bluuebunny/crossref_metadata_2025 huggingface dataset:
Fat absorption is not complete by midgut but is dependent on load of fat
Authors: Lin H. C. , Zhao X. T. , Wang L.
Published: December 2017

Since the intubation study of B. Borgstrom, A. Dahlqvist, and G. Lundh (J. Clin. Invest. 36: 1521-1536, 1957) in humans, the completion of fat absorption within the proximal small intestine has been widely accepted. Based on this report, it has been assumed that the distal small intestine is exposed to fat only in the setting of pathology. This concept may be flawed, since completeness of fat absorption was calculated from the recovery of a water-soluble marker but the aqueous phase is now known to move independently from fat. To reexamine the question of whether fat absorption is complete by midgut, we measured the recovery of a fat-specific marker, 99mTc-thiocyanate, in a canine model equipped with duodenal and midgut fistulas. The fistulous output allowed for the measurement of the amount of fat entering the small intestine and the amount of fat entering the distal one-half of the small intestine. Emulsion meals containing 15 or 60 g of corn oil were tested. The importance of fat exposure of the distal one-half of the small intestine was further confirmed by comparing the fistulous fat recovery under two different patterns of exposure [allowing (ALL) or denying (150 cm) access to the distal small intestine]. We found that fat recovery depended on 1) the dose of fat (15 vs. 60 g; P < 0.0005), 2) the pattern of exposure (150 cm vs. ALL; P < 0.01), and 3) the fistulous position (duodenal vs. midgut; P < 0.005). Specifically, under a 150-cm exposure pattern, whereas 8.8 +/- 1.8 g (means +/- SE) of fat emptied into the duodenum after the 15-g fat meal, 32.6 +/- 3.2 g emptied after the 60-g fat meal. Correspondingly, although 3.5 +/- 1.5 g of fat were recoverable from the midgut fistulous output after the 15-g meal, a much larger amount, 17.1 +/- 5.6 g of fat, was recoverable and therefore not absorbed by the proximal one-half of the small intestine after the 60-g meal. The amount of fat recovery at each fistula was reduced when chyme was allowed access to the whole gut (by triggering fat-induced ileal brake). We conclude that the intestinal length required for fat absorption depends on the load of fat in the meal so that, even after usual meals, absorption of fat is not complete by midgut.
Interleukin-1 beta release from rat gastric fundus
Authors: Montuschi P. , Tringali G. , Mirtella A. , Parente L. , Ragazzoni E. , Preziosi P. , Navarra P.
Published: December 2017

Interleukin-1 (IL-1) is known to regulate gastric functions via a central action at the hypothalamic level, and it has also been shown that this cytokine can directly modulate rat gastric motility. This study was conducted to determine whether IL-1 beta is produced and released by rat gastric fundi in vitro. IL-1 beta immunoreactivity was released in measurable amounts from explanted rat gastric tissue. This release was not affected by electrical stimulation of the gastric strips or by agents that induce IL-1 biosynthesis. It could be inhibited only by the glucocorticoid dexamethasone. Ex vivo experiments confirmed the inhibitory role of glucocorticoids and showed that IL-1 beta release can be inhibited by agents that reduce gastric acid secretion, suggesting that the latter might stimulate IL-1 beta synthesis and release. In light of the well-established gastroprotection exerted by IL-1, H(+)-induced IL-1 beta release might serve as a protection against mucosal injuries caused by acid secretion, and the inhibition of this release by glucocorticoids might be involved in the pathogenesis of gastric damage associated with severe stress or steroid therapy.
Effects of lipid administration on lymphatic apolipoprotein A-IV and B output and synthesis
Authors: Nishimura M. , Seishima M. , Ohashi H. , Noma A.
Published: December 2017

We examined the mesenteric lymphatic and portal venous transport of triglyceride (TG), free fatty acids (FFA), apolipoproteins (apo)A-IV and B in response to a bolus duodenal infusion of a TG-free control solution, and long-chain (18:1) and medium-chain (8:0) TG (LCT and MCT, respectively) emulsions in the rat. Additionally, intestinal and hepatic apo A-IV and apo B mRNA levels were also measured. Lymph apo A-IV, apo B (B-48), FFA, and TG output increased after LCT infusion, whereas only apo A-IV and FFA outputs increased after MCT infusion. On the other hand, portal FFA and apo A-IV transports increased at 15 min after MCT infusion but not after LCT infusion. Portal TG and apo B transports were not altered by either MCT or LCT infusion. Jejunal apo A-IV mRNA was increased after both MCT and LCT infusions. Hepatic apo A-IV mRNA levels increased only after MCT infusion. Conversely, neither LCT nor MCT had any effect on apo B mRNA levels in intestine or liver. These results indicate that apo A-IV is regulated by MCT absorption and that fatty acid reesterification and lipoprotein assembly are not prerequisite for such regulation. Conversely, it is likely that apo B-48 participates only in the formation and/or transport of chylomicrons after LCT absorption.
Regulation of AE2 Cl-/HCO3- exchanger during intestinal development
Authors: Chow A. , Zhou W. , Jacobson R.
Published: December 2017

The Na(+)-independent Cl-/HCO3- exchangers in many tissues are encoded by AE2, which is a member of the anion-exchanger (AE) gene family. Molecular regulation of AE2 remains mostly unknown. In this study, AE2 mRNA levels during enterocyte differentiation and intestinal development were examined in rat small intestines. AE2 mRNA levels did not show obvious segmental variation or vary along the crypt-villus axis. In contrast, AE2 mRNA decreased between days 14 and 21 after birth, the period corresponding to the transition period between the suckling and weanling stages in rats. Effects of L-thyroxine and dexamethasone on AE2 expression were examined because these hormones play important roles in gene regulation during development. L-Thyroxine administration starting on day 9 after birth led to an approximately 60% decrease (P < 0.001) in AE2 mRNA on day 13. Dexamethasone had no effect on AE2 mRNA level regardless of whether the hormone was administered alone or in conjunction with L-thyroxine. Our results indicate that AE2 mRNA in the intestine is regulated during development and that this regulation may in part be related to hormonal changes.
Comparative analysis of the ontogeny of a sodium-dependent bile acid transporter in rat kidney and ileum
Authors: Christie D. M. , Dawson P. A. , Thevananther S. , Shneider B. L.
Published: December 2017

An apical sodium-dependent bile acid transporter (ASBT) has recently been cloned and characterized in the rat ileum. Northern and Western blotting revealed both the ASBT mRNA and protein in rat kidney. The coding sequence of the kidney transcript was found to be identical to the previously cloned ileal ASBT. Indirect immunofluorescence studies localized the ASBT protein to the apical membrane of the renal proximal convoluted tubule. Kinetic analysis of sodium-dependent taurocholate uptake using membrane vesicles revealed a similar Michaelis-Menten constant value for taurocholate in the kidney and intestine. ASBT protein and function were present in the kidney but not the ileum from 7-day-old rats. On postnatal day 7, there was a sevenfold increase in ASBT steady-state mRNA levels in the kidney relative to the ileum, yet nuclear run-on assays revealed that the nascent transcription rates at this age were virtually the same. This suggests that the difference in the neonatal expression of the ASBT gene in the kidney and ileum may be in part due to differences in mRNA stability.
Nitric oxide modulates regional blood flow differences in the fetal gastrointestinal tract
Authors: Fan W. Q. , Smolich J. J. , Wild J. , Yu V. Y. , Walker A. M.
Published: December 2017

We studied the role of endogenous nitric oxide (NO) in the regulation of gastrointestinal (GI) circulation in 11 chronically instrumented and unanesthetized late-gestation fetal sheep. Systemic and GI blood flows were measured by the radiolabeled microsphere technique. Mean arterial pressure (MAP), heart rate, blood flows, oxygen delivery, and vascular resistance were determined before and after infusion of the specific NO synthase inhibitor, N omega-nitro-L-arginine (L-NNA), to cumulative doses of 10 and 25 mg/kg. At both L-NNA doses, MAP increased, and combined ventricular output and heart rate decreased. GI blood flow and oxygen delivery decreased and vascular resistance increased for the stomach, all segments of the small intestine, and proximal colon and cecum but were unchanged in the middle and distal colon and rectum. Because blood flow reduction in the small intestine was pronounced (from 176 to 107 ml.min-1.100 g-1, P < 0.001) and blood flow in the large intestine was unchanged, distribution of intestinal blood flow became more uniform. Overall, blood flow reduction was proportionally greater in GI circulation than in the remainder of fetal circulation. In three additional animals we established that L-NNA reduced blood flow to the mucosal-submucosal layer (P < 0.02) but not to the muscularis serosa of the small intestine. In the same animals, L-arginine (250 mg/kg) restored systemic hemodynamics and partially restored small intestinal blood flow. Our results suggest that NO is an important differential regulator of vascular tone in the developing GI circulation.
Ileal transposition into the upper jejunum affects lipid and bile salt absorption in rats
Authors: Tsuchiya T. , Kalogeris T. J. , Tso P.
Published: December 2017

To determine whether ileal transposition affects absorption and transport of lipids and bile salts, we studied the absorption and lymphatic transport of triglyceride, cholesterol, and sodium taurocholate in rats with the distal quarter of their small bowel transposed to the proximal jejunum and in control rats whose intestines were transected and reanastomosed without transposition. Three weeks after transposition or sham surgery, rats were equipped with duodenal or jejunal and intestinal lymph duct cannulas and then given continuous duodenal or jejunal infusions of lipid emulsion containing triolein (40 mumol/h + [3H]triolein) and cholesterol (7.8 mumol/h + [14C]cholesterol) for 8 h. Lymph lipid output was measured; after 8 h of lipid infusion, luminal and mucosal radioactive lipid distribution was also quantified. Transposition had no effect on triglyceride absorption and transport, but cholesterol absorption and transport were both significantly attenuated in the transposed rats. In a separate study we examined whether ileal transposition would alter the kinetics of bile salt absorption. Six weeks after either transposition or sham surgery, rats were given a duodenal bolus injection of 14C-labeled sodium taurocholate mixed in rat bile, and the output of radiolabeled bile salt through a bile fistula was measured. Appearance of radiolabeled taurocholate was gradual in the control rats, peaking at approximately 90 min after administration. Appearance of labeled bile salt was rapid in the transposed rats, peaking within 60 min after administration. In conclusion, ileal transposition has no effect on triglyceride absorption but attenuates cholesterol absorption and transport, possibly by promoting premature absorption of bile salts.
Enterostatin efflux in cat intestinal lymph: relation to lymph flow, hyaluronan, and fat absorption
Authors: Townsley M. I. , Erlanson-Albertsson C. , Ohlsson A. , Rippe C. , Reed R. K.
Published: December 2017

The question addressed in this study was whether enterostatin, the pancreatic procolipase activation peptide, modulates intestinal hyaluronan turnover via lymph. In anesthetized cats, segments of ileum were surgically isolated from the proximal and distal gut, the draining lymphatic was cannulated, and the segment was autoperfused in situ. In several groups, concentrations of immunoreactive enterostatin in lymph were compared with that in plasma at baseline and elevated lymph flow and in the absence and presence of fat absorption. The baseline ratio of lymph enterostatin to that in plasma (L/P) in the absence of fat absorption was 1.44 +/- 0.29 compared with 4.93 +/- 0.42 after cream feeding (P < 0.05). In a separate group, when the intestinal lumen was perfused for 2 h with a mixture of oleic acid and taurocholate, enterostatin L/P doubled compared with baseline. At high lymph flows, enterostatin concentrations fell in all groups, resulting in an L/P of 0.47 +/- 0.09 (P < 0.05) in the absence of fat absorption, 0.77 +/- 0.35 after oleic acid, and 1.26 +/- 0.13 in the cream-fed group. These changes correlate with the pattern of hyaluronan efflux from the ileum into lymph after fat absorption [R.K. Reed, M.I Townsley, V.H. Pitts, T.C. Laurent, and A.E. Taylor. Am. J. Physiol, 263 (Gastrointest. Liver Physiol. 26): G6-G11, 1992] However, in separate groups when enterostatin was introduced into ileum, either as a close intra-arterial bolus or via the intestinal lumen, there were no resultant changes in efflux of hyaluronan from the intestine into lymph. In conclusion, despite the fact that delivery of pancreatic exocrine secretions to the ileal lumen was blocked in this model, enterostatin concentration in lymph increased after fat absorption. Nonetheless, it seems clear that enterostatin does not modify intestinal hyaluronan turnover.
Progesterone and estradiol inhibit CFTR-mediated ion transport by pancreatic epithelial cells
Authors: Sweezey N. B. , Gauthier C. , Gagnon S. , Ferretti E. , Kopelman H.
Published: December 2017

The cystic fibrosis (CF), gene product, CF transmembrane conductance regulator (CFTR), is responsible for adenosine 3',5'-cyclic monophosphate (cAMP)-activated Cl- transport in epithelial cells, and mutant CFTR accounts for the pathology in the CF pancreas. We have previously shown that both isolated rabbit pancreatic acini and the human pancreatic duct cell line PANC-1 possess a cAMP-activated Cl- conductance identified as CFTR. We report here that preincubation in either of the female hormones progesterone or beta-estradiol inhibits activation by cAMP, but not by Ca2+ ionophore, of PANC-1 cell volume reduction under isotonic conditions. cAMP-activated cell volume reduction is sensitive to antisense, but not sense, CFTR oligodeoxynucleotide. Furthermore, progesterone inhibits cAMP-activated Cl- efflux from rabbit acinar cells. Moreover preincubation with progesterone, but not beta-estradiol, reduces CFTR mRNA and protein levels as measured using polymerase chain reaction amplification of reverse-transcribed acinar RNA and Western blots of protein from acinar membranes. We conclude that female hormones inhibit CFTR functional activity in pancreatic epithelial cells by different mechanisms.
Differential regulation of hepatocyte DNA synthesis by cAMP in vitro in vivo
Authors: Westwick J. K. , Fleckenstein J. , Yin M. , Yang S. Q. , Bradham C. A. , Brenner D. A. , Diehl A. M.
Published: December 2017

Adenosine 3',5'-cyclic monophosphate (cAMP) prevents epidermal growth factor (EGF)-induced DNA synthesis in many types of cultured cells, including hepatocytes, but its effects on cellular proliferation in vivo are unknown. This study compares the effects of supplemental cAMP on hepatocyte proliferation induced in vivo by 70% partial hepatectomy (PH) and in vitro by EGF and determines the effects of cAMP on AP-1, a family of growth-regulatory transcription factors, and the kinase cascades that normally activate AP-1. Although injection of dibutyryladenosine 3',5'-cyclic monophosphate (30 mg/kgip) at the time of PH increased liver cAMP concentrations at least 100-fold for several hours, it did not inhibit hepatic incorporation of [3H]thymidine or proliferating cell nuclear antigen expression 24 h after PH. cAMP treatment led to a complete inhibition of extracellular signal-related kinase (ERK) activity and transiently reduced NH2-terminal Jun nuclear kinase (JNK) activity after PH but did not decrease the expression of c-jun mRNA or protein. Consistent with the known cAMP stimulation of jun-B in cultured cells, cAMP treatment increased jun-B mRNA, protein, and DNA binding activity post-PH. Surprisingly, cAMP treatment enhanced Raf kinase activity after PH in rats. In primary hepatocyte cultures, supplemental cAMP inhibited JNK and ERK activity, total AP-1 and c-Jun transcriptional activities, and DNA synthesis. Thus elevated cAMP inhibited ERK and JNK activity in culture and in vivo and inhibited hepatocyte proliferation in culture but not in vivo. This suggests that in vivo mechanisms compensate for cAMP inhibition of certain growth-related signaling cascades and emphasizes potential risks of extrapolating from simple cell culture systems to explain physiology in intact animals.
ATP-dependent transport of beta-estradiol 17-(beta-D-glucuronide) in rat canalicular membrane vesicles
Authors: Vore M. , Hoffman T. , Gosland M.
Published: December 2017

The ATP-dependent transport of beta-estradiol 17-(beta-D-glucuronide) (E217G), a cholestatic metabolite of estradiol, was investigated in rat liver canalicular membrane vesicles. ATP-dependent transport was dependent on time and temperature and occurred into an osmotically sensitive space; kinetic analysis indicated a saturable transport system (Michaelis-Menten constant value, 75 microM; maximum transport rate, 598 pmol.min-1.mg protein-1). The steroid conjugates estradiol glucuronide, estriol 3-glucuronide, estriol 16 alpha-glucuronide, testosterone glucuronide, and the three-sulfate conjugate of 17G were effective inhibitors of transport. Bromosulfophthalein, S-(2,4-dinitrophenyl)glutathione, and glutathione disulfide, all substrates of the canalicular ATP-dependent non-bile acid organic anion transport system, were also effective inhibitors, whereas taurocholate had no effect on transport. Conversely, E217G inhibited the ATP-dependent transport of S-(2,4-dinitrophenyl)glutathione. Daunorubicin, vinblastine, etoposide, cyclosporin, and PSC-833, substrates/modulators of P-glycoprotein, were also potent inhibitors of E217G transport, and E217G competitively inhibited the ATP-dependent transport of daunorubicin. C219, a monoclonal antibody against P-glycoprotein, inhibited ATP-dependent transport of E217G and daunorubicin but not of taurocholate or S-(2,4-dinitrophenyl)glutathione. These data indicate that E217G is substrate of both the non-bile acid organic anion transport system and P-glycoprotein but not of the ATP-dependent bile acid transport system in canalicular membranes.
Evidence that endogenous GRP in rat stomach mediates omeprazole-induced hypergastrinemia
Authors: Takehara Y. , Sumii K. , Tari A. , Yoshihara M. , Sumii M. , Haruma K. , Kajiyama G. , Wu S. V. , Walsh J. H.
Published: December 2017

To investigate the physiological role of endogenous gastrin-releasing peptide (GRP) in regulating the release of gastrin, we evaluated the response of intragastric pH, gastrin, and GRP after omeprazole treatment in rats. A significant elevation of the plasma level of GRP (P< 0.01) and a significant reduction of the antral content of GRP (P <0.05) were observed after the administration of 100 mg/kg omeprazole. The antral content of GRP was significantly decreased 12 h after omeprazole administration and thereafter gradually returned to control levels. Peak values for intragastric pH and plasma GRP were observed 3 h after omeprazole administration and before the peak of serum gastrin. The bombesin antagonist [D-Phe6]-bombesin-(6,13)-methyl ester significantly inhibited gastrin release after omeprazole treatment (P < 0.05). These observations indicate that omeprazole-induced inhibition of acid secretion stimulates the release of GRP and suggest that the secretion of GRP induced by omeprazole may stimulate the secretion of gastrin, at least in the early phase.
Canine H(+)-K(+)-ATPase alpha-subunit gene promoter: studies with canine parietal cells in primary culture
Authors: Muraoka A. , Kaise M. , Guo Y. J. , Yamada J. , Song I. , DelValle J. , Todisco A. , Yamada T.
Published: December 2017

H(+)-K(+)-adenosinetriphosphatase (H(+)-K(+)-ATPase) is the principal enzyme responsible for the process of gastric acid secretion. This enzyme is expressed in a cell-type-specific manner in gastric parietal cells. To explore the mechanisms regulating its expression, we transfected differentiated canine parietal cells in primary culture with H(+)-K(+)-ATPase-luciferase reporter genes and assessed transcriptional activities. Deletional analysis of the 5'-flanking region of this gene demonstrated a remarkable increment in transcriptional activity associated with a segment between bases -54 to -45 (5' GCTCCGCCTC 3') relative to the transcriptional initiation site. Gel shift assays with competition and supershift analysis demonstrated that this segment is specifically bound by the transcription factor Sp1. A point mutation, eliminating Sp1 binding, diminished basal transcriptional activity by 80%, indicating that this Sp1 binding site is important for constitutive transcriptional activity. Although these studies indicate that Sp1 is required to maintain a high concentration of the H(+)-K(+)-ATPase gene in the parietal cell, its cell-type-specific expression must rely on other elements because Sp1 is a ubiquitously expressed transcription factor.
Esophageal sensation in spinal cord-injured patients: balloon distension and cerebral evoked potential recording
Authors: DeVault K. R. , Beacham S. , Castell D. O. , Streletz L. J. , Ditunno J. F.
Published: December 2017

We sought to determine the esophageal sensory function in patients with a C6 or C7 spinal cord injury. A balloon was repetitively distended 10 cm above the lower esophageal sphincter in five patients and nine normal control subjects. Sensation was reported on a scale from 0 to 2 with progressive distension to pain threshold (level 2). Cortical responses were recorded from midline scalp electrodes. Blinded determinations of quality and reproducibility of the potentials were performed. All subjects experienced sensation with esophageal balloon distension. Volumes to sensation showed a trend toward a higher sensory threshold in patients but were significant only for first sensation, not pain. In all subjects, a triphasic evoked potential response consisting of a negative-positive-negative complex was noted with distension but not with sham distension. Characteristics (amplitude, latency, reproducibility, and quality) of the evoked potentials were not different in patient and control groups. These data suggest sensory pathways from the distal esophagus are intact in patients with a C6 or C7 spinal cord injury.
Structure, glycosylation, and localization of rat intestinal guanylyl cyclase C: modulation by fasting
Authors: Scheving L. A. , Russell W. E. , Chong K. M.
Published: December 2017

Guanylyl cyclase C (GC-C), an intestinal receptor guanylyl cyclase, binds diarrhea-producing bacterial ligands such as the Escherichia coli heat stable enterotoxin. We examined the regulatory influence of feeding and fasting on the expression, structure, and biochemical properties of GC-C. When solubilized at 4 degrees C under nonreducing conditions, GC-C from both fed and fasted rats migrated on 7% sodium dodecyl sulfate-polyacrylamide electrophoretic gels as two extremely large aggregates that barely penetrated the stacking and resolving gels. Chemical reduction of disulfide linkages disaggregated GC-C in fed but not fasted rat samples, causing it to migrate as smaller forms (approximately 220 and 240 kDa). Although GC-C aggregates from fasted rats resisted this disaggregating effect of chemical reduction, they rapidly acquired it within 90 min of refeeding. When solubilized at denaturing temperatures (95 degrees C) under reducing conditions, GC-C aggregates largely disassembled into four smaller proteins (relative molecular weight approximately 140,000, 131,000, 85,000, and 65,000). However, the 131-kDa glycoprotein was disproportionately increased in fasted rat membranes. This unit and the 220-kDa unit were sensitive to endoglycosidase H. Subcellular fractionation and immunohistochemical studies revealed a major redistribution of GC-C from surface to intracellular enterocyte sites during fasting.
Evidence for diminished visceral pain with aging: studies using graded intraesophageal balloon distension
Authors: Lasch H. , Castell D. O. , Castell J. A.
Published: December 2017

Graded intraesophageal balloon distension (IEBD) has been utilized in the past to evaluate esophageal pain thresholds. With use of a technique that we have found to provide reproducible results for pain thresholds, two groups of normal individuals without esophageal symptoms or diabetes were studied. Group 1 included 10 "young" (age < 65 yr) individuals (mean age 27 yr, range 18-57 yr). Group 2 included 17 individuals age 65 yr or greater (mean age 72.5 yr, range 65-87 yr). Catheters with latex balloons (Wilson-Cook) were used in all 27 subjects with the balloon located 10 cm above the lower esophageal sphincter. Sequential inflations of 2-ml increments were performed until a total volume of 2 ml above the point of pain or to a maximum of 30 ml was reached. A series of two sequential inflations were performed on each subject on the day of the testing, and the mean value was taken to indicate pain threshold volumes for all 27 subjects. In the group of elderly volunteers, 5 subjects felt no pain even at the maximum inflatable volume of the balloon (30 ml) and were assigned a maximum threshold value of 30 ml. Mean pain threshold volumes for the young subjects was 17 +/- 0.8 ml of air (+/- SE) and for the elderly subjects was 27 +/- 1.4 ml (P < 0.01 and 95% confidence interval = 7.1-13.3). Our conclusion is that IEBD results in the esophagus indicate an age-related decrease in human visceral pain threshold.
Tachykininergic mediation of viscerosensitive responses to acute inflammation in rats: role of CGRP
Authors: Julia V. , Bueno L.
Published: December 2017

Tachykinins, colocalized with calcitonin gene-related peptides (CGRP) in sensory afferents, are involved in viscerosensitive responses. We investigated the role of tachykinins and CGRP in both nociceptive and visceromotor responses to inflammation. Visceral pain was assessed by abdominal muscle contractions. Gastric emptying was evaluated after gavage with reconstituted milk containing 51Cr-labeled sodium chromate. Acetic acid or 9% NaCl was injected intraperitoneally before the meal. RP-67580, SR-48968, human CGRP [hCGRP-(8-37)], or their vehicles were injected before acetic acid or saline. RP-67580, SR-48968, or their vehicles were injected before CGRP and the meal. GR-73632 or GR-76349 was injected before the meal. Acetic acids inhibited gastric emptying and increased the number of abdominal contractions. RP-67580 reduced the inhibition of gastric emptying without affecting the abdominal response. SR-48968 only reduced the acetic acid-induced increase of abdominal contractions. hCGRP-(8-37) reduced both responses induced by acetic acid. CGRP mimicked the effects of acetic acid. RP-67580 abolished CGRP-induced gastric emptying inhibition, whereas SR-48968 only diminished visceral pain. GR-73632 reduced gastric emptying, and GR-64349 increased abdominal response. In inflammation, neurokinin receptors (NK1 and NK2) mediate the gastric emptying inhibition and visceral pain, respectively. These responses involve a release of CGRP.
Importance of vagus nerves in duodenal acid neutralization in anesthetized pigs
Authors: Glad H. , Svendsen P. , Olsen O. , Schaffalitzky de Muckadell O. B.
Published: December 2017

During the cephalic phase of gastric acid secretion, vagally mediated synchronous stimulation of bicarbonate provides protection against the acid. The purpose of this study was to determine simultaneously the effect of electrical vagal stimulation (EVS) on pancreatic, hepatic, and duodenal mucosal bicarbonate secretion, thereby estimating their relative importance in vagally induced duodenal acid neutralization. Splanchnicotomy increased vagally induced pancreaticobiliary bicarbonate secretion, whereas duodenal mucosal bicarbonate secretion was unchanged. After splanchnicotomy, EVS (10 ms, 15 mA, 12 Hz) significantly increased pancreatic bicarbonate secretion (0-4.17 mmol/h), hepatic bicarbonate secretion (0.16 to 0.22 mmol/h), and duodenal mucosal bicarbonate secretion (0.17 to 0.31 mmol/h). Pancreaticobiliary bicarbonate secretion was atropine resistant, whereas vagally induced duodenal mucosal bicarbonate secretion was diminished by atropine (2.0 mg/kg). After splanchnicotomy, EVS (10 ms, 15 mA, 12 Hz) had no effect on portal plasma concentration of secretin, whereas vasoactive intestinal peptide was increased (14-29 pM). EVS at 12 Hz with varying duration (3 or 10 ms) and amplitude (3-50 mA) had no further effect on the bicarbonate secretion from the three organs. In addition, biliary [14C]mannitol clearance was shown not to be a reliable marker of canalicular bile secretion in pigs. These results suggest that in the anesthetized pig 1) vagal stimulation is only of minor importance to hepatic bicarbonate secretion; 2) vagal stimulation activates pancreatic bicarbonate secretion through both cholinergic muscarinic and noncholinergic transmission; and 3) vagal stimulation induces duodenal mucosal bicarbonate secretion mainly through cholinergic muscarinic transmission. In conclusion, these results suggest that only pancreatic and duodenal bicarbonate production play a role in vagally induced duodenal acid neutralization.
Endogenous adenosine inhibits evoked substance P release from perifused networks of myenteric ganglia
Authors: Moneta N. A. , McDonald T. J. , Cook M. A.
Published: December 2017

Isolated myenteric ganglion networks were prepared from guinea pig ileum and were used in a perifusion protocol to examine the effects of interstitial adenosine on evoked release of substance P-like immunoreactivity (SPLI). The release of SPLI evoked by elevated extracellular K+ concentration was increased in the presence of tetrodotoxin (TTX), indicating tonic inhibition of SPLI release and revealing net inhibitory interganglionic transmission. Perifusion in the presence of the adenosine A1 receptor-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine enhanced evoked SPLI release, which was further enhanced in the additional presence of TTX, indicating that adenosine contributes some, but not all, of the overall inhibitory tone within the networks. In addition to neural release of adenosine per se, an additional source was investigated. Perifusion in the presence of alpha, beta-methylene-ADP plus guanosine 5'-monophosphate, which inhibits ecto-adenosinetriphosphatase (ATPase) activity, enhanced SPLI release, indicating that hydrolysis of released ATP contributes to the total interstitial nucleoside concentration and thereby to the overall inhibitory tone. It is concluded that endogenous adenosine, some of which arises from ATP metabolism, is an important contributor to the overall inhibitory tone present in myenteric ganglion networks.
Electrical responses of gastric smooth muscles in streptozotocin-induced diabetic rats
Authors: Xue L. , Suzuki H.
Published: December 2017

Electrical responses of gastric smooth muscles produced by transmural nerve stimulation, acetylcholine, norepinephrine, or K-free solution were investigated in streptozotocin-induced diabetic rats, using intracellular microelectrode techniques. In muscles from diabetic rats, 1) the resting membrane potential remained unchanged, 2) slow waves disappeared or were markedly reduced in amplitude, 3) the excitatory junction potential was absent, and in most cases only an inhibitory junction potential of reduced amplitude was elicited, 4) the amplitude of the hyperpolarization generated after superfusion with K-free solution was reduced, 5) the sensitivity of the acetylcholine-induced membrane depolarization was increased, and 6) the norepinephrine-induced hyperpolarization was reduced because of functional loss of alpha- and beta-adrenoceptors. Thus diabetes mellitus caused functional impairment of neuromuscular transmission, reduced the maximum activity of the electrogenic pump, increased the sensitivity of muscarinic receptors, reduced the sensitivity of adrenoceptors, and reduced the myogenic activity in gastric smooth muscles. These alterations in the properties of smooth muscle may be involved in the diabetes-induced gastroparesis.
Glutamine or glutamate release by the liver constitutes a major mechanism for nitrogen salvage
Authors: Remesy C. , Moundras C. , Morand C. , Demigne C.
Published: December 2017

The aim of the present study was to investigate mechanisms of N salvage by the liver when a diet is protein deficient. For this purpose, rats were adapted to a slightly deficient (11% casein) or moderately surfeit (22% casein) dietary protein level. Animals were sampled during the postprandial or the postabsorptive period, and fluxes across the digestive tract and liver were determined. During the postabsorptive period there was a negative balance of glutamine across the digestive tract in both diet groups. During the postprandial period the digestive balance of glutamine was still negative, despite a substantial supply of dietary glutamine and glutamate, suggesting that glutamine utilization is maximal during this period. There was a net production of glutamate and glutamine by the liver in both diet groups, but glutamine release was 73% higher in rats fed the low-protein diet. In these animals, because of the relatively low capacity of ureagenesis, N utilization was shifted toward glutamine synthesis: overall uptake of amino acids by the liver was approximately 5.3 micromol/min, and net release of glutamine + glutamate was approximately 2.9 micromol/min (hence a 55% cycling, on a molar basis). This cycling was only 12% in rats adapted to the 22% casein diet. When liver ammonia uptake was taken into account, N cycling showed parallel changes: 64% or 15% in rats adapted to the 11% or 22% casein diet, respectively. Besides glutamine delivery, glutamate was also released by the liver, representing an N source for extrasplanchnic tissues. With protein-deficient diets, hepatic glutamine delivery mainly serves to fulfill substrate needs for intestinal metabolism, which represents a mechanism for N salvage. This shift of N metabolism from urea toward glutamine production may imply a glutamate transfer from periportal to glutamine-synthesizing perivenous hepatocytes.
Acute pancreatitis in rats: effects of sodium taurocholate, CCK-8, and Sec on pancreatic microcirculation
Authors: Plusczyk T. , Westermann S. , Rathgeb D. , Feifel G.
Published: December 2017

With use of in vivo microscopy, pancreatic duct permeability, red blood cell (RBC) velocities, functional capillary density (FCD), and overall changes in capillary blood flow (perfusion index) were estimated after intraductal infusion of sodium taurocholate (0.8 ml, 4%) alone or in combination with systemic administration of cholecystokinin (CCK, 0.3 microg/100 g body wt) or secretin (Sec, 10 microg/100 g body wt). Sodium taurocholate mediated a significant increase in pancreatic duct and capillary permeability within 105 +/- 26 s followed by a transient decrease in RBC velocities and a sustained decrease in FCD, which were paralleled by dramatic flow heterogeneity. Therefore, a significant reduction in overall capillary blood flow was calculated. CCK stimulation aggravated the microcirculatory failure due to a decrease in RBC velocities, which was accompanied by an increase in acinar cellular necrosis. Sec stimulation attenuated microcirculatory failure due to a more moderate reduction of FCD. The enhanced pancreatic duct and capillary permeability, which enables free diffusion of pancreatic digestive enzymes into the parenchyma, is the initiating event in acute biliary pancreatitis, causing microcirculatory failure and tissue damage. The microcirculatory changes are secondary and a propagating factor for the development of acini necrosis. Stimulation with CCK worsened the course of acute biliary pancreatitis.
Newly synthesized cholesterol in human bile and plasma: quantitation by mass isotopomer distribution analysis
Authors: Empen K. , Lange K. , Stange E. F. , Scheibner J.
Published: December 2017

The purpose of this study was to quantitate the contribution of newly synthesized cholesterol to bile and plasma in humans. Eight healthy volunteers were intravenously infused with 0.125 mmol of [1-(13)C]acetate per kilogram per hour for 15 h. During continuous enteral nutrition, plasma aliquots and samples of duodenal bile were collected hourly. The trimethysilylether of unesterified cholesterol was analyzed by gas chromatography-mass spectrometry for quantitation of the mass fragments M(+0) [mass-to-charge ratio (m/z) 368], M(+1) (m/z 369), M(+2) (m/z 370), M(+3) (m/z 371), and M(+4) (m/z 372). The fractional syntheses of plasma and biliary cholesterol were determined using mass isotopomer distribution analysis. After 6 h of infusion, the 13C enrichment of the acetate pool remained constant at 12%. The fractional synthesis increased continuously during [13C]acetate infusion and reached 4.2% and 5.3% in cholesterol of plasma and bile, respectively. Both were highly correlated, but the fractional synthesis of biliary cholesterol exceeded that of plasma (P < 0.05). It may be concluded that the contribution of de novo cholesterol synthesis to bile exceeds that to plasma but is minor in humans.
Enhanced colonic Na+ absorption in cystic fibrosis mice versus normal mice
Authors: Grubb B. R. , Boucher R. C.
Published: December 2017

Because there are reports that electrogenic Na+ absorption is increased in colonic epithelia of cystic fibrosis (CF) subjects, we tested whether amiloride-sensitive Na+ absorption was increased in the colonic epithelia of CF mice compared with normal mice on high- or low-Na+ diets. When mice consumed a diet high in Na+, none of the colonic regions (distal colon, proximal colon, or cecum) from either group of mice exhibited an amiloride-sensitive short-circuit current (Isc). However, when mice were placed on a low-Na+ diet for 2 wk, all three intestinal regions from the CF mice exhibited a significant response to amiloride (P < or = 0.05). In contrast, normal mice on the low-Na+ diet exhibited an amiloride-sensitive Isc that was smaller and only significant in the cecum and distal colon. Measurement of plasma aldosterone levels revealed that the CF mice on the low-Na+ diet had significantly greater aldosterone levels than similarly treated controls [8,906 +/- 1,039 (n = 14) vs. 5,243 +/- 1,410 pg/ml (n = 14), respectively]. When mice were infused with a constant dose of aldosterone (1 microg x g(-1) x day(-1)) for 7 days, the distal colon of the CF mice still had a significantly greater amiloride-sensitive Isc than did the normal distal colon. If the presence of CF transmembrane conductance regulator (CFTR) down-regulates Na+ absorption in the colonic tissue from normal mice, our data suggest that at least some CFTR may be colocalized with the Na+ channel. Alternatively, other factors may be involved.
Duodenal and ileal nutrient deliveries regulate human intestinal motor and pancreatic responses to a meal
Authors: Keller J. , Runzi M. , Goebell H. , Layer P.
Published: December 2017

It is assumed that in humans pancreatic and gastrointestinal motor responses to a meal are coordinated and regulated mainly by duodenal nutrient exposure. On the other hand, there is evidence that the distal intestine may participate in the regulation of gastrointestinal functions. The aim of this study was to compare human pancreatic and intestinal motility responses to a meal and to correlate them with nutrient exposure of the proximal and distal intestine. After intubation with an oroileal multilumen tube for marker perfusion, duodenal and ileal aspiration, and intestinal manometry, 14 healthy subjects received a mixed test meal (1,257 kJ). Intraluminal nutrient concentrations, enzyme activities, and small intestinal motility were analyzed for 6 h postprandially. Duration of duodenal nutrient exposure was 3.4 +/- 0.2 h, and duration of pancreatic enzyme response and fed motor pattern was 2.5 +/- 0.2 and 3.5 +/- 0.3 h, respectively. Durations of pancreatic secretory and motor responses were correlated (P < 0.05), but neither duration of digestive secretory nor of motor activity correlated with that of prandial duodenal nutrient concentrations. By contrast, they were associated with the relative increase in ileal nutrient delivery late postprandially (P < 0.05). Physiological late postprandial delivery of nutrients to distal intestinal sites is correlated with the termination of digestive pancreatic and motor responses and may participate in their control.
Different pathways mediate cholecystokinin actions in cholelithiasis
Authors: Chen Q. , De Petris G. , Yu P. , Amaral J. , Biancani P. , Behar J.
Published: December 2017

Smooth muscle from gallbladders with cholesterol stones exhibits impaired response to cholecystokinin (CCK). This study investigated whether the impaired response is mediated by different signal-transduction pathways responsible for CCK-induced contraction in prairie dog and human gallbladders with cholesterol stones. Gallbladder muscle cells were isolated enzymatically to study contraction. Protein kinase C (PKC) activity was measured by examining the phosphorylation of a specific substrate peptide from myelin basic protein Ac-MBP-(4-14). Gallbladder muscle cells from high-cholesterol-fed prairie dogs contracted less in response to CCK octapeptide (CCK-8) than those from the control group. However, inositol-1,4,5-trisphosphate (IP3), diacylglycerol, and guanosine 5'-O-(3-thiotriphosphate) induced the same magnitudes of contraction in these two groups. In control prairie dog and human gallbladders, the maximal contraction caused by 10(-8) M CCK-8 was blocked by the calmodulin antagonist CGS9343B but not by the PKC inhibitor H-7. Conversely, in gallbladders with cholesterol stones from prairie dogs or human patients, the maximal contraction induced by 10(-8) M CCK-8 was blocked by H-7 and chelerythrine but not by CGS9343B. In these gallbladders CCK-8 caused a significant PKC translocation from the cytosol to the membrane. High CCK concentrations may activate the calmodulin-dependent pathway in functionally normal gallbladder muscle and the PKC-dependent pathway in muscle from gallbladders with cholesterol stones. The defect of gallbladder muscle after cholesterol feeding and stones might reside in the steps before G protein activation.
Cytokine regulation of fibroblast growth factor receptor 3 IIIb in intestinal epithelial cells
Authors: Kanai M. , Rosenberg I. , Podolsky D. K.
Published: December 2017

Proliferation and function of the intestinal epithelium is modulated by a range of regulatory peptides, including cytokines and peptide growth factors. To define mechanisms integrating these regulatory systems, the effects of growth factors and cytokines on the expression of the fibroblast growth factor (FGF) receptor 3 (FGFR3) IIIb expressed on intestinal epithelial cells were examined in Caco-2 cells. Regulated expression of FGFR3 IIIb was associated with acquisition of the differentiated state. Keratinocyte growth factor (KGF), a ligand of another member of the FGF receptor family, enhanced expression of FGFR3 IIIb, but acidic FGF, the ligand for FGFR3 IIIb itself, had no effect. Epidermal growth factor and transforming growth factor-beta also markedly enhanced FGFR3 IIIb expression in a different temporal pattern. In addition, FGFR3 IIIb expression was increased 10-fold by the cytokine interleukin-2. These studies demonstrate integration between cytokines and growth factor ligand-receptor systems in intestinal epithelial cells.
Constitutive NOS isoforms account for gastric mucosal NO overproduction in uremic rats
Authors: Mendez A. , Fernandez M. , Barrios Y. , Lopez-Coviella I. , Gonzalez-Mora J. L. , Del Rivero M. , Salido E. , Bosch J. , Quintero E.
Published: December 2017

To study whether renal failure enhances gastric mucosal nitric oxide (NO) formation in the rat, we measured 1) in vivo NO concentration and 2) NO synthase (NOS) activity, content, and mRNA expression in gastric mucosal homogenates of uremic and sham-operated anesthetized rats. Gastric mucosal NO release was measured by an electrochemical technique. NOS content was analyzed by Western immunoblots, using specific monoclonal antibodies. Constitutive (Ca2+ dependent; cNOS) and inducible (Ca2+ independent; iNOS) NOS activities were assayed by following the conversion of L-[U-14C]arginine to [U-14C]citrulline. mRNA expression for the constitutive neuronal (ncNOS), endothelial (ecNOS), and iNOS isoforms was determined by reverse transcription-polymerase chain reaction. Under basal conditions, gastric mucosal NO concentration was significantly greater in uremic compared with control rats. This was accompanied by significantly greater gastric mucosal cNOS activity in uremic rats than in control rats, whereas no differences were observed in iNOS activity between both groups of animals. Moreover, total enzyme content and the levels of gastric mucosal mRNA expression for ncNOS, ecNOS, and iNOS showed no significant differences between uremic and sham-operated rats. These data confirm that, in uremic rats, enhanced Ca2+-dependent NOS activity is responsible for gastric mucosal NO overproduction and suggest that the main regulatory mechanism is not transcriptional but translational and/or posttranslational in nature.
Sumatriptan, a selective 5-HT1 receptor agonist, induces a lag phase for gastric emptying of liquids in humans
Authors: Coulie B. , Tack J. , Maes B. , Geypens B. , De Roo M. , Janssens J.
Published: December 2017

Sumatriptan, a 5-hydroxytryptamine1 (5-HT1) receptor agonist at enteric neuronal 5-HT receptors, causes a relaxation of the gastric fundus and inhibition of antral contractile activity. The present study examined the effect of sumatriptan on gastric emptying of solids and liquids in humans. In eight healthy subjects the gastric emptying rate for liquids and solids was measured using the carbon-labeled glycine and octanoic acid breath test after subcutaneous administration of placebo or sumatriptan. Sumatriptan increased the gastric half-emptying time of liquids (P < 0.0005) and induced a prolonged lag phase for liquids (P < 0.0005) in all subjects. Sumatriptan increased gastric half-emptying time (P < 0.005) and the lag phase of solids (P < 0.05) in all subjects. In two healthy subjects gastric emptying of liquids and solids after subcutaneous administration of sumatriptan was studied by radioscintigraphy. Radioscintigraphy confirmed the delayed emptying and the prolonged lag phases after sumatriptan. In conclusion, sumatriptan delays gastric emptying of solids and liquids in healthy subjects. Moreover, sumatriptan induces a lag phase for liquids. The mechanism by which sumatriptan alters gastric emptying remains to be studied.