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Context: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments., Objective: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media., Methods: The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIF mod ) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant., Results: Fa/FeSSIF mod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations., Discussion: The compatibility of Fa/FeSSIF mod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo., Conclusion: The optimized setup uses FaSSIF mod as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.

Objective: There is a need for a technique allowing studies of human mucosal specimens collected during different clinical conditions. This study elucidates if square wave pulse analysis discriminates between epithelial and transmural electrical resistance and if there is an association with transepithelial permeability of molecular probes., Methods: Mucosae from esophagus (surgical resections: n = 14; endoscopic biopsies: n = 15) and jejunum (n = 12) and Caco-2 cell monolayers were investigated in Ussing chambers. Transmural and epithelial electrical resistance were recorded by the use of standardized current pulses. Permeability was assessed using two fluorescein-labeled probes (weight 376 and 4000 Da)., Results: Baseline epithelial electrical resistance was higher in esophageal mucosa (~280 Ω*cm(2)), than in jejunal (~10 Ω*cm(2)) and Caco-2 cells (~140 Ω*cm(2)). The subepithelial contribution to the transmural resistance was higher in jejunal preparations (+88%) and Caco-2 cells (+75%), than in esophageal (+30%). During hypoxia the subepithelial resistance was unchanged, whereas the epithelial resistance decreased significantly in jejunal mucosa and Caco-2 cells. These findings coincided with increased transepithelial probe permeability and signs of disturbed morphology. Esophageal epithelia were resistant to hypoxia. However, exposure to deoxycholic acid and trypsin abolished the esophageal epithelial resistance and increased probe permeability. Endoscopic esophageal biopsies from patients with erosive reflux disease exhibited significantly lower epithelial resistance and higher current than healthy subjects., Conclusion: Square wave pulse analysis in Ussing chambers is suitable for assessment of epithelial electrical resistance that can reflect transepithelial permeability of molecular probes with known size. Moreover, the technique discriminated between healthy and reflux-diseased esophageal mucosal biopsies.

Circadian clocks were recently discovered in the rat and mouse colon as well as mouse stomach and jejunum. The aim of this study was to determine whether clocks in the upper part of the gut are synchronized with those in the lower part, or whether there is a difference in their circadian phases. Moreover, the profiles of core clock-gene expression were compared with the profiles of the clock-driven Wee1 gene expression in the upper and lower parts of the gut. Adult rats were transferred to constant darkness on the day of sampling. 24 h expression profiles of the clock genes Per1, Per2, Rev-erbalpha, and Bmal1 and the cell-cycle regulator Wee1 were examined by a reverse transcriptase-polymerase chain reaction within the epithelium of the rat duodenum, ileum, jejunum, and colon. In contrast to the duodenum, the rhythms in expression of all genes but Rev-erbalpha and Bmal1 in the colon exhibited non-sinusoidal profiles. Therefore, a detailed analysis of the gene expression every 1 h within the 12 h interval corresponding to the previous lights-on was performed. The data demonstrate that rhythmic profiles of the clock gene Per1, Per2, Bmal1, Rev-erbalpha, and clock-driven Wee1 expression within the epithelium from different parts of the rat gut exhibited a difference in phasing, such that the upper part of the gut, as represented by the duodenum, was phase-advanced to the lower part, as represented by the distal colon. Our data demonstrate that the circadian clocks within each part of the gut are mutually synchronized with a phase delay in the cranio-caudal axis. Moreover, they support the view that the individual circadian clocks may control the timing of cell cycle within different regions of the gut.

Hemolink, an oxidized, ring-opened raffinose-crosslinked hemoglobin-based oxygen carrier produced by Hemosol Inc., stimulates esophageal peristalsis, possibly by interference with neural NO-mediated effects. The effects of Hemolink on jejunal tone and contractions, arterial pressure and heart rate were measured in anesthetized rats, and the effect of selected agents in attenuating or reversing these effects was studied. Infusion of L-NAME was used to validate the study model; it caused an immediate increase in tone and initiated phasic contractions indicating that the model was responsive to NO-mediated effects. Hemolink administration caused effects on intestinal motor function similar to those caused by L-NAME, including increases in basal tone and contraction amplitude. Rat whole blood caused none of these changes. The Hemolink-induced effects were less immediate in some animals compared to those observed after L-NAME. As well there was greater inter-animal variability on the effects. Hemolink administration also caused a mild increase in arterial blood pressure and a reciprocal decrease in heart rate in some animals. Co-administration of morphine, a common analgesic that has been reported to influence the motility of the GI tract; L-arginine, a substrate for NO synthesis; and glycopyrrolate, an anti-cholinergic agent, did not significantly modulate the Hemolink effects, whereas nitroglycerin, an NO donor; and nifedipine, a slow calcium-channel blocker, attenuated or reversed these effects.

Background: Although some symptoms of Crohn's disease may be related to gastrointestinal motility disorders, studies on gastrointestinal motility in inactive Crohn's disease are lacking., Methods: Fasting and postprandial motor activity (1 h) was recorded in the gastric antrum and upper small intestine of 35 patients with inactive Crohn's disease and 18 controls, using conventional manometry., Results: Motor disorders were observed in 26 of 35 patients. The number of phase-II contractions was reduced (1.3 +/- 0.7/min versus 1.8 +/- 0.6/min in controls; P < 0.02) (mean +/- standard deviation), whereas the incidence of propagated single (2.2 +/- 3.2/h versus 0.5 +/- 0.6/h; P < 0.03) and clustered contractions (3.8 +/- 7/h versus 1.1 +/- 1.4, P < 0.04) was markedly increased. Motor abnormalities were more frequent and severe in patients with Crohn's ileitis than in controls, and in patients with gastrointestinal symptoms than in asymptomatic patients., Conclusion: Most patients with inactive, uncomplicated Crohn's disease show marked gastrointestinal motor disorders, characterized either by reduced incidence of small-bowel contractions and increased incidence of single or clustered propagated contractions.

Background: Exocrine pancreatic secretion is regulated by luminal factors, bile-pancreatic juice (BPJ), and food chyme. The effects of 10 days' chronic deprivation of luminal chyme on the stimulation of exocrine pancreatic secretion by dietary protein were examined in rats with or without BPJ in the jejunum., Methods: The jejunum was deprived of ingested food by preparing a whole-jejunum blind loop. The BPJ was diverted by a common bile-pancreatic duct catheter and was returned to the upper jejunum (with BPJ) or ileum (without BPJ)., Results and Conclusion: In rats with the ingested food and BPJ in the jejunum (control), secretion rates in terms of volume, protein, amylase, and trypsin increased more than twofold from the rates in the fasting state after a jejunal injection of peptic hydrolysate of casein. In contrast, the secretions were not increased by the protein injection in the rats deprived of jejunal chyme with or without BPJ in the jejunum. Even in the chyme-deprived group the protein and trypsin secretion of the fasting state was significantly higher in BPJ-diverted rats than in rats with BPJ. These results showed that chronic deprivation of the jejunal chyme impaired responses of the exocrine pancreas to dietary protein but not the hypersecretions of the pancreas by BPJ diversion.

Background: Motility disorders are believed to be of major pathogenetic importance in small-intestinal bacterial overgrowth (SIBO). The aim of this study was to investigate interdigestive and postprandial motility in a group of patients with SIBO and to compare the results with those of healthy volunteers., Methods: Twenty healthy subjects and 14 patients with SIBO were included. Exclusion criteria were obvious predisposing conditions. Antroduodenojejunal pressure recording was performed after an overnight fast. After a 5-h interdigestive recording a standard meal was given, and postprandial recording performed for 30 min., Results: Significantly fewer patients than healthy subjects had phase-III activity in the antrum (3 of 14 versus 15 of 20; P < 0.01), and more patients lacked phase III completely (5 of 14 versus 0 of 20; P < 0.05). Propagated single contractions in the proximal duodenum during late phase II and postprandially were also significantly reduced (1 (0-5) versus 8 (5-12) per 30 min (median; interquartile range (IQR)) (P < 0.01) and 0.5 (IQR, 0-6.5) versus 8 (IQR, 6-13) per 30 min (P < 0.01), respectively). In the distal part of the duodenum the patients had significantly prolonged duration of phase III (7.8; IQR, 5.6-9.2 versus 5.9; IQR, 4.2-6.6 min) (P < 0.05) and increased motility index of phase III (6685; IQR, 4870-9999 versus 3605; IQR, 2579-5544 mm Hg x min/30 min) (P < 0.05), late phase II (10,285; IQR, 6105-11,384 versus 6650; IQR, 4639-9102) (P < 0.05), and postprandially (12,960; IQR, 8454-18,644 versus 7917; IQR, 6132-10,551) (P < 0.05). Retrograde contractions predominated in the late part of phase III in the proximal duodenum in both groups. The cycle length of the MMC and the number of clustered contractions showed no difference between the two groups., Conclusions: A significant proportion of patients with SIBO, compared with healthy subjects, lack interdigestive phase-III activity, not only in the small intestine but also in the gastric antrum. They also have fewer propagated contractions in the proximal duodenum during interdigestive phase II. On the other hand, the motility index in the distal part of the duodenum was higher in patients with SIBO during phase III, late phase II, and postprandially. The results are compatible with a reduced clearing function in the stomach and proximal duodenum and/or a compensatory increase of motility in the region of the duodenojejunal flexure.

Tissue oxygen measurements were evaluated as a monitor of the jejunal flap in seven female landrace pigs. A small polarographic sensor (diameter 0.55 mm) was used in which interstitial tissue oxygen tension was measured continuously in a jejunal flap and a muscle flap (rectus abdominis) during arterial and venous occlusion. Mean (SEM) tissue oxygen tension in the two types of flap were 44(9) mmHg (jejunal flap) and 47(8) mmHg (rectus flap). After arterial occlusion for 30 minutes the values dropped to 17(4) mmHg for the jejunal flap and 12(2) mmHg for the muscle flap. The decline became significant after five minutes. During venous occlusion (30 minutes) the values fell to 20(4) mmHg and 14(1) mmHg. The arterial occlusion was undetectable by the naked eye, but the enteric tissue after venous occlusion became severely congested and blue-black in colour. The condition returned to normal after release of the clamp. We conclude that direct measurement of tissue oxygen tension in a jejunal flap is a reliable method of detecting impaired perfusion. This method may in the future be used to monitor vascularised jejunal autografts.

Background: The last part of duodenal phase III of the migrating motor complex behaves as a retroperistaltic pump. We have compared the phase-III-like gastroduodenojejunal activity induced by erythromycin with the naturally occurring phase III, focusing on peristaltic patterns. The effect of two doses of erythromycin, 3 mg/kg/h and 12 mg/kg/h (in four subjects), or saline, given intravenously for 15 min, was studied in nine fasting healthy subjects (five men and four women)., Methods: Motility was recorded on three different days. On one day standard 5-h eight-channel antroduodenojejunal manometry was performed and saline infused 30 min after the first phase III. On the other two study days, erythromycin in the low or the high dose was infused and recording performed for another 2-h period., Results: The low dose of erythromycin induced a phase III in the stomach in all subjects within 12.8 +/- 1.4 min. In contrast, the higher dose did not induce phase-III activity within the 1st h after infusion but induced marked antral pressure waves. The duration of the erythromycin-induced phase III and the naturally occurring antral phase III was 4.7 +/- 1.7 and 1.9 +/- 0.3 min, respectively (p < 0.01). The duration of the erythromycin-induced phase III in the proximal jejunum was 44% shorter than the spontaneous one (p < 0.01). The propagation velocity, from the proximal duodenum to the proximal jejunum, of the erythromycin-induced phase III was slower than that of the spontaneous phase III: 5.7 +/- 0.9 and 15.9 +/- 3.9 cm/min, respectively (p < 0.01). In the proximal duodenum the proportion of retrograde pressure waves (of all propagating waves) was about 10% in early phase III, increasing to about 85% in late phase III in both the spontaneous and erythromycin-induced phase III. In the proximal jejunum retrograde pressure waves were not observed in phase III., Conclusions: Erythromycin given in a low dose is very effective in inducing phase-III-like motility. The last part of duodenal phase III is characterized by retroperistalsis also when this motility phase is induced by erythromycin.

In chronic experiments in dogs the evacuatory and absorptive duodenal functions and the level of duodenogastric reflux (DGR) in sham-operated dogs and dogs with transected Treitz ligament (TL) and resected duodenojejunal junction (DJJ) were studied. The electrophysiologic characteristics of the antrum, duodenum, and DJJ in sham-operated dogs were examined. It was shown that there is a coordination of gastric and duodenal solid carbohydrate food emptying. The process of evacuation from both organs was characterized by three closely correlated phases, phase 2 of emptying being exponential. In the TL transection and DJJ resection groups the coordination of gastric and duodenal emptying disappeared. The rate of carbohydrate solid food evacuation from the duodenum decreased, on average, by 45.5% +/- 5.5% (P < 0.05); phase 2 of duodenal emptying became unexponential, and the level of DGR considerably increased. The rate of duodenal absorption of main organic chyme components increased significantly in most of the time intervals studied. Significantly higher amplitudes of slow waves and spike potentials were recorded from the DJJ than from the duodenum. We conclude that the DJJ and TL are possible regulators of duodenal emptying. The DJJ is probably a functional sphincter that provides coordinated activity of the stomach and duodenum.

Psychologic stress may be a provoking factor in the alterations in phase-2 motor activity of the migrating motor complex (MMC) which have been recorded in patients with the irritable bowel syndrome (IBS). To test this, changes in phase-2 duodenojejunal motor activity during 20 min of psychologic stress in 10 patients with IBS were compared with those shown by 10 healthy subjects. Autonomic arousal in response to the stressor was assessed by cardiovascular responses and self-reported levels of anxiety and tension. IBS and controls showed a significant cardiovascular and subjective response to stress which was comparable in the two groups. In general, duodenal phase-2 motor activity was suppressed during stress in both IBS and controls. Jejunal motor activity showed a similar inhibitory response in both groups, but the change in motility index was significant for controls only. Qualitatively, stress did not cause clustered contractions in either the IBS or the control group. However, in IBS patients with clustered contractions in the basal period there was inhibition of this pattern during stress. These findings suggest that acute psychologic stress profoundly suppresses, rather than enhances, duodenojejunal MMC phase-2 motility in healthy subjects. IBS patients, irrespective of their underlying phase-2 motor pattern show similar, although less marked, changes in motility.

The effect of fat emulsion in the upper intestine on the maximal gastric acid response to pentagastrin was studied in chronic gastric fistula (GF) rats with a 4-cm blind loop of the duodenum anastomosed to the jejunum (Roux-en-Y). Fat emulsion in the loop inhibited the acid response by 85%. To localize the site of the inhibitory mechanism, GF rats were provided with Thirty-Vella loops of the duodenum (bile and pancreatic ducts transplanted to the proximal jejunum) or with Thirty-Vella loops of the proximal jejunum and a Roux-en-Y loop of the duodenum to prevent gastric juice from entering the duodenum. Perfusion of the duodenal loop with fat emulsion mixed with bile and pancreatic juice reduced the acid response by 49%, but perfusion of the proximal jejunal loop did not alter the response. It is concluded that the intestinal mechanism for inhibition of acid secretion by fat is located in the duodenum in rats.

In order to study the importance of the presence of food in the intestinal lumen during the process of adaptation occurring after diminished absorptive surface, four groups of rats were operated upon. In two experimental groups a jejuno-ileal bypass was created, which excluded about 85% of the small intestine. The two control groups underwent laparotomy and suture-marking of the intestine. One experimental and one control group received standard oral nutrition. The other two groups were solely nourished by total parenteral nutrition (TPN). Two weeks after operation the animals were sacrificed; intestinal wet and dry weight per 3 cm and villus height were determined from five small intestinal segments. The functioning part of the small intestine of the shunt-operated animals was hypertrophic in both the orally fed and the TPN groups as compared with the sham-operated controls with the corresponding nutrition. The hypertrophy comprised significant changes of wet and dry weight and villus height. These values were, however, more increased in the orally fed animals, expressed in absolute figures. The percentual increase of villus height was greater in the TPN animals. The experiments demonstrated that rats with adequate parenteral nutrition two weeks after 85% small intestinal bypass operation develop hypertrophic changes of the intestinal mucosa. This indicates the existence of a non-food-dependent mechanism in the development of adaptive mucosa changes, nevertheless the presence of food seems to stimulate quantitatively higher changes. The presence of food is also of importance for maintaining the intestinal mass.

In a previous communication we demonstrated that pentagastrin-induced gastric acid secretion is strongly and equally inhibited by intrajejunal infusions of hypertonic glucose, hypertonic sodium chloride, and triglycerides. Samples of peripheral venous blood obtained during these experiments were now analysed for insulin, glucose, pancreatic glucagon, and enteroglucagon. Pancreatic glucagon was stimulated weakly only by triglycerides. Enteroglucagon secretion was strongly stimulated by glucose, moderately by triglycerides, and unaltered after sodium chloride. Insulin secretion was stimulated only during the glucose infusion. We concluded that enteroglucagon is not responsible for the jejunal inhibition of gastric acid secretion in man by jejunal administration of hyperosmolal NaCl solution but may participate in the inhbition evoked by jejunal administration of glucose of triglycerides. Furthermore, it is unlikely that enteroglucagon is in itself insulinogenic in man.

The effect of long-term oral trypsin inhibitor administration on the exocrine pancreas was studied in unoperated rats and in rats operated on by a 30% proximal small intestinal resection. The following observations were made: in unoperated rats sacrificed 18 hours after the last trypsin inhibitor ingestion there was an increase of the wet weight of pancreas, increase of the pancreatic protein, and an increase of pancreatic and intestinal trypsin(ogen) and of pancreatic amylase by comparison with the controls. In operated rats, treated and examined in an identical way, no influences on the exocrine pancreas were found. It is suggested that the abolishment of the trypsin inhibitor effects on the exocrine pancreas in operated rats reflects the removal of the site of production of one or more intestinal hormone(s) or factor(s) responsible for these effects. In unoperated rats examined 4 hours after the last trypsin inhibitor ingestion a reduction of the pancreatic trypsinogen and amylase and an increase of the intestinal amylase were found, indicating a secretory response of the pancreas to the intraluminal trypsin inhibitor; the low values of intestinal trypsin found in these rats probably reflect inhibition of rat trypsin by the bovine lung trypsin inhibitor.

Endoluminal release of serotonin (5-HT), substance P (SP), and motilin was quantitated after thoracic vagal nerve stimulation in the cat. In duodenum and jejunum, simultaneous release of these compounds was observed. In contrast, vagal stimulation did not augment the rate of luminal secretion of either 5-HT or SP in the distal ileum. Immunohistochemical studies demonstrated 5-HT in both enterochromaffin (EC) cells and nerves throughout the small bowel. However, we were unable to visualize any SP-containing EC cells in the cat, which suggests that the source of luminal SP in this species must be intramural nerves.

In five patients in whom a jejuno-ileal by-pass had been previously performed for massive obesity, a relaparotomy was performed because of subjective complaints or unsatisfactory weight reduction. At the reoperation morphometric studies were made of the functioning segments and the by-passed intestine. Length and circumferential measurements were taken, and the villous height and mucosal thickness were measured from histological biopsies. The results were compared with the findings in a control group. After shunt operation adoptive hypertrophy in the functioning remnant, a considerable length growth and dilatation of the gut, as well as a marked increase in villous height and total mucosal thickness, were demonstrated. These adaptive changes seem to be more marked in the distal part of the small intestine. No atrophy of the mucosa could be demonstrated in the excluded intestinal loop.

Three groups of rats were twice given cysteamine subcutaneously in a dose of 20 mg/100 g body weight. Nine of 10 controls developed severe duodenal ulcers. In contrast, the ulcer formation was inhibited significantly in the rats submitted, before exposure to cysteamine, to a bile diversion operation consisting of jejunopylorostomy and Roux-en-Y anastomosis without gastric resection. However, rats submitted to the same operation but drinking a solution with 5 mmol/l sodium salts of taurocholic and glycocholic acid, 1:3, developed severe duodenal ulcers after cysteamine injections (8 of 10). The conclusion is that neither the chemical cysteamine nor hydrochloric acid alone can be made responsible for cysteamine-induced duodenal ulcer in the rat, but that bile salts clearly enhance the ulcerogenic property of cysteamine.

The effect of rioprostil, a PGE1 analogue, on the interdigestive motility of the upper human small intestine was investigated in 8 normal volunteers in a double-blind, placebo-controlled study. Rioprostil was administered intraduodenally in a dose of 600 micrograms. The myoelectrical activity was recorded simultaneously at 8 different levels of the jejunum, at 10 cm intervals. Rioprostil, 600 micrograms, does not disrupt the migrating motor complex (MMC) and does not change the characteristics of phase 3 of the MMC, except for an increased propagation velocity. The main effect of rioprostil, 600 micrograms, is a marked inhibition of phase 2 contractions without induction of propulsive motility patterns during phase 2. This may explain why rioprostil in a dose of 600 micrograms is not markedly diarrheogenic in man.

The effect of intrajejunal (i.j.) infusion of fat on meal-stimulated gastric acid secretion and release of pancreatic glucagon (PG), enteroglucagon (EG), gastric inhibitory polypeptide (GIP), and vasoactive intestinal polypeptide (VIP) was studied in seven healthy volunteers. I.j. fat markedly inhibited meal-stimulated acid secretion as compared to a control study with i.j. saline infusion. The acid inhibition was accompanied by augmental plasma concentrations of EG, GIP, and VIP but not of PG, suggesting that EG, GIP, and VIP may be among mediators of fat-induced jejunal inhibition of acid secretion. Concentration-time relationship makes it unlikely that the observed inhibition could be ascribed to any single peptide studied.

Effects of hypoxia and pH alterations on the spontaneous contractions and responses to cholinergic stimuli or KCl were investigated in isolated human intestines. The longitudinal strip of human intestine showed spontaneous contractions. The spontaneous contraction was abolished by hypoxia with nitrogen gas substitution (95% N2 and 5% CO2) but not by substitution with acidic (pH 6.53) or alkaline (pH 7.75) solution. Contractile responses to acetylcholine (ACh) were not altered by treatment with hypoxia or pH alterations. KCl (10 mM)-induced contraction was inhibited by hypoxia but not by pH alterations. Transmural electrical stimulation elicited a transient contraction that was blocked by tetrodotoxin or atropine. Contractions induced by electrical stimulation at a low frequency (5 Hz) was not altered by hypoxia or pH alterations. The metabolic pathway related to energy generation and utilization for the spontaneous contraction and KCl-induced contraction seems to be more dependent on oxygen supply than that for ACh-induced contraction. The contractile mechanism in human intestine seems to be resistant to pH alterations.

The intestinal myoelectric effects of four motor-stimulating drugs were compared in conscious dogs. Dogs were fed a standardized 400-kcal meal, and the myoelectric activity was monitored before and after drug administration. Graded doses of metoclopramide, cisapride, bethanechol, and cholecystokinin (CCK) were compared by means of a computer program to identify spike bursts and determine their frequency, duration, and length of migration. Bethanechol and CCK produced the greatest increase in myoelectric activity in terms of spike burst frequency and duration but the least in terms of length of spike burst spread. Metoclopramide had minimal measurable myoelectric effects. Cisapride had the greatest effect on the length of spike burst migration but little effect on spike burst frequency and duration. The results suggest that cisapride is a more efficient prokinetic agent than bethanechol, CCK, or metoclopramide. The greater length of spike burst spread caused by cisapride was associated with a more rapid rate of transit along the monitored segment of bowel when compared with control. This confirms the correlation between length of spike burst spread and propulsive efficiency.

Four mongrel dogs were prepared with a Heidenhain pouch, a gastric fistula, and a 90-cm-long Thiry-Vella loop. After recovery, dose-response curves were obtained with different doses of pentagastrin, and the maximal acid output was determined. The jejunal loop was perfused for 3 h with either 5% liver extract or with 0.15 M NaCl at a rate of 114 ml/h. To verify that the stomach could release gastrin and that the assay could detect that change, antral perfusion with liver extract was performed. Serum gastrin levels and acid output were measured every 30 min. Perfusion of the jejunal loop with liver extract resulted in a significant increase in acid output from the Heidenhain pouch and the gastric fistula, whereas perfusion with saline solution failed to show any changes. The magnitude of acid response from the Heidenhain pouch and gastric fistula was 11% and 18%, respectively, as compared with maximal pentagastrin stimulation. The serum gastrin levels remained unchanged during both liver extract and saline perfusion of the jejunal loop, in contrast to the marked increase in serum gastrin level after antral perfusion. The results confirm the existence of the intestinal phase of gastric acid stimulation in dogs as an entity and show that the magnitude of this phase is significantly lower than has been suggested by results of earlier studies. Furthermore, the results suggest that the intestinal phase of gastric secretion in dogs is most probably elicited through a humoral agent other than gastrin.

The physiological significance of neurotensin, with respect to gut motility in man, may be to mediate postprandial, fat-induced changes in the motility pattern of the gastrointestinal tract. There is strong experimental evidence that this effect of neurotensin is endocrine-mediated. The role of neurotensin as a paracrine hormone, neurotransmitter or neurocrine hormone remains to be determined.

Four mongrel dogs were prepared with a Heidenhain pouch, a gastric fistula, and a 90-cm-long Thiry-Vella loop. After recovery, the jejunal loop was perfused for 3 h with either 5% liver extract or with 0.15 M NaCl, and measurements of gastric acid and pepsin secretion and serum gastrin levels were performed. The experiments were repeated during beta-adrenergic blockade induced by intravenous infusion of propranolol in a dose of 20 micrograms/kg/min. As control, propranolol was also given alone without intestinal perfusion. Perfusion of the jejunal loop with liver extract caused a significant acid secretion from the Heidenhain pouch and gastric fistula. In addition, significant pepsin secretion was obtained, but only from the gastric fistula. The serum gastrin levels remained unchanged during intestinal perfusion. Beta-adrenergic blockade did not influence any of these measurements. The results suggest that the intestinal-phase hormone also stimulates pepsin secretion in dogs. Furthermore, it seems that neither the release nor the action of this hormone is controlled by the beta-adrenergic nerves in the gut.

In chronic gastric fistula (GF) rats, HCl and a hyperosmolal solution of polyethylene glycol (PEG) in the upper intestine inhibit pentagastrin-stimulated gastric acid secretion by different mechanisms, but their anatomic sites have not yet been established. In the present study GF rats were provided with Thiry-Vella loops of the duodenum and the bile and pancreatic ducts transplanted to the proximal jejunum, or with Thiry-Vella loops of the proximal jejunum. In the latter rats the duodenum was anastomosed as a blind loop to the jejunum to prevent any gastric juice from entering the duodenum. Duodenal loop perfusion with 0.20 M HCl inhibited the acid response to pentagastrin by 62%, but perfusion with 1200 mOsmol x kg-1 of PEG solution did not alter the response. In contrast, acidification of the proximal jejunal loop did not alter but hyperosmolality inhibited the response by 41%. The study shows that the mechanism for inhibition by intestinal acidification is confined to the duodenum and that for inhibition by hyperosmolality is located in the proximal jejunum--but whether only to the proximal part is unknown.

Myoelectric activity induced by a synthetic analogue of the duodenal polypeptide motilin, was studied in isolated vascular-perfused canine duodenum and stomach, and in conscious dogs with serosal electrodes implanted in the stomach and the small intestine. In the isolated preparation, the duodenum was found to be four times as sensitive as the antrum to the polypeptide, showing a dose-dependent increase in spike activity within two minutes after administration of the polypeptide. By contrast, in the conscious fasted animal, the only response to motilin, above a threshold dose, was the interpolation of a premature migrating myoelectric complex in the spontaneous interdigestive sequence, appearing fifteen to twenty minutes after the start of infusion. Since the essential difference between the ex vivo and the intact intestine was the preservation of efferent and afferent nervous connections in the latter, it seems that in the conscious animal, the response to exogenous motilin is modulated by the innervation of the intestine, or, alternatively, motilin interacts with the centre controlling the pattern of motor activity in the small intestine rather than directly with smooth muscle. The latter hypothesis is supported by the observation that motilin had no effect on the motor activity of the small intestine during the infusion of pentagastrin which abolishes spontaneous migrating myoelectric complexes.

The administration of hypertonic glucose and saline and of fat intrajejunally in man caused a marked and almost identical inhibition of pentagastrin-stimulated gastric acid secretion. Hypertonic glucose administered intrajejunally in Heidenhain pouch dogs resulted in an equal inhibition of pentagastrin-induced acid secretion from the pouch and the main stomach, whereas hypertonic saline had no effect. The study demonstrates the existence of potent jejunal inhibitors of gastric secretion, which seem to operate independently of vagal innervation.

A Levine tube was placed under radiological control in the stomach, and a thin polyethylene tube in the proximal jejunum of 6 healthy volunteers. The stomach and proximal part of jejunum were perfused for 2 hours with 1% acetylcholine, 20% meat extract (Bovril), and 15% liver extract (LE) alone and in combination with simultaneous infusion of different doses of exogenous pentagastrin intravenously. A significant increase in serum gastrin concentration was found with antral perfusion of LE only, whereas perfusion of the proximal jejunum did not change the basal level of the serum gastrin concentration. No change from control values was observed in gastric acid, and pepsin output on perfusing proximal jejunum with LE alone, or in combination with pentagastrin. Reflux to the stomach varied between 0-1.4%, as determined by addition of radioactive B12 to the perfusates. The experiments showed that gastrin was released from the antrum of the stomach by perfusion with 15 per cent LE, but not from the jejunum under the present experimental conditions. In the present experiments Bovril and acetylcholine perfusions did not cause significant responses from the antrum or from the proximal jejunum.

Studies on the relevance of scintigraphy and breath hydrogen analysis to the measurement of small bowel transit time are outlined. The main dietary factor influencing small bowel transit time appears to be the level of unabsorbable carbohydrate. The rates of gastric emptying and small bowel transit seem to be largely independent of one another. A weak correlation exists between the time for 50% of a meal to enter the caecum and the contraction frequency of the upper jejunum. Unabsorbed food in the ileum may increase the period over which material remains in the small intestine. Absorption cannot be predicted from a knowledge of transit kinetics alone. Diarrhoea may arise if rapid small bowel transit causes unduly rapid entry of fluid into the colon. In the irritable bowel syndrome, accelerated small bowel transit occurs in patients with diarrhoea.

Perfusion studies of the proximal jejunum were performed in healthy volunteers to define the influence of glycochenodeoxycholic acid (GCDC) 2.5 mmol/1 on the net movements of water and electrolytes, the bidirectional fluxes of sodium, potassium, and chloride, and the transmural electrical potential difference (PD). The flux data supported the notion that active sodium transport is inhibited by luminal GCDC, which on the other hand elicits active secretion of chloride. PD was 3 +/- 1 mV, lumen negative, and was not influenced by GCDC. The flux data fit a previously proposed model for the GCDC effect.

Circadian changes in activities and electrophoretic pattern of the intestinal brushborder enzymes alkaline phosphatase (EC 3.1.3.1), isomaltase (EC 3.2.1.10) and sucrase (EC 3.2.1.26) of normal rats and of rats with a lesion of the dorsomedial hypothalamus (DMH-rats) were studied. In contrast to the rhythm found in normal rats, there are no significant differences between the average enzyme activities in the light or dark period for the DMH-rats. The peak ratio in the electrophoretic pattern for sucrase-isomaltase (SI) over pro-sucrase-isomaltase (pro-SI) changes over 24 hr with higher values during the active (dark) period of the normal rat. In DMH-rats this ratio is much higher, but no significant difference could be demonstrated between the values near the acrophase in these rats.