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The effects of short-time exposure to cigarette smoke on duodenal mucosal bicarbonate secretion were studied in anesthetized rabbits and rats. The bicarbonate secretion was measured by continuous titration of recirculating luminal perfusate. In artificially ventilated rabbits, intermittent exposure to cigarette smoke during two 10-min periods caused a marked (approximately 40%) decrease (p less than 0.01) in duodenal bicarbonate secretion. After the exposures, secretion gradually recovered and had returned to the pre-exposure rate after 50 min. The decrease in secretion was associated with decreases in heart rate (approximately 15%) and blood pressure (approximately 30%) that, however, were of shorter duration. Neither reduced amounts of smoke (1/6 or 1/3) nor nicotine (25-1,000 micrograms/kg, intravenously) had any major effect on the bicarbonate secretion. In the spontaneously breathing rat, smoke was administered for 1-2 breaths every 30 s during a 5-min period. This exposure resulted in a significant (p less than 0.05) decrease in bicarbonate secretion and some increase in the blood pressure. Exposure to smoke had no effect on the secretion in rats with both splanchnic nerves cut, suggesting neural sympathetic mediation of the smoke-induced inhibition.

Prompt and long-standing acid control following once-daily administration of antisecretory drugs is desirable. The objective of this study was to determine whether co-administration of a well-characterized H2-receptor antagonist, famotidine, can be combined with the proton-pump inhibitor omeprazole.Intragastric 24-h pH-metry was performed in healthy, Helicobacter pylori-negative volunteers on day 1 and after 8 days of daily administration of 20 mg omeprazole, 10 mg famotidine, or a combination of these in a three-way crossover design.A combination of famotidine and omeprazole raised the gastric pH level to4 in less than 1 h. The percentage of daytime with pH4 on day 1 was significantly higher with the combination of omeprazole and famotidine (median: 37%) than that with omeprazole alone (22%; p0.05). On day 8, daytime intragastric pH4 following treatment with omeprazole (median: 55%) or a combination of omeprazole and famotidine (61%) was superior (p0.05) to that with famotidine (21%). On day 1 treatment with both famotidine and the combination (famotidine and omeprazole) showed a significantly shorter time to reach a pH of 4 (medians: 93 and 63 min, respectively) compared with treatment with omeprazole alone (173 min; p0.05).Compared with treatment with omeprazole alone, on day 1 famotidine and omeprazole in combination improved the duration of and time to reach intragastric pH4. With regard to duration with pH4, the combination therapy was superior to famotidine alone on day 8. The rapid acid control with an H2-receptor antagonist may be combined with the long-lasting antisecretory effect of a proton-pump inhibitor.

Surveillance of patients with Barrett's esophagus usually is performed with standard white-light endoscopy (SDWLE) and the collection of 4 biopsy specimens (every 1-2 cm of the metaplastic segment), based on Seattle protocol. New endoscopic techniques are used routinely, but have been validated based only on low-grade evidence. We aimed to validate the use of high-definition magnifying endoscopy with multiple-band imaging (HDMEMBI) with a targeted biopsy collection for the detection of dysplasia, using SDWLE with quadrant biopsy collection as the reference.In a cross-over study, patients with suspected or histologically verified BE (without known neoplasia) seen at a tertiary referral high-volume endoscopy center in Sweden, from November 2009 through November 2012, were assigned randomly to undergo HDMEMBI (n = 63) or SDWLE (n = 47) as the initial procedure, followed by the other procedure in 1 to 4 months. The primary end point was the total number of subjects found to have low-grade dysplasia or high-grade dysplasia (HGD) by each technique. Secondary end points included the number of biopsy specimens taken and the duration of each procedure.There was no significant difference between groups in diagnostic yield for low-grade dysplasia (14 in HDMEMBI vs. 13 in SDWLE) or HGD. Four HGDs were found: 3 using HDMEMBI and 1 using SDWLE. Significantly fewer biopsy specimens were collected during the HDMEMBI procedure (P.001). The diagnostic yield for the detection of dysplasia per biopsy specimen collected therefore was significantly higher for HDMEMBI than SDWLE (0.25 vs. 0.07; P = .018). There was no significant difference in the duration of procedures.There is no significant difference in the detection of dysplastic lesions using HDMEMBI with targeted collection of biopsy specimens vs SDWLE with 4-quadrant biopsy specimen collection. However, HDMEMBI requires the collection of significantly fewer biopsy specimens, providing better value for health care providers. ClinicalTrials.gov number: NCT01694511.

For obscure reasons Helicobacter pylori infection of the gastric mucosa is maintained despite a pronounced host defence response. The present study elucidates possible H. pylori-related interference in the oxy- and nitro-radical formation pathways.Male Mongolian gerbils were infected with two different H. pylori strains, TN2GF4 and SS1. At 3, 6, 12 or 18 months after inoculation, gastric expressions of myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and nitrotyrosine were assessed by Western blotting.Expression of both iNOS and MPO was markedly up-regulated in the H. pylori-infected animals compared with non-infected controls. The TN2GF4-infected animals initially (at 3 and 6 months) demonstrated pronounced expression of both iNOS and MPO. The SSI-infected animals exhibited a slower onset with significantly increased iNOS after 12 and 18 months. Nitrotyrosine expression was slightly elevated in the infected groups at 3 and 6 months compared with that in the controls. Nitrotyrosine levels then decreased and were no longer significantly different from those of controls (TN2GF4-infected animals) or were lower (SS1-infected animals) than in the controls.The results indicate that peroxynitrite formation as reflected by nitrotyrosine expression is low or even inhibited in chronic H. pylori infection despite pronounced expression of enzymes representing both the oxy- and nitro-radical formation pathways. The results support the theory that H. pylori survival is related to functional inhibition of mucosal enzymatic NO and/or oxy-radical formation.

Background & Aims: Angiotensin II is a potent activator of smooth muscles but has not been much investigated with regard to gastrointestinal motor activity. This study explores expression of the renin–angiotensin system (RAS) in human esophageal musculature and actions by Angiotensin II both in vitro and in vivo. Methods: Muscular specimens of esophageal body and lower esophageal sphincter were obtained from patients undergoing resection as a result of mucosal neoplasm. Healthy volunteers participated in functional examinations of esophageal motility assessed by high-resolution manometry and multiple transmucosal potential-difference measurements. Results: Gene transcripts of key components of RAS were found in the esophageal musculature. Immunohistochemistry revealed a distinct staining for Angiotensin II type 1 (AT1) receptors in the muscular bundles and blood-vessel walls, whereas Angiotensin II type 2 receptors were confined to blood vessels only. Angiotensin II caused concentration-dependent contractions in vitro, which were inhibited by the AT1 receptor antagonist losartan but not by the Angiotensin II type 2 receptor antagonist PD123319. Administration of the AT1 receptor antagonist candesartan reduced the amplitude of swallow-induced peristaltic contractions and both the length and pressure amplitude of baseline high-pressure zone at the esophagogastric junction. Neither swallow-induced axial movements, nor the contraction after transient lower esophageal sphincter relaxations, were influenced by candesartan pretreatment. Conclusions: The study demonstrates a local RAS in the musculature of the distal esophagus and that Angiotensin II is a potent stimulator of esophageal contractions via the AT1 receptor. The results suggest that Angiotensin II participates in the physiological control of the human esophageal motor activity.

The Mongolian gerbil is considered as the model of choice when studying adenocarcinoma related to Helicobacter pylori infection. The purpose of this study was to compare two different H. pylori strains and elucidate whether adenocarcinomas developed in gerbils.Male gerbils were separated into three groups: one control and two groups infected with two different strains of H. pylori, TN2GF4 and SS1. At 3, 6, 12 or 18 months after inoculation 5 animals from each group were sacrificed. The stomach was used for culture, and for histology.Inflammation was seen after 3 months in all the infected animals. In the controls no pathology was found at any time. Intestinal metaplasia was found in both the infected groups. Glands buried in the submucusal layer, changes that might be misinterpreted as adenocarcinoma, were found in 10% of the SS1 and in 65% of the TN2GF4 animals. Adenocarcinoma was not found in any of the gerbils.All studies claiming to have found H. pylori-induced adenocarcinomas in gerbils describe atypical glands penetrating into the muscularis propria and interpret these as invasive growths due to cancer. An alternative interpretation is that the deranged glandular structures grow in and below the submucosa. It is suggested that atypical glands in the muscularis layer are not enough as a diagnostic criterion for gastric adenocarcinoma. It is concluded that adenocarcinoma has not yet been shown convincingly to develop in Mongolian gerbils infected with H. pylori. Nevertheless, it is a model well suited for studying gastritis, gastric ulcer and premalignant changes such as metaplasia.

Background To further improve the success rate of intestinal transplantation there is a need to find early appearing indicators of rejection. The specific aim of this study was to compare Angiotensin (Ang) II type 1 receptor and Ang II type 2 receptor expression in relation to histological signs of rejection. Methods Mice of the C57BL6 strain with syngeneic intestinal grafts were compared to mice subjected to allogeneic intestinal transplantation with BalbC strain as donors. Local expression of Ang II type 1 and 2 receptor was evaluated using rt-PCR and Western blot and compared to histological picture in grafts and native intestine. Results The Ang II type 2 receptor protein expression was markedly up-regulated in the allogeneically transplanted graft from day 1 postoperatively. Histological signs of rejection were not seen until day 6. Conclusion Intestinal allograft transplantation in mice is associated with a marked up-regulation of the Ang II type 2 receptor. However, the detailed role of the renin-angiotensin system in the immune rejection following intestinal transplantation remains to be clarified.

The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K(i) value of 0.4 nM for the AT(2) receptor and a K(i) > 10 microM for the AT(1) receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT(2) receptor in more detail.

BACKGROUND Interference with the L-arginine/nitric oxide pathway may be a virulence strategy for the gastric pathogen Helicobacter pylori. This study evaluates a bioassay for such inhibitory actions on nitric oxide synthase. METHODS Cultured murine macrophages were stimulated by lipopolysaccharide and interferon-gamma. Nitric oxide synthesis and the expression of inducible nitric oxide synthase (iNOS) at increasing concentrations of L-arginine were analysed using chemiluminescence and Western blotting, respectively. RESULTS The bioassay was evaluated against nitrite accumulation and two established NOS inhibitors. Bacterial extracts or whole cells of one H. pylori strain inhibited nitric oxide production at low L-arginine concentrations (2-20 microM). A higher concentration of L-arginine (200 microM) was not associated with such inhibition. The iNOS expression was not affected by any of the additives compared to stimulated controls. CONCLUSIONS This bioassay is a reliable and simple method for analysing iNOS inhibition, resolving effects on enzyme activity or enzyme expression. H. pylori water extract and whole cells exert an L-arginine-dependent NOS inhibition, not influencing iNOS expression.

The present study explores some aspects of the triggering of the acid-induced oesophago-salivary reflex. In addition to hydrogen ions, there are two acid-dependent molecules with messenger potential in the oesophageal lumen: CO2 and NO. The aim of this study was to clarify whether oesophageal NO and CO2 participate in the regulation of salivary neutralizing capacity in response to acid exposure.Healthy volunteers received oesophageal acidification composed of HCl, with NO3-, or HCO3- or NO3- and HCO3- in combination. In a second series of experiments, the exposure period was divided into 2 separate 10-min events. Saliva volume and titratable buffering capacity were used to calculate alkaline secretion.Salivary alkaline secretion increased markedly following 20 min intraluminal exposure to HCl. The initial part of this response was 22% +/- 2.2% larger (P0.05) if NO3- was present. When HCO3- was added, or if NO3- and HCO3- were given simultaneously, the secretory response tended to be lower. The accumulated responses over 70 min to 2 short HCl exposures (10 min each separated by a 30 min 'rest') compared to one long one lasting 20 min were similar regardless of the presence of NO3-.The data suggest that oesophageal intraluminal NO facilitates initiation of the oesophago-salivary reflex. CO2 seems to have a negligible effect on alkaline salivation, and repeated stimulation does not influence the magnitude of the response over time.

The aim of the present study was to assess luminal nitric oxide (NO) levels in the oesophagus during baseline and acidic conditions and to clarify the sources of such oesophageal NO formation.Healthy volunteers received an intra-oesophageal infusion of either HCl (100 mM) or NaCl (50 mM) on two separate study days. After a low nitrate diet, nitrate load or no dietary restrictions/pretreatment, direct intraluminal measurements of NO formation were performed using a tonometric technique. Endoscopy was performed and mucosal biopsies were taken and analysed by means of immunohistochemistry, Western blot and RT-PCR.No intra-oesophageal NO was detected during baseline conditions with pH neutrality. During the infusion of HCI the NO levels rose dramatically to around 12000 ppb. This high rate of NO formation fell by 95% following deviation of saliva. NO formation after an acute nitrate load was almost doubled during acid perfusion compared to control. Immunohistochemistry demonstrated distinct staining for iNOS in the oesophageal squamous epithelial cells, and Western blot and RT-PCR confirmed the presence of iNOS.Two sources exist for intra-oesophageal NO formation, both dependent on the luminal acidity: 1) chemical reduction of salivary nitrite, a mechanism related to dietary intake of nitrate, and 2) NO formation within the oesophageal mucosal epithelium by enzymatic degradation of L-arginine. In the latter case, the NO synthase has antigenic characteristics, indicating the inducible isoform, although a functional behaviour suggests an unconventional subtype.

Fandriks L, von Bothmer C, Aneman A, Olbe L, Pettersson A. Intragastric nitric oxide/nitrite in Helicobacter pylori-infected subjects. Background: Nitrite (NO 2 ) in swallowed saliva is reduced to nitric oxide (NO) and other nitrogen oxides by the intragastric acidity. This mechanism is probably important for the intragastric clearance of ingested micro-organisms and nitrosating compounds. The study examines the balance between intragastric NO and NO 2 in relation to endogenous acid production and infection with Helicobacter pylori. Methods: Six healthy H. pylori-negative and six H. pylori-positive volunteers with no known gastroduodenal pathology were examined after an overnight fast. Gastric NO was measured using a chemiluminescence technique and pH as well as NO 2 were analysed in gastric aspirates. Results: Gastric NO was slightly lower in H. pylori-positive subjects (1560 ± 21 [ ppb) than in uninfected controls (2112 ± 430 ppb; P > 0.05) during basal conditions, whereas both pH and NO 2 concentration were similar in the two groups. During inhibition of acid secretion (omeprazole 20 mg b.i.d. over 5 days) median pH and mean NO 2 - concentration in gastric aspirates were significantly higher in H. pylori positives than in the controls. Furthermore, during omeprazole treatment the intragastric NO levels were almost absent in H. pylori positives, whereas approximately 50% remained in H. pylori-negative individuals. Conclusion: Proton-pump inhibition in H. pylori-infected individuals abolishes the intragastric chemical reduction of swallowed NO 2 - in the fasting stomach.

To investigate the potential of specific angiotensin II subtype 1 (AT1) receptor blockade to modify the mesenteric hemodynamic response to acute hypovolemia and retransfusion.Prospective, randomized, controlled experimental study.University-affiliated animal research laboratory.Fasted, anesthetized, ventilated, juvenile domestic pigs of both sexes.Acute, graded hypovolemia by 20% and 40% of the total estimated blood volume followed by retransfusion in control animals (CTRL; n = 10) and animals pretreated with the AT1 receptor blocker candesartan (CAND; n = 10).Invasive monitoring of arterial and central venous blood pressures, cardiac output, portal venous blood flow, and jejunal mucosal blood flow. Blood gases were repeatedly analyzed to calculate oxygen delivery and consumption. Thirty minutes after each level of hypovolemia at 20% and 40%, cardiac output was decreased in CTRL animals from a baseline of 2.9 +/- 0.1 to 1.8 +/- 0.2 and 1.1 +/- 0.2 L/min, with no differences compared with CAND animals. Cardiac output was restored to 3.0 +/- 0.3 L/min 30 mins after retransfusion in CTRL animals, with no significant intergroup differences. Baseline portal venous blood flow (Q(MES)) and jejunal mucosal perfusion (PU(JEJ)) were greater in CAND animals compared with CTRL animals. During graded hypovolemia, CAND animals maintained Q(MES) and PU(JEJ) at significantly higher levels compared with CTRL animals, particularly after 40% hemorrhage (+221% and + 244%, respectively, relative to the mean values in CTRL animals). The same pattern was observed after retransfusion. Moreover, the calculated mesenteric critical oxygen delivery was significantly greater in CTRL animals (74 mL/min) compared with CAND animals (34 mL/min). No animals died in the CAND group, whereas four animals died during 40% hypovolemia or retransfusion in the CTRL group.Specific AT1 blockade before acute hypovolemia significantly ameliorated mesenteric and, in particular, jejunal mucosal hypoperfusion. In addition, cardiovascular stability was improved, and mortality in conjunction with acute hypovolemia and retransfusion could be completely avoided. These findings support a fundamental role of the renin-angiotensin system in the mesenteric response to acute hypovolemia and indicate a substantial interventional potential for candesartan in conjunction with circulatory stress.

Objective: Lowered gut blood perfusion and the associated intestinal mucosal barrier dysfunction is considered important in the pathophysiology leading to critical illness. Intestinal mucosal nitric oxide formation has been attributed a key role in the regulation of epithelial permeability and other properties of the intestinal mucosal barrier. This study was performed to delineate intestinal mucosal NO formation during hypovolemia or sepsis, both of which are associated with intestinal hypoperfusion. Materials and methods: Seventeen pigs were subjected to 2 h of severe hypovolemia (bleeding induced) or sepsis (systemic infusion of live Escherichia coli) or no treatment (controls). Jejunal mucosal NO production was monitored by a tonometer. Mesenteric blood flow was measured as portal venous blood flow by an ultrasonic transit time flowmeter probe, and oxygen delivery and consumption were calculated from regional blood samples. Results: Intestinal perfusion and oxygen delivery were reduced by the same order of magnitude in both groups. Jejunal mucosal NO production and oxygen consumption decreased markedly in the hypovolemia group but remained stable in the group subjected to septic shock. Conclusions: These data suggest that blood loss inhibits jejunal mucosal NO production as part of a general downregulation of nonvital organs. Sepsis represents a more complex stress condition with activation/maintenance of host defense mechanisms as reflected by maintained jejunal mucosal NO production despite reduced gut blood perfusion.

The splanchnic organs represent a major target for sympathetic outflow and an important region for haemodynamic effects on cardiovascular homeostasis. We have studied regional haemodynamic and sympathetic changes in the splanchnic bed during standardized circulatory stress from positive end-expiratory pressure ventilation (PEEP). We investigated eight patients undergoing major upper abdominal surgery using a radiotracer method to measure plasma spillover of norepinephrine as an index of sympathetic nerve activity using arterial, portal and hepatic venous blood sampling. Mesenteric and hepatic perfusion were measured by ultrasound transit time flowmetry and blood-gas analyses. Steady state measurements were performed before and during PEEP ventilation at 10 cm H2O. Plasma spillover of norepinephrine in the mesenteric and hepatic organs represented mean 49 (SEM 8)% and 7 (2)%, respectively, of systemic norepinephrine spillover at baseline, and PEEP ventilation did not cause any significant changes. However, PEEP ventilation significantly decreased portal venous blood flow while hepatic blood flow was preserved by a compensatory increase in hepatic arterial blood flow. Mesenteric and hepatic oxygen delivery changed according to blood flow, and there were no changes in regional oxygen consumption. Thus PEEP ventilation altered mesenteric and hepatic perfusion, independent of any change in corresponding sympathetic nerve activity. Regulation of hepatic blood supply, not related to sympathetic activity, maintained liver oxygenation during PEEP ventilation despite a simultaneous decrease in mesenteric perfusion.

Background & Aims: Acid exposure of the duodenum elicits various functional responses, e.g., an increased mucosal alkaline secretion. Despite low pH in luminal contents, the mucosal secretion of bicarbonate-rich fluid results in pH neutrality at the surface epithelium. It follows that it is probably not luminal pH that triggers the secretory response. The present study was undertaken to investigate if CO 2 could serve as an intermediate messenger between luminal acid and the mucosal secretory response. Methods: Experiments were performed on chloralose-anesthetized rats. The duodenal mucosal alkaline secretion was measured by in situ pH-stat titration. Results: Exposure of the duodenal mucosa to CO 2 , administered either as a pregassed solution (pH 4, PCO 2 700 mm Hg) or as an acidified bicarbonate solution (pH 6.4, PCO 2 240 mm Hg), raised the alkaline output by approximately 65%. This response was blocked by the nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester (0.3 mmol/L intraluminally) but not by indomethacin (5 mg/kg intravenously). Conclusions: Exposure of the duodenal mucosa to solutions with high concentrations of CO 2 increases the mucosal alkaline secretion despite an almost neutral pH. Data indicate that the L-arginine/NO pathway is involved in the mediation of this response. GASTROENTEROLOGY 1998;115:680-685

Duodenal mucosal alkaline secretion increases in response to hydrochloric acid exposure. The tentative role of nitric oxide (NO) in the mediation of this response was investigated. The mucosal alkaline output by a duodenal segment was recorded by in situ titration in chloralose-anaesthetized rats. In some experiments the duodenal blood flow was estimated by laser-Doppler flowmetry. Exposure of the duodenum to acid (0.01 M HCl, 5 min) increased the alkaline secretion by approximately 85%. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10 mg kg-1 intravenously or 0.3 mM intraluminally) blocked the secretory increment after mucosal acid exposure. Mean arterial pressure and basal alkaline secretion were markedly raised, whereas duodenal blood flow was decreased, when L-NAME was given intravenously (i.v.). Intraluminal (i.l.) administration left mean arterial pressure as well as duodenal blood flow unaltered, and the duodenal mucosal alkaline secretion was only slightly elevated. The stereoisomer NG-nitro-D-arginine methyl ester (D-NAME) had no effect on either basal or acid-induced duodenal alkaline output. In animals receiving L-arginine (10 mg kg-1 min-1 i.v., or 3 mM i.l.) and L-NAME, the acid exposure elicited an increase in duodenal mucosal alkaline secretion, similar to that observed in controls. The results suggest that the acid-induced increase in duodenal mucosal alkaline secretion involves NO synthesis, which takes place close to the lumen, probably within the mucosa.

Considerable urinary excretion of dopamine metabolites indicates that large amounts of dopamine are produced in unknown locations of the body. This study assessed the contribution of mesenteric organs (gastrointestinal tract, spleen, and pancreas) to the total body production of dopamine in humans and examined the presence of the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase, in gastrointestinal tissues. Blood sampled from an artery and portal and hepatic veins in eight subjects and from arterial and renal venous sites in other subjects was analyzed for plasma concentrations of dopamine and its metabolites. The activity and distribution of tyrosine hydroxylase was also examined in tissue samples from the stomach and duodenum. Higher concentrations of dopamine and its metabolites in portal venous than arterial plasma indicated substantial production of dopamine by mesenteric organs (12.0 nmol/min) amounting to 42-46% of the renal removal of circulating dopamine metabolites. Tissue samples showed immunoreactive tyrosine hydroxylase in nonneuronal cell bodies and detectable levels of tyrosine hydroxylase in nonneuronal cell bodies and detectable levels of tyrosine hydroxylase enzyme activity. The results show that mesenteric organs produce close to half of the dopamine formed in the body, most of which is unlikely to be derived from sympathetic nerves but may reflect production in a novel nonneuronal dopaminergic system.

This study using sampling of blood from the portal vein, in addition to arterial and hepatic sites, to estimate separately spillovers of norepinephrine from mesenteric organs and the liver in seven patients undergoing upper abdominal surgery. Conventional measurements in arterial and hepatic venous plasma provided a measure of net hepatomesenteric NE spillover (403 pmol/ml) that indicated a 13% contribution of these organs to total body spillover of NE into systemic plasma (3,071+/-518 pmol/min). The net hepatomesenteric spillover of NE into systemic plasma was much lower than the spillover of NE from mesenteric organs into portal venous plasma (1,684+/-418 pmol/min). This and the hepatic spillover of NE into systemic plasma (212+/-72 pmol/min) indicated a considerable combined spillover of NE from hepatomesenteric organs (1,896+/-455 pmol/min). The sum of the latter estimate with the difference between total body and net hepatomesenteric NE spillovers provided an adjusted total body spillover of NE into both systemic and portal venous plasma (4,564+/-902 pmol/min). Mesenteric organs made a 37% contribution, and the liver made a 5% contribution to the adjusted total body spillover of NE. Thus, a substantial proportion of total body sympathetic outflow is directed towards mesenteric organs; this is obscured by efficient hepatic extraction of NE (86+/-6%) when measurements are restricted to arterial and hepatic venous plasma.

The present paper describes and evaluates a methodologic approach for registration of the fast, interdigestive, motility-related changes in gastric acid and bicarbonate outputs seen in man.The technique is based on continuous gastric luminal perfusion and measurements of pH and PCO2 in gastric effluent and concomitant intragastric/duodenal manometry. Fourteen healthy volunteers participated.Direct acid secretory estimations from pH recordings, corrected for hydrogen ion activity, correlated closely with values obtained by conventional titration. After intragastric infusion of bicarbonate, 96 +/- 5% of the newly measured steady-state value was registered virtually instantaneously provided that corrections for the PCO2 electrode time constant and the perfusion/aspiration time were made. In the neutral pH range (pH 5-7), practically full quantitative recovery of intragastrically infused bicarbonate was obtained. In the acid pH interval (pH 2-5) the recovery was significantly lower (53 +/- 6%; p0.01). With an aspirate without air admixture and during high perfusion rates (31 and 46 ml/min), full recovery of bicarbonate was obtained also at an acid pH, whereas a reduced perfusion rate (16 ml/min) significantly (p0.05) reduced the recovery rate.With the pH/PCO2 technique both acid and bicarbonate assessments have a close to on-line time resolution. Acid output is measured accurately, but the method potentially underestimates actual bicarbonate levels in the acid pH range, a combined effect of diffusion of CO2 into air bubbles in the aspirate and into the gastric mucosa from the lumen. A high gastric perfusion rate minimizes this source of error. The pH/PCO2 technique is well suited for studies of the interaction between secretion and motility in the human stomach.

The immunologic reactivity of the gastric mucosa is poorly understood. The origin and dynamics of immunoglobulin A (IgA) occurring in the gastric lumen were investigated in healthy, Helicobacter pylori-negative volunteers.Gastroduodenal manometric motility recordings were combined with gastric luminal perfusion, enabling calculation of gastric acid output and analysis of the total IgA output.Acid output and total IgA correlated with the migrating motility complexes (MMC). The gastric IgA release showed maximal values in association with gastric motility phase III (maximal motor activity) and lowest values during phases I and II (none or irregular motor activity). The IgA output correlated with neither swallowed saliva (as indicated by amylase in the gastric perfusate) nor duodenogastric reflux (as indicated by gastric occurrence of bilirubin and/or duodenally infused PEG4000). Stimulation of gastric acid secretion by sham feeding during phase II-like motor activity (n = 6) induced a rapid and transient doubling of IgA output. There was no significant correlation between gastric acid secretion and gastric IgA release.Substantial amounts of IgA are released into the human stomach, most likely originating from the gastric mucosa. The up-regulation of IgA release in association with the activity front of the MMC and anticipatory to food intake suggests a neuroendocrine control of gastric mucosal immune responses.

Release and removal of norepinephrine (NE) by hepatomesenteric organs in anesthetized swine were examined using measurements of NE in arterial, portal, and hepatic venous plasma. NE spillover from the liver and mesenteric organs increased during splanchnic nerve stimulation, validating these measurements as indexes of sympathetic outflow. Administration of the neuronal uptake-blocking drug desipramine reduced mesenteric NE extraction more than hepatic extraction, suggesting that neuronal uptake was more important for NE removal in mesenteric organs than in the liver. Circulating NE was removed by the liver more efficiently than by mesenteric organs, whereas mesenteric NE spillover (2.46 nmol/min) exceeded liver NE spillover (0.74 nmol/min). Hepatomesenteric NE spillover represented 53% of total body spillover; NE clearance was 42% of total body clearance. Because of efficient hepatic extraction of NE released by mesenteric organs, the sum of mesenteric and hepatic NE spillovers (3.20 pmol/min) exceeded net hepatomesenteric spillover estimated using arterial and hepatic venous measurements alone (1.96 pmol/min). Thus valid assessment of the substantial amounts of NE released by hepatomesenteric organs requires separate examination of mesenteric and hepatic spillovers.

Acid secreted by the gastric parietal cells is an important factor in the digestive process. The acidity is, however, a potential threat to the organism itself and several protective mechanisms are utilized to prevent autodigestion. Today, it is well established that there exists a bicarbonate secretion by the gastroduodenal surface epithelium which neutralizes gastric acid1,2. Micro-pH-electrodes have been used to demonstrate a pH-gradient immediately above the epithelial cells; pH at the cell surface being neutral despite highly acidic luminal contents3,4. In the duodenum, this transport of bicarbonate is probably the most important factor for protection against gastric acid, whereas it plays a more subordinate role in the stomach1,5.

Experiments were performed on chloralose anaesthetized rats. A duodenal segment was decentralized by means of bilateral vagotomy and splanchnicotomy. The mucosal alkaline secretion by the segment was measured using an in situ pH-stat titration. The duodenal alkaline secretion was raised by about 100% utilizing two different secretagogues; vasoactive intestinal polypeptide (VIP) and prostaglandin E2 (PGE2). Direct splanchnic nerve stimulation (10 Hz, 5 min, bilaterally), or exogenous administration of the alpha-2-adrenoceptor agonist clonidine (15 micrograms h-1 kg-1), inhibited the secretion stimulated by PGE2, but not by VIP. The results suggest that the sympathetic nerves exert their inhibitory effect mainly on enteric secretomotor neurones.

This paper describes and evaluates a method for simultaneous recordings of duodenal motility and mucosal secretions in chloralose-anaesthetized cats. Biliary and pancreatic secretions were diverted by separate cannulation of each duct. A 2 cm segment of the proximal duodenum was isolated between two luminally situated balloons (the proximal balloon being positioned immediately distal to the pylorus). Each balloon was connected to a barostatic device maintaining a constant pressure within the balloon independent of the degree of contraction. Motor activity in the duodenal wall was recorded as changes in balloon volume. The duodenal segment was perfused at a constant rate with isotonic saline containing [14C]PEG 4000 as a non-absorbable marker. The recovered perfusate was sampled in 5 min fractions and analysed with regard to alkalinity (back titration) and concentration of marker (liquid scintillation). Net alkalinization and net fluid transport was calculated with conventional equations. The sensitivity of the analytical procedures was tested bench-side. The technique was evaluated in vivo during basal conditions and during acid exposure of the mucosa. Exposing the duodenal segment to 30 mM HC1 induced a marked change in the duodenal functional state with the occurrence of a polarized duodenal motility pattern, net fluid secretion and an increased alkaline secretion.

Acid exposure of the duodenal mucosa is a well-known stimulant of the mucosal alkaline secretion. We have previously reported that a minor blood loss inhibits this secretory increment via activation of the splanchnic nerves. In the present study the pharmacological characteristics of the splanchnic neural inhibition of the alkaline secretion were investigated. Duodenal HCO3- secretion was measured by in-situ titration in chloralose-anaesthetized rats. Exposure of the duodenal mucosa to hydrochloric acid (0.01 M, 5 min) increased the secretion by approximately 60%. A 10% decrease in blood volume simultaneously to the luminal acidification abolished the secretory increase, as previously reported. Treatment with either guanethidine or yohimbine blocked the bleeding-induced inhibition of the secretion after acid-exposure. Neither prazosin nor propranolol did prevent such hypovolaemia-induced inhibition of duodenal alkaline secretion. The present results suggest that the splanchnic neural inhibition of acid-induced duodenal HCO3- secretion is mediated via adrenergic nerve fibres and alpha-2 adrenoceptors.

Experiments were performed on acutely vagotomized cats during chloralose anaesthesia. In order to avoid sympathoadrenergic influences, the adrenal glands were ligated and the splanchnic nerves were cut bilaterally in all animals. The gastric lumen was perfused with saline and the H+ secretion was calculated from pH measurements in the perfusate. HCO3- secretion by the duodenal mucosa was titrated in situ. Omeprazole (4 mg kg-1 i. v., dissolved in PEG400, 40% w/v) did not influence basal or vagally induced HCO3-secretions, but inhibited by about 80% the H+ secretory response induced by electric vagal stimulation. Acute administration of ranitidine (5 mg kg-1 i. v.) transiently lowered arterial pressure, an effect which was followed by a sustained compensatory tachycardia. Ranitidine raised basal duodenal HCO3- secretion by 50% and inhibited vagally induced gastric H+ secretion by about 70%, whereas vagally induced HCO3- secretion was not influenced. The results suggest that vagal nerve stimulation raises the duodenal bicarbonate secretion via a mechanism independent of the level of gastric H+ secretion.

This study was conducted to elucidate if nitric oxide is released by the porcine jejunal mucosa upon selective stimulation of AT2 receptors and the possible involvement of iNOS, and to investigate the presence of jejunal AT1 and AT2 receptors. Young landrace pigs were anaesthetized with ketamine and α-chloralose. Jejunal luminal NO output was assessed by intraluminal tonometry and analysed by chemiluminescense. Western blot analysis quantified mucosal iNOS and detected AT1 and AT2 receptor protein expression. AT1 and AT2 receptor RNA expression was detected by rtPCR. Baseline luminal NO output correlated significantly to baseline mucosal iNOS-protein content. In animals treated with the AT2-receptor agonist CGP42112A (n = 11) luminal NO output increased significantly (at 0.1 micrograms kg-1 min-1 and 1.0 micrograms kg-1 min-1), but not in animals simultaneously treated with the AT2-receptor antagonist PD123319 (bolus 0.3 mgkg-1, infusion 0.03 mg kg-1 h-1) (n = 7). No differences in iNOS protein expression were found between groups or before/after the administration of drugs. Western blot and rtPCR recognised expression of the AT1 and AT2 receptors in jejunal tissue. The results suggest that activation of AT2 receptors increases jejunal luminal NO output. This response was not due to an increase in the expression of the iNOS protein in the mucosa.

The aim of the present study was to investigate the impact of isoflurane on regional neurogenic mechanisms in the control of vascular tone. Therefore, regional determinations of sympathetic activity and hemodynamics were made in chloralose-anesthetized swine before and during administration of 1.4% isoflurane. Sympathetic activity was examined from spillover of norepinephrine (NE) into the circulation using an isotope dilution technique. Administration of isoflurane caused a marked decrease in mesenteric (65±9 pmol.min -1 .100 g -1 ; P

Acid exposure of the duodenal mucosa increased duodenal HCO 3 post− secretion by ~60%. When the acid exposure was performed simultaneously with an arterial bleeding of 0.6 ml/100 g body wt (10% of the total blood volume), the increase in duodenal HCO 3 post− secretion was totally abolished. When the acid exposure and bleeding procedures were performed at the same time in rats with bilaterally cut splanchnic nerves, alkaline secretion increased by 60%, as it did in the unbled rats. Direct electrical stimulation of the splanchnic nerves (10 Hz, supramaximal intensity) inhibited the stimulatory effect of duodenal acid exposure on alkaline secretion. Taken together, the data suggest that the sympathetic nervous system, because of splanchnic nerve activation, inhibits the acid-induced increase in duodenal HCO 3 post− secretion.

Aims/hypothesis: In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo. Methods: Six-week-old male C57BL/6J wild-type and Adipoq −/− mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 μg/g) three times/week from weeks 4–12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35–50 kg/m2) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry. Results: AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8+ T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p

Summary Bariatric surgery is currently the most effective procedure for the treatment of obesity. Given the role of the gut microbiota in regulating host metabolism and adiposity, we investigated the long-term effects of bariatric surgery on the microbiome of patients randomized to Roux-en-Y gastric bypass or vertical banded gastroplasty and matched for weight and fat mass loss. The two surgical procedures induced similar and durable changes on the gut microbiome that were not dependent on body mass index and resulted in altered levels of fecal and circulating metabolites compared with obese controls. By colonizing germ-free mice with stools from the patients, we demonstrated that the surgically altered microbiota promoted reduced fat deposition in recipient mice. These mice also had a lower respiratory quotient, indicating decreased utilization of carbohydrates as fuel. Our results suggest that the gut microbiota may play a direct role in the reduction of adiposity observed after bariatric surgery., Graphical Abstract, Highlights • RYGB and VBG induce long-term alterations in the human gut microbiome • The changes in the microbiome do not depend on BMI • RYGB and VBG have different effects on bile acid and TMAO metabolism • The surgically altered microbiome contributes to fat mass regulation, Bariatric surgery durably alters the human gut microbiome. Here, Tremaroli et al. demonstrate that two types of bariatric surgery, Roux-en-Y gastric bypass and vertical banded gastroplasty, produce long-term alterations of the gut microbiome independently of BMI and that these alterations modulate host metabolism and fat mass deposition.

Experiments were performed on rats anaesthetized with chloralose. A duodenal segment was perfused with recirculating isotonic saline, and alkalinization of this perfusate (HCO3- secretion) was measured by continuous pH-stat titration. Stereotaxic electric unipolar stimulations were performed in the perifornical region of the hypothalamus. Stimulation points eliciting an increased arterial pressure were stimulated for a period of 15 min. Duodenal HCO3- secretion decreased in 19 out of 25 experiments and increased in four out of 25 experiments. Inhibitory responses to hypothalamic stimulation were blocked either by thoracic epidural anaesthesia or by the adrenolytic agent guanethidine, suggesting a spinal pathway to the duodenum, presumably in the thoracic splanchnic nerves, and involvement of adrenergic neurons.