Intestinal secretion induced by vasoactive intestinal polypeptide. A comparison with cholera toxin in the canine jejunum in vivo.

The effect of vasoactive intestinal polypeptide (VIP) on intestinal water and electrolyte transport and transmucosal potential difference was investigated in the dog jejunum in vivo and compared to secretion induced by cholera toxin. Isolated jejunal loops were perfused with a plasma-like electrolyte solution. VIP (0.08 mug/kg per min) was administered directly into the superior mesenteric artery by continuous infusion over 1 h. From a dye dilution method, it was estimated that a mean plasma VIP concentration of 12,460 pg/ml reached the loops. VIP caused secretion of water and electrolytes; for example, chloride: control, 8 mueq/cm per h absorption; VIP, 92 mueq/cm per h secretion. A marked increase in transmucosal potential difference (control, -1.0 mV; VIP, -5.9 mV, lumen negative) occurred within 1 min after starting VIP infusion. Analysis of unidirectional fluxes showed increased plasma-to-lumen flux of sodium and chloride and decreased lumen-to-plasma flux of sodium. Chloride and bicarbonate were actively secreted against an electrochemical gradient. Although sodium secretion occurred down an electrochemical gradient, flux ratio analysis suggested a component of active sodium secretion. VIP caused a slight increase in protein output into the loops; light microscopy revealed capillary dilatation and closed intercellular spaces. The effect of VIP was readily reversible. Except for the delayed onset of secretion, the effect of cholera toxin was qualitatively similar to VIP; however, capillary dilatation and increased protein output were not noted with cholera toxin.

The importance of 5-hydroxytryptamine receptors in the gut.

Most of the 5-hydroxytryptamine (5-HT) present in the adult human body is located in the gastrointestinal tract. The vast majority is contained in enteroendocrine cells, the rest exists mainly in myenteric interneurons separated from the mucosa by an intraenteric barrier. Physiological studies suggest that 5-HT plays a vital role in mediating both sensory and reflex responses to gastrointestinal stimuli and, thus, this transmitter is closely implicated in gut reactions. This review outlines some of the evidence for different 5-HT receptors, summarizes the role of 5-HT in mediating gut sensitivity and motor activity, secretion and more complex activities, such as emesis and diarrhoea and identifies the clinical role of drugs acting on 5-HT receptors in the treatment of emesis, diarrhoea, the control of abdominal pain and discomfort and the rectification of gastrointestinal motility.

Effect of guar gum on hunger and satiety after meals of differing fat content: relationship with gastric emptying.

To determine whether the satiating effects of fiber are due to delaying gastric emptying or slowing absorption of meals, 3% guar gum was added to high- and low-fat soups and gastric emptying rate, hunger, and satiety were measured in eight male volunteers. Guar gum delayed the emptying of the low-fat soup but the small delays in the return of hunger and decline of fullness were significantly correlated with the gastric emptying, suggesting mediation by gastric mechanoreceptors. The high-fat soup also emptied more slowly but this had no effect on the return of hunger or the decline in fullness. The delays in the return of hunger and decline of fullness were far greater when guar gum was added to the fatty soup; these delays were not correlated with the small additional delay in gastric emptying. This is more compatible with slowed absorption and prolonged contact of nutrients with intestinal chemoreceptors.

Viscosity of food gums determined in vitro related to their hypoglycemic actions.

Experiments were carried out in vitro and in normal human subjects to evaluate alternative food-grade viscous polysaccharides as agents for reducing postprandial hyperglycemia and to assess the relationship between the in vitro and in vivo performance of the polysaccharides. A 1:1 mixture of xanthan and locust bean gum (X/LBG) had the greatest viscosity at equivalent concentrations and shear rates and was more effective than guar gum, xanthan, or locust-bean gum at inhibiting glucose movement in vitro. It was not, however, more efficient in lowering postprandial blood glucose and plasma insulin in human subjects when incorporated in a drink containing 50 g glucose. When the different gums were acidified and reneutralized to mimic conditions in the gut, there was a better correlation between viscosity and blood glucose and plasma insulin levels. This effect may explain why X/LBG was no more effective than the other gums in reducing postprandial hyperglycemia in man.

Interaction of insulin, glucagon-like peptide 1, gastric inhibitory polypeptide, and appetite in response to intraduodenal carbohydrate.

The relation between gastrointestinal incretin hormones in the control of insulin release and short-term satiety by intestinal carbohydrate was investigated in 8 fasted, healthy male volunteers. Insulin, gastric inhibitory polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and appetite ratings were measured during, and food intake was measured after, intraduodenal infusions of glucose or saline. Studies were conducted under hyperinsulinemic and euglycemic conditions. Raising plasma insulin with intravenous insulin infusion to concentrations slightly above usual postprandial concentrations (356.4 +/- 4.8 pmol/L) had no effect on GIP, GLP-1, or appetite ratings before the intraduodenal infusions began. Intraduodenal glucose infusion resulted in a further increase in plasma insulin to a peak of 779.4 +/- 114.0 pmol/L, caused an early increase in plasma GIP and a later increase in GLP-1 concentrations (P < 0.01), suppressed appetite (P < 0.05), and reduced energy intake (P < 0.01) compared with intraduodenal infusion of saline. There was a close association between the increase in GLP-1 and decrease in appetite. Infusion of octreotide to suppress the release of gastrointestinal hormones prevented the rise in insulin, GIP, and GLP-1 induced by intraduodenal glucose infusion and reversed the suppression of appetite and reduction in energy intake. These results suggest that 1) when infused to result in plasma concentrations slightly above usual postprandial concentrations, insulin does not inhibit its own release and 2) the effects of intraduodenal glucose on appetite may be mediated through the release of GLP-1 and not insulin.

The effect of adrenoceptor antagonists on the ileal brake mechanism in the rat.

1. Studies were carried out in the rat to investigate the effect of adrenoceptor antagonists on stomach to caecum transit time under control conditions and during ileal infusion of Intralipid. Stomach to caecum transit time (SCTT) of the head of the meal was measured by use of environmental hydrogen analysis and the distribution of the meal was assessed by a scintigraphic technique. 2. Four adrenoceptor antagonists were used in these studies, the alpha 1 antagonist prazosin, the alpha 2 antagonist, idazoxan, the beta 1 antagonist atenolol and the beta 2 antagonist ICI 118551. 3. None of the antagonists affected SCTT of the head of the meal during ileal infusion of saline. However, the alpha 1 and beta 1 antagonists significantly reversed (P less than 0.05) the delay in SCTT induced by ileal infusion of Intralipid whereas the alpha 2 antagonist, idazoxan, potentiated this delay (P less than 0.05). 4. Study of the distribution of the radiolabelled meal showed that the Intralipid delayed SCTT by slowing both gastric emptying (P less than 0.05) and small bowel transit (P less than 0.05). 5. Prazosin delayed gastric emptying under control conditions (P less than 0.001) but did not alter significantly the effect of ileal lipid on the distribution of the meal, 100 min or 200 min after gavage.6. The meal distribution was more compatible with the hydrogen analysis after administration of the ,beta-adrenoceptor antagonists. The reversal of the lipid-induced delay in SCTT caused by atenolol was associated with more radioactivity in the large intestine 200min after the gavage. ICI 118551 had no significant effects on either the distribution of the meal or the SCTT of the head of the meal.7. In conclusion, the data confirm that the sympathetic nervous system normally modulates or mediates the mechanisms that influence gastrointestinal transit in the rat and suggest that these mechanisms may be involved in the ileal brake effect. Nevertheless the data also suggest that simple measurement of the transit of the head of the meal by use of environmental hydrogen analysis may sometimes give a misleading impression of the action of drugs on gastrointestinal transit of the bulk of a test meal.

The effects of atropine and secoverine on gastric secretion and motility in the mouse isolated stomach.

The isolated perfused stomach of the mouse was used to study the effect of atropine and secoverine on bethanechol-induced gastric acid secretion and gastric motility. Both atropine and secoverine inhibited cholinergically induced gastric acid secretion and gastric motility. Inhibition of gastric acid secretion by atropine and secoverine occurred at a similar dose-range (10(-9) and 2 X 10(-9) M). Secoverine inhibited bethanechol-induced hypermotility at doses (10(-11) M and above) that were lower than those of atropine (2 X 10(-9) M and above) required to produce this effect. Secoverine, unlike atropine markedly inhibited gastric motility at lower doses than those which affected secretion.

The action of loperamide in inhibiting prostaglandin-induced intestinal secretion in the rat.

1 The mechanisms by which loperamide inhibits the intestinal secretion induced by prostaglandin E2 were investigated in rat jejunum. 2 In vivo loperamide prevented prostaglandin-induced fluid secretion but did not reduce the associated rise in the transintestinal potential difference. 3 In intestinal sheets the electrical response to prostaglandin E2 was enhanced in the presence of loperamide. 4 The ionic basis of these changes was determined by measuring Na+ and Cl- fluxes across intestinal sheets. Loperamide did not reduce the prostaglandin-induced increase in net Cl- secretion, although it prevented the inhibition of mucosal-to-serosal Na+ movement. 5 Loperamide does not alter cyclic adenosine 3',5'-monophosphate (cyclic AMP) levels by a direct action at the enterocyte, since in isolated enterocytes neither basal nor prostaglandin-stimulated cyclic AMP levels were affected by the drug.

Gastrointestinal dynamics and pharmacology for the optimum design of controlled-release oral dosage forms.

This article encompasses a brief discussion of the principles of pharmacodynamics of different types of drugs and the mechanisms of absorption at different sites in the gastrointestinal tract. The importance of factors such as the pH, the unstirred layer or microclimate, gastric emptying, intestinal contact time, metabolism in the gut wall, and bacterial degradation in the colon is discussed. Methods that can be used to alter the absorption of drugs such as formulation in a viscous form, a form that floats in the stomach, position release forms, combination with other drugs that may influence absorption, etc. are examined in detail.

Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5 HT3-receptor antagonist, in patients with irritable bowel syndrome.

The effect of granisetron, a specific 5-hydroxytryptamine 3-receptor antagonist, on the anorectal responses to rectal distension and a 1000-calorie meal was assessed in 12 patients with irritable bowel syndrome. Each patient was studied on three occasions, receiving intravenously either 40 mcg/kg granisetron, 160 mcg/kg granisetron or normal saline. Granisetron caused a dose-dependent reduction in rectal sensitivity, manifested by an increase in the threshold volumes at which the sensations of gas, desire to defecate, urgency and discomfort were perceived. This reached significance for all sensations at the higher dose level (P < 0.01). No significant changes in anal pressures, rectal compliance or distension-induced motor activity occurred following drug administration. A dose-dependent reduction in post-prandial motility was observed following intravenous granisetron and this was highly significant at 160 mcg/kg (P = 0.005). These results suggest that the 5 hydroxytryptamine receptor antagonists may have a therapeutic role in patients with irritable bowel syndrome.

A comparative study of the effects on colon function caused by feeding ispaghula husk and polydextrose.

Polydextrose is a new soluble food ingredient which cannot be digested by intestinal enzymes and so may affect colonic function. Studies in healthy volunteers compared the effects of diet supplementation with 30 g/day polydextrose, a standard dose of 7 g/day ispaghula and two mixtures containing 2 g/day ispaghula with either 30 g/day polydextrose or 10 g/day polydextrose with a control period. During the 10-day periods, the mass, frequency and consistency of faeces were assessed as well as the whole-gut transit time, ease of defaecation, flatulence and palatability of the preparations. All preparations significantly increased the weekly faecal mass above control values (P less than 0.05) but there were no significant differences between the preparations. Transit time and stool frequency were not affected significantly by any of the preparations (P greater than 0.05). Both preparations supplying 30 g/day polydextrose softened stool consistency equally but the other preparations had no effect. All preparations caused flatulence and other gas-related problems but polydextrose caused more than ispaghula, even at the lowest dose of 10 g/day. More volunteers preferred taking the polydextrose drinks than the sachets of ispaghula which formed a viscous drink with water. Despite superior palatability and equally effective stool bulking, polydextrose is unlikely to be an alternative laxative to ispaghula because of the unacceptable levels of flatulence.

A comparative study of the effect of cimetidine and ranitidine on the rate of gastric emptying of liquid and solid test meals in man.

Paired studies were carried out on 18 healthy male volunteers (20.9 +/- 1.9 years; mean +/- S.D.) to compare the effect of oral doses of the H2-receptor antagonists, ranitidine and cimetidine, on the rate of gastric emptying of radiolabelled solid and liquid test meals. Oral administration of ranitidine 300 mg accelerated the emptying of a liquid meal from the stomach, but it had no significant effect on the rate of emptying of a solid meal. Oral administration of either 400 or 800 mg cimetidine did not alter the rate of emptying of either the liquid or the solid meals from the stomach.

The effect of oral vancomycin on chronic idiopathic constipation.

BACKGROUND: A case study reporting the efficacy of oral vancomycin in a patient with chronic idiopathic constipation prompted this prospective trial of oral vancomycin in eight female patients (aged 21-61 years) with severe constipation resistant to the action of dietary fibre. METHODS: The trial was divided into two consecutive 14-day periods. During the first period, each patient was given ispaghula, 3.5 g twice a day, and during the subsequent period they took 250 mg vancomycin t.d.s. per os, as well as the fibre supplement. During both periods they collected stools and recorded daily bowel symptoms (stool frequency, straining, stool consistency, subjective stool volume) in a diary. At the end of each period whole gut transit time and the breath hydrogen response to a standard meal, giving oro-caecal transit time, were measured along with gastrointestinal symptoms which were assessed on visual analogue scales. RESULTS: Vancomycin caused a significant improvement in stool frequency, consistency, ease of defecation and the amount of stool patients felt they produced (all P < 0.05), but objective measures of daily stool weight and whole gut or oro-caecal transit time were not significantly different. Basal breath hydrogen levels were higher after vancomycin treatment in seven out of eight patients. One patient experienced a complete remission of symptoms when she took vancomycin and remains in remission after 14 months. This patient showed no elevation in basal breath hydrogen level. CONCLUSION: Although this study does not support the use of vancomycin for most patients with constipation, the results suggest that modification of the intraluminal flora may be of value in the treatment of the occasional case of idiopathic constipation.

Effect of naloxone, domperidone and idazoxan on the delay in gastric emptying induced by ileal lipid.

Studies were carried out on 22 healthy male volunteers to investigate whether intravenous administration of either the opiate antagonist, naloxone, or the dopamine antagonist, domperidone, or the alpha 2-adrenoreceptor antagonist, idazoxan, could reverse the delay in gastric emptying induced by ileal infusion of lipid emulsion. Ileal infusion of 50% lipid emulsion significantly delayed the rate of gastric emptying compared with ileal infusion of isotonic saline (P less than 0.01). Intravenous infusion of naloxone (20 micrograms kg-1 hour-1) or prior administration of either intravenous domperidone (20 mg) or idazoxan (0.2 mg kg-1) did not inhibit the delay in gastric emptying induced by ileal infusion of lipid emulsion. These observations indicate that feedback regulation of gastric emptying by ileal lipid does not appear to be mediated by either dopaminergic or enkephalinergic neurons, nor by alpha 2-adrenoreceptors.

Effect of sumatriptan, a new selective 5HT1-like agonist, on liquid gastric emptying in man.

Paired studies were carried out on 12 healthy male subjects to compare the effect of intravenous doses of the 5-HT1-like agonist sumatriptan (GR43175; 3 mg), 10 mg metoclopramide and saline control on the rate of gastric emptying of a radiolabelled liquid test-meal. Intravenous administration of metoclopramide accelerated gastric emptying by decreasing the lag period, while intravenous administration of sumatriptan delayed gastric emptying by increasing the lag period. The observation that sumatriptan causes a delay in gastric emptying in normal healthy volunteers, but relieves nausea and vomiting during migraine attacks, suggests that sumatriptan may be acting via a central mechanism to relieve symptoms of nausea and vomiting associated with migraine.

The effect of two alpha 2-adrenoreceptor agonists and an antagonist on gastric emptying and mouth to caecum transit time in humans.

Experiments were performed to investigate the effect of two alpha 2-adrenoreceptor agonists, clonidine and lidamidine, and a specific alpha 2-adrenoreceptor antagonist, idazoxan, on gastric emptying and mouth to caecum transit time (MCTT) of a radiolabelled meal in 27 healthy male subjects. Lidamidine (20 mg p.o.) and clonidine (0.3 mg p.o.), given alone had no significant effect on gastric emptying or MCTT suggesting that the anti-diarrhoeal action of clonidine and lidamidine are unlikely to be explained by a slowing of small intestinal transit. Idazoxan (20 mg p.o.) reversed the effect of clonidine in 10 subjects, who showed a delay in MCTT after taking clonidine, but did not alter MCTT under basal conditions. These results suggest that although the sympathetic nervous system can influence upper gastrointestinal motility by an action on alpha 2-adrenoreceptors, this action does not exert a tonic influence on upper gastrointestinal motility under basal conditions.

Effects of meals on objective and subjective measures of daytime sleepiness.

Effects of recent food ingestion on daytime sleepiness were assessed in 16 subjects (8 men and 8 women) who were each studied on two occasions, 28 days apart. On each occasion, subjects ate a high-fat low-carbohydrate (CHO) (fat/CHO energy ratio 54:41) meal and an isoenergetic low-fat high-CHO meal (fat/CHO energy ratio 7:88) 4 h apart in a counterbalanced order. Sleepiness was measured at 2-hr intervals by using the Multiple Sleep Latency Test and the Akerstedt electroencephalograph sleepiness test. To control for circadian factors, one group (4 men, 4 women) ate the meals 2 h later than did the other group of subjects. There were no differences in sleepiness according to the composition of the meal. Sleepiness in the Multiple Sleep Latency Test was significantly greater 1.5 h after the meals were eaten than before (F 11.37; df 1,15; P = 0.004). Sleepiness was also enhanced in the Akerstedt sleepiness test 3 h 20 min after the meals. The results suggest that the meals induced an enhancement in sleepiness that was not solely due to circadian rhythms.

The effects of pH on colonic bacteria grown in continuous culture.

A model of the proximal colon was used to investigate the effects of pH on fermentation by colonic bacteria in vitro. Twelve continuous anaerobic cultures of human faecal bacteria were maintained at constant pH in a medium simulating ileostomy effluent. Five cultures were maintained at pH 7, five at pH 6, and two at pH 5. The pH of each of three further cultures was altered after they had reached steady state, either from 7 to 6 and then to 5, or from 5 to 6 to 7. Both experimental designs showed that the pH exerted an important effect on bacterial metabolism without causing major changes in bacterial populations. Osmolality was lower in cultures run at a low pH. Total volatile fatty acid concentration was decreased at pH 5, and the production of propionic acid rather than acetic acid was favoured at pH 6. Changing the pH had no significant influence on the production of ammonia in these systems.

An examination of the effects of isoenergetic intragastric infusions of pure macronutrients on cold pain perception in healthy human volunteers.

Our previous study demonstrated that meals, particularly when rich in fat, significantly reduced the pain induced by the cold pressor stimulus in healthy human subjects. To determine the mechanisms involved, the aim of this study was to bypass the taste and cognitive component of food and to investigate the scope of these analgesic effects with direct intragastric infusion of pure macronutrients in a group of 16 healthy human volunteers (eight male and eight female) on the response to cold-induced pain. All subjects underwent the cold pressor test (CPT) on three occasions in a counterbalanced order: before and after intragastric intubation and infusion of isoenergetic fat (10% intralipid), carbohydrate (CHO-maltodextrin), and a control infusion of isotonic saline. All solutions were of equal volume and administered at room temperature. The CPT was carried out four times on each test day, once before intubation, and 0.5, 1.5, and 2.5 h after intragastric infusion. Radial pulse and blood pressure measurements and visual analogue scales of mood/emotional state were carried out before and after each CPT. There were no significant differences in pain scores between the three test conditions, suggesting that by bypassing the cognitive and taste component of eating, the trigger for any postingestive analgesic effects of food are lost.

Influences of fat, energy, and time of day on mood and performance.

Paired studies testing the effects of lower energy high-fat, low-CHO meals (3181 kJ, fat:CHO energy ratio 54:41) and higher energy low-fat, high-CHO meals (3599 kJ, fat:CHO energy ratio 7:88) were conducted in 18 healthy males. The meals were eaten at 1030 h by group A (nine subjects) and 1230 h by group B (nine subjects). Subjective lassitude increased following ingestion of all four meals, but there was little change in performance. In addition, group A, but not group B, felt significantly less vigorous, imaginative, and antagonistic, and significantly more dreamy, feeble, and fatigued after the lower energy high-fat, low-CHO meal than after the higher energy low-fat, high-CHO meal. These results suggest that in the morning, fat exerts a greater depression on alertness and mood than carbohydrate irrespective of a reduction in energy content, but this effect varies according to the time at which food is eaten, and is less evident at lunch time.