the jejunal lumen initially increased BF by 42 +/- 9% but was followed by vasoconstriction. Inhibition of NO synthase with 25 mg/kg i.v. N-nitro-L-arginine (L-NNA) decreased BF by 27 +/- 5% and increased AP by 37 +/- 11%. After treatment with L-NNA and after acute and chronic administration of capsaicin, the bile-oleate-induced maximal increases in BF above control levels were 42 +/- 7%, 65 +/- 12%, and 58 +/- 8%, respectively. The observed inhibitory effect of L-NNA on the intestinal hyperaemic response to the bile-oleate mixture was reversed by pretreatment with L-arginine (100 mg/kg i.v.). In capsaicin pretreated rats the subsequent bile-oleate-induced hyperaemia was reduced in magnitude but the inhibitory effects of L-NNA were proportionately the same as in animals not receiving capsaicin. These findings support the hypothesis that NO is involved with bile-oleate-induced mesenteric hyperaemia.

G A A b st ra ct s of the oxyntic mucosa, increased apoptosis, oxidative stress, and surface layer erosion. Inflammation was also observed in the mucosa as shown by the activation of the NFkB pathway and increases in TFF1, TIMP1 and Cox-2 expression. The pit region of the mucosa was affected by changes in cell interactions due to changes in beta-catenin and E-cadherin expression, loss of interaction in adherent junctions and activation of the beta-catenin pathway. Many of these changes, already detectable in 20-day-old fetuses, were specific of the offspring and were not observed in dams. All pups were refed a normal diet after weaning. We evaluated the persistence of stomach changes by comparing adult rats with MMD during gestation and suckling period and normal diet thereafter with control rats. The gastric mucosa thickness remained smaller in than that of control rats. SOD expression, NFkB activity, and apoptotic cell loss remained increased. CONCLUSIONS: These results indicate that the deleterious effects of MDD during gestation and lactation were accompanied by inflammatory and ulcerative states that were not reversed by the ingestion of a normal diet after weaning.

The pathogenesis of reflux esophagitis results from an imbalance between aggressive factors damaging the esophagus and the natural antireflux barriers. The local renin-angiotensin system (RAS) exists in esophageal mucosa, however, its contribution to the mechanism of esophageal integrity has not been clarified. Angiotensin-(1-7) (Ang-(1-7)) which is an important component of the RAS, was recently implicated in gastroprotection but its effect on damage induced by reflux esophagitis (RE) has not been explored. We evaluated the possible protective effect of Ang-(1-7) against mucosal lesions induced by the acute RE induced in anesthetized rats by ligating of the pylorus and the limiting ridge (transitional region between the forestomach and the corpus of stomach). Rats were pretreated 30 min before induction of RE either with 1) vehicle (saline), 2) Ang-(1-7) (5 75 μg/kg i.p.), 3) Ang-(1-7) (50 μg/ kg i.p.) without and with A 779 (2.5 mg/kg i.p.), a selective antagonist of Ang-(1-7) Mas receptor, 4) Ang 1-7 (50 μg/kg i.p.) without and with capsaicin (125 mg/kg s.c.) to induce functional ablation of sensory nerves, and 5) antisecretory treatment with PPI inhibitor, pantoprazole (10 mg/kg i.g.). Four hrs after induction of esophagitis, the damage was graded with mucosal lesion index (LI) from 0-6, the esophageal blood flow (EBF) was determined by H2-gas clearance technique and the RT-PCR expression and plasma levels of proinflammatory cytokines IL-1β and TNF-α was determined by ELISA. The esophageal LI and wet weight in esophagitis were significantly higher and the EBF was decreased by 35% as compared with the intact mucosa Pretreatment with Ang-(1-7) which in intact rats increased the EBF by 25% without any damage and alteration in plasma IL-1β and TNF-α levels, almost completely prevented, similarly as pantoprazole, the esophageal mucosal injury and significantly increased EBF by about 18% as compared to that in vehicle-controls with RE. The esophagoprotective effects and the rise in EBF induced by Ang-(1-7) were completely abolished by A779. Capsaicin denervation which by itself failed to affect the esophageal lesions, also reduced the esophagoprotective and hyperemic effects of Ang-(1-7) and both protection and hyperemia were restored by co-treatment with CGRP (10 μg/kg s.c.). Ang(1-7) significantly decreased the RE-induced increase in mRNA expression and plasma IL1β and TNF-α levels and these effects were also abolished by pretreatment with A779 and capsaicin-sensory denervation. We conclude that Ang-(1-7), a potent vasodilatatory member of angiotensin family peptides, exhibits esophagoprotection against the esophageal damage induced by reflux esophagitis via mechanism involving activation of Mas receptor, the stimulation of sensory nerves releasing of vasodilatatory CGRP and the suppression of expression and release of IL-1β and TNF-α.

I n 1929, Drury and Szent Gyorgi extracted adenosine (ADO) from different tissues and observed striking cardiovascular responses to injections of this purified adenine nucleoside.’ Nearly 40 years ago, Berne et al. proposed that myocardial generation of ADO was a major metabolic mechanism regulating blood flow in the circulation of the heart.2-4 Subsequently, Burnstock led the way in identifying discrete receptors for adenine nucleosides and nucleotides5 In his widely accepted terminology, the Pl purinergic receptor has a greater affinity for ADO than for the nucleotides, and the P2 purinoceptor has a higher affinity for adenosine 5’-triphosphate (ATP) and diphosphate than for ADO. The Pl purinoceptor has two subtype receptors; binding to the Al subtype inhibits adenylate cyclase, and binding to the A2 receptor subtype activates enzymatic synthesis of intracellular 5’cyclic adenosine monophosphate (CAMP).‘,’ A2 receptor activation on vascular smooth muscle (VSM) cells, causing intracellular CAMP accumulation, has been proposed as a general mechanism underlying the precapillary vasodilator effect of ADO8 in different vascular beds, including the mesenteric.’ However, other putative second messenger mechanisms have also been implicated in ADO-induced vasodilation.‘0-‘2 These include stimulation of a G proteinI inhibition of Ca2+ influx into VSM myoplasm, ‘**” inhibition of a phosphatidylinositol-dependent kinase,‘” opening of K+ channels to hyperpolarize VSM cells,” and generation of endothelial nitric oxide, I8 although there is evidence against the last mechanism.” Based on extrapolation of findings from other muscle systems, one can predicate a model for ADO vasodilation in mesenteric VSM cells (Figure 1). ADO binding to the A2 receptor subtype on the cell surface activates adenylate cyclase via a stimulatory G protein. The ensuing accumulation of CAMP and activation of a protein kinase closes the sarcolemmal Ca’+ slow channel, thereby attenuating the inward diffusion of Ca’+ from the extracellular compartment. CAMP accumulation also enhances Ca2+adenosine triphosphatase extrusion of Ca2+ from the myoplasm into the sarcoplasmic reticulum and the extracellular space. The decrease in myoplasmic [Ca”] relaxes VSM cells and dilates the blood vessel. For nearly all of the 20th century, Barcroft’s notion has dominated the explanation of physiological regulation of vasodilation.20 According to his concept, the altered chemical environment produced by tissue metabolism relaxes nearby VSM to elicit an increase in local blood flow. Despite the demonstration of other regulatory mechanisms, local metabolic factors have been viewed as especially important in the control of blood flow through the intestinal vasculature.” Particularly telling evidence favoring the metabolic theory has been generated from studies of intestinal vascular autoregulatory responses in which the challenge of either a diminished blood flow or an increased oxygen demand evokes a localized hyperemia of the gut. Examples of such intestinal autoregulatory phenomena include postprandial hyperemia,22 pressure-flow autoregulation,‘j reactive hyperemia,24 autoregulatory escape,” and poststimulation hyperemia.” However, it should be noted that nearly all research in this area has tended to focus narrowly on single-mediator candidates without much consideration of associated regulatory systems. Three major criteria for validating candidate local regulators of mesenteric hyperemias are: (1) the substance must be present in intestinal tissue in measurable quantities that increase with either a diminished blood flow or an enhanced local metabolism; (2) when administered, the substance exogenously must relax mucosal resistance vessels and must increase blood flow through mucosal, nutrient capillaries; and (3) the substance should have effective antagonists of either its VSM receptors or its biosynthetic enzymes.‘0727 Confidence in the putative vasodilator regulator would also be increased if it had been shown to fulfill the role of vasodilator metabolite in at