The Influence of Simulated Fasted Gastrointestinal pH Profiles on Diclofenac Sodium Dissolution in a Glass-Bead Flow-Through System

High inter- and intra-individual variability in the pH of fluids in the human gastrointestinal (GI) tract has been described in the literature. The aim of this study was to assess the influence of physiological variability in fasted pH profiles of media along the GI tract on diclofenac sodium (DF-Na) dissolution from matrix tablets. Four individual in vivo fasted pH profiles were selected from the literature that differed in pH values and transit times from the stomach to the proximal colon. Using a glass-bead device flow-through dissolution system, these pH profiles were simulated in vitro using a specific media sequence and considering simulated intestinal buffer capacities corresponding to in vivo literature data. Dissolution experiments were then performed in the same system with media sequence following individual pH profiles. In dissolution experiments, where influences of simulated gastric emptying time (GET), gastric pH value, small intestinal transit time, and colonic pH were studied; high influence of gastric pH value and GET on DF-Na dissolution was observed. The effect of variability in pH profiles in the range of individual in vivo data on DF-Na dissolution was also clearly observed in experiments, where dissolution studies were performed following three simulated in vivo individual pH profiles. The differences in DF-Na release between three individual pH profiles were substantial; they also reflected in simulated plasma concentration profiles and can be attributed to pH dependent diclofenac solubility.     

Effect of a glucagon-like peptide 1 analog, ROSE-010, on GI motor functions in female patients with constipation-predominant irritable bowel syndrome

The glucagon-like peptide 1 (GLP-1) analog ROSE-010 reduced pain during acute exacerbations of irritable bowel syndrome (IBS). Our objective was to assess effects of ROSE-010 on several gastrointestinal (GI) motor and bowel functions in constipation-predominant IBS (IBS-C). In a single-center, randomized, parallel-group, double-blind, placebo-controlled, dose-response study, we evaluated safety, pharmacodynamics, and pharmacokinetics in female patients with IBS-C. ROSE-010 (30, 100, or 300 μg sc) or matching placebo was administered once daily for 3 consecutive days and on 1 day 2-10 days later. We measured GI and colonic transit by validated scintigraphy and gastric volumes by single-photon emission computed tomography. The primary end points were half time of gastric emptying of solids, colonic transit geometric center at 24 h, and gastric accommodation volume. Analysis included intent-to-treat principle, analysis of covariance (with body mass index as covariate), and Dunnett-Hsu test for multiple comparisons. Exposure to ROSE-010 was approximately dose-proportional across the dose range tested. Demographic data in four treatment groups of female IBS-C patients (total 46) were not different. Gastric emptying was significantly retarded by 100 and 300 μg of ROSE-010. There were no significant effects of ROSE-010 on gastric volumes, small bowel or colonic transit at 24 h, or bowel functions. The 30- and 100-μg doses accelerated colonic transit at 48 h. Adverse effects were nausea (P < 0.001 vs. placebo) and vomiting (P = 0.008 vs. placebo). Laboratory safety results were not clinically significant. In IBS-C, ROSE-010 delayed gastric emptying of solids but did not retard colonic transit or alter gastric accommodation; the accelerated colonic transit at 48 h with 30 and 100 μg of ROSE-010 suggests potential for relief of constipation in IBS-C.     

Effect of thyroidal state on the gastrointestinal transit and emptying of young broilers

1. In newly hatched broilers, propylthiouracil and thyroid powder added to the diet produced hypothyroidism and hyperthyroidism, respectively. After 4-5 days of treatment body and thyroid weight changed, but no differences in body temperature were found. 2. The hyperthyroidal animals had high mortality rate and the hypothyroidal ones showed significantly lower glycemia values. 3. The gastrointestinal transit and emptying of 8 and 15 days old hypo-, hyper- and euthyroidal broiler chicks were measured using 14C-PEG-4000 as a marker. 4. Hypothyroidism prolonged GI transit and emptying, whereas hyperthyroidism modified these parameters in a way dependent of the elapsed time after the test meal: at 0.5 and 1 hr transit and emptying were quick, but at 2 and 4 hr the transit was slow. 5. Hyperthyroidism also delayed the transit of large bowel intraluminal contents in 15-day-old chickens. 6. These results are very similar to those of starvation, suggesting an important interaction between diencephalon, thyroid gland and GI motility in young chickens.     

Small bowel motility and colonic transit are altered in dogs with moderate renal failure

Although gastrointestinal complications are common in patients with renal disease, the effects of renal dysfunction on bowel motility and gut transit times are not well known. We assessed gastrointestinal electromyographic activity, gastric emptying rate, orocolonic transit time, oroanal transit time, and xylose absorption before and after surgically inducing a 66% decrease in glomerular filtration rate in dogs. Moderate renal failure induced no gross or microscopic gastrointestinal lesions but caused a 16-42% increase in gastrointestinal motility indexes. We found a 24% decrease in the propagation velocity of the myoelectrical migrating complex in the duodenojejunal segment, a 30% decrease in phase I duration in duodenal and jejunal regions, a 20% increase in the total irregular electrical activity of the small intestine, and a 22% increase in duration of the meal response in the duodenum and jejunum. Renal failure did not change xylose absorption, gastric emptying rate, and orocolonic transit time but decreased colonic transit time by 38%. The mean weight of feces was increased. These results indicate that moderate renal failure alters duodenojejunal motility and decreases colonic transit time.     

B-type natriuretic peptide decreases gastric emptying and absorption

Natriuretic peptides have been shown to decrease contractility of isolated gastric smooth muscle cells. However there is a paucity of research showing whether this effect has functional significance in the whole animal. The objective of this study was to test whether intravenously administered B-type Natriuretic Peptide (BNP) has an effect on gastric emptying and/or absorption in a whole animal mouse model. C57BL/6-Wild-type (WT) and Natriuretic Peptide Receptor type A (NPR-A) knockout (KO) mice were used in these studies. Gastric contractility was examined in anesthetized mice before and after BNP vs. vehicle injection. Gastric emptying of gavage fed 70 Kilo Dalton (kDa) FITC-dextran and absorption of 4 kDa FITC-dextran were compared in BNP vs. vehicle treated conscious WT and KO mice. BNP decreased gastric contractility (measured in change in intragastric pressure) from 2.26 +/- 0.29 to 1.44 +/- 0.11 mmHg (P < 0.05), pressure returned to 2.08 +/- 0.17 after 5 BNP half-lives (P < 0.05). There was no significant change in the vehicle or KO. BNP also decreased gastric emptying in WT mice compared to vehicle, 87.8 +/- 0.8% vs. 97.3 +/- 1.04% (P < 0.05) and this effect showed a dose-response relationship. In KO mice emptying was 95.8 +/- 0.5% (BNP) vs. 91.7 +/- 0.7% (Vehicle) (P > 0.05). The absorption in WT mice was 28.2 +/- 7.8 (relative fluorescence units) for BNP vs. 91 +/- 25.9 for vehicle (P < 0.05). For KO mice absorption was 64.3 +/- 14.9 for BNP vs. 60.6 +/- 17.4 for vehicle (P > 0.05). The results show that BNP decreases intragastric pressure, emptying and absorption by acting via the NPR-A receptor. We postulate that this effect is aimed at decreasing preload through decreased water and electrolyte absorption from the GI tract and may also be responsible for the symptoms of impaired gastrointestinal function observed in heart failure patients.     

Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat

A novel peptide called ghrelin or motilin-related-peptide (MTLRP) was found in the stomach of various mammals. We studied its effect on the motor function of the rat gastrointestinal tract. In normal, conscious unoperated animals, ghrelin/MTLRP (5 or 20 microg/kg iv) significantly accelerated the gastric emptying of a methylcellulose liquid solution (gastric residue after 15 min: 57 +/- 7, 42 +/- 11, 17 +/- 4, and 9 +/- 3% of the ingested meal with doses of 0, 1, 5, and 20 microg/kg iv, respectively) Transit of the methylcellulose liquid solution was also accelerated by ghrelin/MTLRP in the small intestine but not in the colon. Des-[Gln(14)]ghrelin, also found in the mammalian stomach, was as potent as ghrelin in emptying the stomach (gastric residue after 15 min: 12 +/- 3% at a dose of 20 microg/kg iv). In rats in which postoperative gastrointestinal ileus had been experimentally induced, ghrelin/MTLRP (20 microg/kg iv) reversed the delayed gastric evacuation (gastric residue after 15 min: 28 +/- 7% of the ingested meal vs. 82 +/- 9% with saline). In comparison, the gastric ileus was not modified by high doses of motilin (77 +/- 7%) or erythromycin (82 +/- 6%) and was only partially improved by calcitonin gene-related peptide (CGRP) 8-37 antagonist (59 +/- 7%). Ghrelin/MTLRP, therefore, accelerates the gastric emptying and small intestinal transit of a liquid meal and is a strong prokinetic agent capable of reversing the postoperative gastric ileus in rat.     

Gastric inhibitory polypeptide does not inhibit gastric emptying in humans

The insulinotropic gut hormone gastric inhibitory polypeptide (GIP) has been demonstrated to inhibit gastric acid secretion and was proposed to possess "enterogastrone" activity. GIP effects on gastric emptying have not yet been studied. Fifteen healthy male volunteers (23.9 +/- 3.3 yr, body mass index 23.7 +/- 2.3 kg/m(2)) were studied with the intravenous infusion of GIP (2 pmol.kg(-1).min(-1)) or placebo, each administered to the volunteers on separate occasions from -30 to 360 min in the fasting state. At 0 min, a solid test meal (250 kcal containing [(13)C]sodium octanoate) was served. Gastric emptying was calculated from the (13)CO(2) exhalation rates in breath samples collected over 360 min. Venous blood was drawn in 30-min intervals for the determination of glucose, insulin, C-peptide, and GIP (total and intact). Statistical calculations were made by use of repeated-measures ANOVA and one-way ANOVA. During the infusion, GIP rose to steady-state concentrations of 159 +/- 15 pmol/l for total and 34 +/- 4 pmol/l for intact GIP (P < 0.0001). Meal ingestion further increased GIP concentrations in both groups, reaching peak levels of 265 +/- 20 and 82 +/- 9 pmol/l for total and 67 +/- 7 and 31 +/- 9 pmol/l for intact GIP during the administration of GIP and placebo, respectively (P < 0.0001). There were no differences in glucose, insulin, and C-peptide between the experiments with the infusion of GIP or placebo. Gastric half-emptying times were 120 +/- 9 and 120 +/- 18 min (P = 1.0, with GIP and placebo, respectively). The time pattern of gastric emptying was similar in the two groups (P = 0.98). Endogenous GIP secretion, as derived from the incremental area under the curve of plasma GIP concentrations in the placebo experiments, did not correlate to gastric half-emptying times (r(2) = 0.15, P = 0.15 for intact GIP; r(2) = 0.21, P = 0.086 for total GIP). We conclude that gastric emptying does not appear to be influenced by GIP. The secretion of GIP after meal ingestion is not suppressed by its exogenous administration. The lack of effect of GIP on gastric emptying underlines the differences between GIP and the second incretin glucagon-like peptide 1.     

Blunting of Colon Contractions in Diabetics with Gastroparesis Quantified by Wireless Motility Capsule Methods

Generalized gut transit abnormalities are observed in some diabetics with gastroparesis. Relations of gastric emptying abnormalities to colon contractile dysfunction are poorly characterized. We measured colon transit and contractility using wireless motility capsules (WMC) in 41 healthy subjects, 12 diabetics with gastroparesis (defined by gastric retention >5 hours), and 8 diabetics with normal gastric emptying (≤5 hours). Overall numbers of colon contractions >25 mmHg were calculated in all subjects and were correlated with gastric emptying times for diabetics with gastroparesis. Colon transit periods were divided into quartiles by time and contraction numbers were calculated for each quartile to estimate regional colon contractility. Colon transit in diabetics with gastroparesis was prolonged vs. healthy subjects (P<0.0001). Overall numbers of colon contractions in gastroparetics were lower than controls (P = 0.02). Diabetics with normal emptying showed transit and contraction numbers similar to controls. Gastric emptying inversely correlated with overall contraction numbers in gastroparetics (r = -0.49). Numbers of contractions increased from the 1^st to 4^th colon transit quartile in controls and diabetics with normal emptying (P≤0.04), but not gastroparetics. Numbers of contractions in the 3^rd and 4^th quartiles were reduced in gastroparetics vs. healthy controls (P≤0.05) and in the 4^th quartile vs. diabetics with normal emptying (P = 0.02). Numbers of contractions were greatest in the final 15 minutes of transit, but were reduced in gastroparetics vs. healthy controls and diabetics with normal emptying (P≤0.005). On multivariate analyses, differences in numbers of contractions were not explained by demographic or clinical variables. In conclusion, diabetics with gastroparesis exhibit delayed colon transit associated with reductions in contractions that are prominently blunted in latter transit phases and which correlate with delayed gastric emptying, while diabetics with normal emptying show no significant colonic impairments. These findings emphasize diabetic gastroparesis may be part of a generalized dysmotility syndrome.     

Effect of solid meal on gastric emptying of,and glycemic and cardiovascular responses to,liquid glucose in older subjects

Gastric emptying is a determinant of the postprandial glycemic and cardiovascular responses to oral carbohydrate. We evaluated the effects of a solid meal on gastric emptying and the glycemic and cardiovascular responses to oral glucose in healthy older subjects. Ten subjects aged 72.1 +/- 1.9 yr were studied. Each subject had measurements of gastric emptying, blood glucose, serum insulin, blood pressure, and heart rate after ingestion of a 50-g glucose drink (300 ml) with (mixed meal) or without (liquid only) a solid meal (300 g ground beef). Gastric emptying of liquid was initially slightly more rapid (P < 0.05) after the mixed meal compared with liquid only at 5 min (92.0 +/- 1.5 vs. 96.0 +/- 1.3%) and much slower (P < 0.05) after 120 min. The time to peak blood glucose was less (39.0 +/- 4.0 vs. 67.5 +/- 10.3 min; P < 0.01) and blood glucose subsequently lower (P < 0.01) after the mixed meal. The increase in serum insulin was greater (P < 0.001) after the mixed meal. Blood pressure fell (P < 0.05) in the first 30 min, with no difference between the two meals. Increase in heart rate after both meals (P < 0.005), was greater (P < 0.05) after the mixed meal. The presence of a noncarbohydrate solid meal had discrepant effects on early and subsequent emptying of a nutrient liquid, which affects postprandial glycemia and increased heart rate.     

Effect of meal viscosity and nutrients on satiety, intragastric dilution, and emptying assessed by MRI

The relationship between the intragastric distribution, dilution, and emptying of meals and satiety was studied using noninvasive magnetic resonance imaging techniques in 12 healthy subjects with four polysaccharide test meals of varying viscosity and nutrient content as follows: 1) low-viscosity nonnutrient, 2) low-viscosity nutrient, 3) high-viscosity nonnutrient, and 4) high-viscosity nutrient. Increasing the nutrient content of the high-viscosity meal delayed gastric emptying from 46 +/- 9 to 76 +/- 6 min (P < 0.004), whereas increasing viscosity had a smaller effect. The volume of secretions within the stomach 60 min after ingestion was higher for the high-viscosity nutrient meal (P < 0.04). A simple model to calculate the total volume of secretion added to the test meal is presented. Color-coded dilution map images showed the heterogeneous process of progressive gastric dilution of high-viscosity meals, whereas low-viscosity meals were uniformly diluted. Fullness was found to be linearly related to total gastric volumes for the nutrient meals (R(2) = 0.98) and logarithmically related for the nonnutrient meals (R(2) = 0.96). Fullness was higher for high- compared with low-viscosity meals (P < 0.02), and with the nutrient meals this was associated with greater antral volumes (P < 0.05).     

Capsaicin increases gastric emptying rate in healthy human subjects measured by 13C-labeled octanoic acid breath test.

The role of capsaicin-sensitive primary afferent sensory nerves in the regulation of gastrointestinal motility in human is not clarified yet. In this study, we investigated the effect of 400 microg capsaicin given intragastrically on gastric emptying measured by 13C-octanoic acid breath test in ten healthy human subjects. Four parameters of gastric emptying curves were taken into consideration: 1) maximum value of the curve, 2) time belonging to this maximum, 3) slope of the rising part of the curve and 4) time belonging to the 50% of the area under the curve. Administration of 400 microg capsaicin significantly increased the slope of gastric emptying curve (from 0.1 +/- 0.01 to 0.139 +/- 0.014 U x min(-1), P < 0.05) and significantly decreased the time belonging to the maximum value of emptying curve (from 150 +/- 18 to 75 +/- 12 min, P < 0.05) and the time belonging to the 50% of the area under the curve (from 112 +/- 15 to 99 +/- 14 min, P < 0.05). According to our results 400 microg capsaicin enhances gastric emptying rate in healthy human subjects.     

Digestive motor effects and vascular actions of CGRP in dog are expressed by different receptor subtypes

Calcitonin gene-related peptide (CGRP) is a 37 AA peptide localized in blood vessels and nerves of the GI tract. Activation of CGRP receptors (subtypes 1 or 2) usually induces vasodilation and/or muscle relaxation, but its effects in dog and on gastroduodenal motility are still unclear. This study looked for the effect of CGRP and the antagonist CGRP8-37, specific for CGRP type 1 receptor, 1) on GI motility (interdigestive and postprandial), and 2) on hemodynamy, in conscious dogs. During the interdigestive period, the infusion of CGRP1-37 (200 pmol/kg/h) or CGRP8-37 (2000 pmol/kg/h) did not modify the duration of the migrating motor complex nor the release nor the motor action of plasma motilin. The gastric emptying of a solid meal (15 g meat/kg) was reduced by the administration of CGRP1-37 (AUC: 2196 +/- 288.6 versus 3618 +/- 288.4 with saline or T12: 78 +/- 7.3 versus 50 +/- 4.3 min; P < 0.01) and this effect was reversed by the antagonist CGRP8-37. CGRP1-37 significantly (P < 0. 01) diminished arterial pressures (118 +/- 1.6/64 +/- 1.4 vs. 125 +/- 1.4/75 +/- 1.2 mmHg with saline) and accelerated the basal cardiac rhythm (110 +/- 1.4 versus 83 +/- 1.6 beats/min). However, CGRP8-37 failed to block the cardiovascular effects of CGRP1-37. In dog, CGRP could influence digestive motility by slowing the gastric emptying of a meal through an action on CGRP-1 receptors. Hemodynamic effects of CGRP were not blocked by CGRP8-37 and seem therefore mediated by CGRP-2 receptor subtype.     

Determination of gastric emptying in nonobese diabetic mice

Animal studies on diabetic gastroparesis are limited by inability to follow gastric emptying changes in the same mouse. The study aim was to validate a nonlethal gastric emptying method in nonobese diabetic (NOD) LtJ mice, a model of type 1 diabetes, and study sequential changes with age and early diabetic status. The reliability and responsiveness of a [(13)C]octanoic acid breath test in NOD LtJ mice was tested, and the test was used to measure solid gastric emptying in NOD LtJ mice and nonobese diabetes resistant (NOR) LtJ mice. The (13)C breath test produced results similar to postmortem recovery of a meal. Bethanechol accelerated gastric emptying [control: 92 +/- 9 min; bethanechol: 53 +/- 3 min, mean half emptying time (T(1/2)) +/- SE], and atropine slowed gastric emptying (control: 92 +/- 9 min; atropine: 184 +/- 31 min, mean T(1/2) +/- SE). Normal gastric emptying (T(1/2)) in nondiabetic NOD LtJ mice (8-12 wk) was 91 +/- 2 min. Aging had differing effects on gastric emptying in NOD LtJ and NOR LtJ mice. Onset of diabetes was accompanied by accelerated gastric emptying during weeks 1-2 of diabetes. Gastric emptying returned to normal by weeks 3-5 with no delay. The [(13)C]octanoic acid breath test accurately measures gastric emptying in NOD LtJ mice, is useful to study the time course of changes in gastric emptying in diabetic NOD LtJ mice, and is able to detect acceleration in gastric emptying early in diabetes. Opposing changes in gastric emptying between NOD LtJ and NOR LtJ mice suggest that NOR LtJ mice are not good controls for the study of gastric emptying in NOD LtJ mice.     

Pressure-geometry relationship in the antroduodenal region in humans

Understanding of the control mechanisms underlying gastric motor function is still limited. The aim of the present study was to evaluate antral pressure-geometry relationships during gastric emptying slowed by intraduodenal nutrient infusion and enhanced by erythromycin. In seven healthy subjects, antral contractile activity was assessed by combined dynamic magnetic resonance imaging and antroduodenal high-resolution manometry. After intragastric administration of a 20% glucose solution (750 ml), gastric motility and emptying were recorded during intraduodenal nutrient infusion alone and, subsequently, combined with intravenous erythromycin. Before erythromycin, contraction waves were antegrade (propagation speed: 2.7 +/- 1.7 mm/s; lumen occlusion: 47 +/- 14%). Eighty-two percent (51/62) of contraction waves were detected manometrically. Fifty-four percent of contractile events (254/473) were associated with a detectable pressure event. Pressure and the degree of lumen occlusion were only weakly correlated (r(2) = 0.02; P = 0.026). After erythromycin, episodes of strong antroduodenal contractions were observed. In conclusion, antral contractions alone do not reliably predict gastric emptying. Erythromycin induces strong antroduodenal contractions not necessarily associated with fast emptying. Finally, manometry reliably detects ~80% of contraction waves, but conclusions from manometry regarding actual contractile activity must be made with care.     

Improved use of the [13C]octanoic acid breath test as intra-individual parameter to study the effect of a prokinetic drug on gastric emptying in preterm infants with oral feeding intolerance

The [¹³C]octanoic acid breath test was used for the measurement of differences in gastric emptying in preterm infants for the evaluation of pharmacological therapy. In order to perform a good intra-individual comparison of the gastric emptying in preterm infants under non-standardisable test conditions, we adjusted t_1/2 for variations in non-recovered label (=label retention) and introduced an “effective half ¹³CO₂ breath excretion time” t_1/2eff=t_1/2/m expressed as min per percentage of the cumulative dose recovered. In a pilot study, we investigated the action of the gastrointestinal prokinetic drug cisapride on gastric emptying in seven premature infants, of whom four suffered from gastric stasis and three had constipation. The postnatal age and weight at the start of treatment ranged from 15 to 64 days and from 815 to 1635 g, respectively. All infants received the standard formula for premature infants (Nenatal, Nutricia). Cisapride was administered orally 0.2 mg/kg, four times daily. The changes in gastrointestinal motility were studied using the total bowel transit time of carmine red. After 7 days of treatment in all children, the gastric emptying coefficient and the half ¹³CO₂ breath excretion time adjusted for label retention were improved (n=7, the gastric emptying coefficient range before treatment was 1.69–3.34 (mean 2.59±0.80) and after treatment it was 2.79–3.76 (mean 3.28±0.30); the half ¹³CO₂ breath excretion time adjusted for label retention range before treatment was 3.0–14.7 min/% dose (mean 7.0±5.0) and after treatment 2.6–4.0 min/% dose (mean 3.1±0.6). The total bowel transit time was only slightly improved in two patients (n=7, mean total bowel transit time before: 23.7 h compared to mean total bowel transit time after 7 days of treatment: 35.5 h). Side effects during cisapride treatment were not seen. We conclude that in premature infants cisapride is effective in shortening gastric emptying time and reducing gastric stasis; the therapeutic role in constipation has to be further investigated.     

Characterizing gastrointestinal transit time in four lemur species using barium-impregnated polyethylene spheres (BIPS)

Differences in dietary profiles and gastrointestinal (GI) morphologies observed across lemur species suggest that there may be variation in patterns of digesta flow through the GI tract related to the method of digesta processing. Using radio-opaque barium-impregnated polyethylene spheres (BIPS), we characterized such patterns in four lemur species: Varecia variegata (VV), Eulemur fulvus (EF), Propithecus verreauxi (PV), and Hapalemur griseus (HG) (n = 2 per species). After an initial radiograph was taken under light sedation, the animals were fed the BIPS together with a small meal. A combination of 30 small (1.5 mm) and 10 large (5 mm) BIPS was administered. Radiographs were then taken on a species-dependent basis up to 48 hr post-dosage. For small BIPS, the gastric transit time (GTT; time of first exit of BIPS from stomach) was 0.25-2 hr for VV, EF, and HG, and approximately 10 hr for PV. The oro-rectal transit time (ORTT; time of first appearance in the rectum) was < 2 hr for VV and EF, and 24.0 hr for PV and HG. The intestinal transit time (ITT, measured as ORTT - GTT) was < 1.5 hr for VV and EF, and approximately 14 hr and 22 hr for PV and HG, respectively. These data suggest that the GTT of digesta as measured with BIPS was rapid for VV, EF, and HG. For VV and EF, the ORTT and ITT were also rapid, while for HG they were much slower. PV was characterized by delayed GTT, and a more rapid ITT compared to HG. Thus, patterns of flow for PV and HG, despite similar ORTT, differed in that HG emptied BIPS more rapidly and ITT was slower. The flow of BIPS did not differ for VV and EF. These data reveal new information in addition to the total tract transit time, and complement existing knowledge regarding anatomy and diet.     

Central TRH receptor 1 antisense blocks cold-induced gastric emptying but not brain c-Fos induction

We studied whether TRH receptor 1 (TRH-R1) antisense oligodeoxynucleotides injected intracisternally, impaired acute cold-induced c-Fos expression in the brain and vagally mediated stimulation of gastric emptying in conscious rats. Cold exposure (4-6 degrees C, 90 min) increased gastric emptying and the number of c-Fos positive cells in the paraventricular nucleus of the hypothalamus, supraoptic nucleus, raphe pallidus, dorsal motor nucleus of the vagus, nucleus of the solitary tract and area postrema compared with rats at room temperature. TRH-R1 antisense abolished cold-induced stimulation of gastric transit but not c-Fos expression in the brain. TRH-R1 mismatch did not alter the gastric response to cold. These data indicate that central activation of TRH-R1 mediates cold-induced stimulation of gastric emptying but does not influence the induction of c-Fos expression in the brain.     

Peripheral administration of GLP-2 to humans has no effect on gastric emptying or satiety

Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are secreted in parallel to the circulation after a meal. Intravenous (IV) GLP-1 has an inhibitory effect on gastric emptying, hunger and food intake in man. In rodents, central administration of GLP-2 increases satiety similar to GLP-1. The aim of the present study was to assess the effect of IV administered GLP-2 on gastric emptying and feelings of hunger in human volunteers. In eight (five men) healthy subjects (age 31.1+/-2.9 years and BMI 24.1+/-1.0 kg m(-2)), scintigraphic solid gastric emptying, hunger ratings (VAS) and plasma concentrations of GLP-2 were studied during infusion of saline or GLP-2 (0.75 and 2.25 pmol kg(-1) min(-1)) for a total of 180 min. Concentrations of GLP-2 were elevated to a maximum of 50 and 110 pmol l(-1) for 0.75 and 2.25 pmol kg(-1) min(-1) infusion of GLP-2, respectively. There was no effect of GLP-2 on either the lag phase (29.5+/-4.4, 26.0+/-5.2 and 21.2+/-3.6 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively) or the half emptying time (84.5+/-6.1, 89.5+/-17.8 and 85.0+/-7.0 min for saline, GLP-2 0.75 or 2.25 pmol kg(-1) min(-1), respectively). The change in hunger rating after the meal to 180 min was also unaffected by infusion of GLP-2. GLP-2 does not seem to mediate the ileal brake mechanism.     

Substrate specificity of human ABCC4 (MRP4)-mediated cotransport of bile acids and reduced glutathione

Obese CCK-1 receptor-lacking Otsuka Long Evans Tokushima fatty (OLETF) rats are hyperphagic relative to control, nonmutant Long Evans Tokushima Otsuka (LETO) rats. This study sought to assess whether the overeating observed in OLETF rats is associated with changes in gastric emptying rates or detection of gastric volume. We performed experiments in both 12- and 29-wk-old OLETF and LETO rats to address possible alterations in gastric functions during the development of increased body weight and blood glucose abnormalities in OLETF rats. Gastric emptying of a 5-g solid chow test meal was not significantly different between strains at either 1, 2, or 4 h postmeal. When rats with ad libitum access to chow were tested, there were no significant differences in gastric emptying between strains at any time period despite OLETF rats consuming significantly more chow than LETO rats. Similar to solid food, 5-min gastric emptying of a 5-ml isosmotic and hyperosmotic saline or glucose load was not significantly different between strains. When the stomach was distended with a 15-ml semisolid chow load, there was no significance difference in emptying at either 1 or 2 h. No significant differences in gastric emptying were detected between 12- and 29-wk-old rats under any conditions. Both young and old OLETF rats, however, reduced sham intake significantly less compared with LETO rats during a brief period of gastric distension by 5- or 10-ml balloon inflation. Finally, OLETF rats showed decreased Fos expression in the nucleus of the solitary tract relative to LETO rats after an 8-ml gastric distension. These findings demonstrate that OLETF rats do not express deficits in controlling gastric emptying rates; however, they exhibit decreased behavioral and vagal responsiveness to gastric distension that may contribute to the increased meal size in these animals.     

Influence of sildenafil on gastric sensorimotor function in humans

After a meal, the proximal stomach relaxes probably through the activation of nitrergic neurons in the gastric wall. Nitric oxide-induced smooth muscle relaxation involves activation of soluble guanylate cyclase, with cGMP production, which is then degradated by phosphodiesterase-5 (PDE-5). The aim of this study was to investigate the effect of sildenafil, a selective PDE-5 inhibitor, on fasting and postprandial proximal gastric volume and on gastric emptying rates in humans. A gastric barostat was used to study gastric compliance and perception to isobaric distension in healthy subjects before and after placebo (n = 13) or sildenafil, 50 mg (n = 15). In 10 healthy subjects, two gastric barostat studies were performed in randomized order to study the effect of placebo or sildenafil on postprandial gastric relaxation. Similarly, solid and liquid gastric emptying rates were studied in 12 healthy subjects. Sildenafil significantly increased fasting intragastric volume (141 +/- 15 vs. 163 +/- 15 ml, P < 0.05) and volumes of first perception. Sildenafil induced a higher and prolonged gastric relaxation either at 30 min (357 +/- 38 vs. 253 +/- 42 ml, P < 0.05) or 60 min (348 +/- 49 vs. 247 +/- 38 ml, P < 0.05) after the meal. Sildenafil did not alter solid half-emptying time but significantly delayed liquid emptying (43 +/- 4 vs. 56 +/- 4 min, P < 0.01). In conclusion, sildenafil significantly increases postprandial gastric volume and slows liquid emptying rate, confirming that meal-induced accommodation in humans involves the activation of a nitrergic pathway. The effect of sildenafil on gastric fundus suggests a therapeutic potential for phosphodiesterase inhibitors in patients with impaired gastric accommodation.