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Reduction by morphine of human postprandial insulin release is secondary to inhibition of gastrointestinal motility.

The effect of morphine (0.1 mg/kg) on insulin secretion stimulated by oral, intraduodenal, or intravenous administration of glucose was studied in seven healthy volunteers. When glucose was given intravenously, morphine had no effect on plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP), or pancreatic glucagon. Following oral glucose, morphine slowed gastric emptying and reduced plasma concentrations of glucose, insulin, and GIP. During intraduodenal infusion of glucose, insulin concentrations in plasma were also decreased by morphine, an effect best explained by decreased small intestinal transit with delayed absorption of glucose and delayed release of GIP. We conclude that clinically relevant doses of morphine have no direct effect on insulin secretion and that the changes observed were secondary to slowed gastric emptying and small intestinal transit.

Adolescent↗

Evaluation of gastrointestinal motility using the hydrogen breath test.

The purpose of the study was to evaluate the validity of a model where intestinal transit is increased and decreased by motility modifying drugs. The measurement of breath hydrogen concentrations after ingestion of lactulose was used to estimate small intestinal transit time. After obtaining base-line values, eight healthy volunteers were pretreated on separate occasions with loperamide, diphenoxylate, metoclopramide and cisapride. Diphenoxylate caused a significant increase in small bowel transit time, whereas both metoclopramide and cisapride significantly shortened it. The H2 breath test therefore seems to accurately reflect the expected transit time. Loperamide did not alter significantly intestinal transit. Possibly this drug counteracts its own delaying influence on small bowel transit by hurrying gastric emptying. Alternatively, not enough time was allowed for it to exert its full effect.

Adult↗

Normal and abnormal gastrointestinal motility.

The study of GI motility is an area of great current interest and excitement. Our knowledge of normal and abnormal GI motility is expanding exponentially. Perhaps one of the most satisfying consequences of this new knowledge is the ability to reassure patients that their symptoms may not be functional but may be based on a specific physiologic dysfunction. Unfortunately, our ability to treat effectively these newly described disorders has lagged behind our ability to diagnose them, but progress is being made, with promising new therapeutic agents on the horizon. Gastroenterologists remain the best friends of surgeons; most of these patients can and should be managed without surgical intervention. Therapeutic nihilism is not justified, because a carefully considered and properly timed operation may be of tremendous symptomatic benefit to selected patients. As more information and follow-up results are gained, the proper role of surgical intervention in these disorders will be better defined.

Antiemetics↗

Action of intragastric ethanol on pancreatic exocrine secretion in relation to the interdigestive gastrointestinal motility in humans.

On different days, fasted volunteers were given either 100 ml of ethanol (40% v/v), glucose (isocaloric to ethanol) or distilled water intragastrically; the instillations always starting during the first observed duodenal phase I of the interdigestive migrating complex (IMC). Both ethanol and glucose produced a fed pattern of motility but only glucose significantly (P less than 0.05) delayed the reappearance of a new duodenal phase III of the IMC when compared to water. Ethanol and glucose significantly increased the 1-h duodenal bicarbonate output 7- and 16-fold, respectively. Glucose, but not ethanol, stimulated the duodenal amylase output when compared to water. Glucose, but not ethanol, caused a significant rise in plasma gastrin concentration; plasma secretin levels not being altered by both substances. We conclude that in non-alcoholic humans, an intragastric administration of ethanol in a concentration present in whisky and in an amount that is consumed in ordinary social drinking has a weak stimulatory action on pancreatic bicarbonate secretion and that this action is not mediated by release of secretin.

Adult↗

Gastrointestinal motility and absorption of calcium during infusion of somatostatin in the rat.

The effect of somatostatin on gastric evacuation, small bowel propulsion and gastrointestinal (GI) absorption of calcium was studied in conscious rats. Nonabsorbable 125I-PVP was deposited in the stomach or in the duodenum and the distribution of the radioactivity along the excised GI specimen was recorded after 15 min. 47Ca in chloride from was administered simultaneously and the amont of radioactivity remaining in the GI speciment at sacrifice could easily be measured. Intravenous infusion of synthetic somatostatin (50 micrograms.kg-1.h-1), which resulted in a manifest although not extreme hypersomatostatinemia had no effect either on gastric evacuation, small bowel propulsion or GI absorption of calcium. The findings do not indicate that somatostatin has a direct effect on GI motility or absorption of calcium.

Animals↗

General pharmacology of the four gastrointestinal motility stimulants bethanechol, metoclopramide, trimebutine, and cisapride.

The pharmacological profile of bethanechol (CAS 674-38-4), metoclopramide (CAS 364-62-5), trimebutine (CAS 39133-31-8) and cisapride (CAS 81098-60-4) was studied in a series of simple pharmacological tests in rats and dogs. Bethanechol stimulated both gastric emptying and intestinal propulsion but displayed also the well-known behavioral effects of a direct muscarinic acetylcholine receptor agonist. Metoclopramide showed the profile of a centrally active dopamine D2 antagonist. In addition, metoclopramide displayed a stimulant effect on spontaneous gastric emptying in rats, an effect that could not be related to dopamine D2 antagonism. The only effect observed with trimebutine was protection from castor oil diarrhea, probably due to its reported interaction with peripheral opiate receptors. Cisapride was a potent stimulant of gastric emptying in rats, 7 times more potent than metoclopramide. Cisapride was also a very specific gastrokinetic, over a large dose range (specificity ratio: greater than or equal to 20) devoid of effects indicative for direct interaction with dopamine or acetylcholine receptors. The relationship between the differential activity profiles of the compounds in the present study and differences in their mechanism of action and side-effect liability is discussed.

Animals↗

Role of cholecystokinin in the regulation of gastrointestinal motility.

Cholecystokinin, a hormone released from endocrine cells of the upper small intestine in response to amino acids and fatty acids in chyme, has potent effects on gut smooth muscle contractility. Depending on the region of the gut, the effect of cholecystokinin may be neurally mediated, direct, or both. Neurally-mediated effects may be relaxant or contractile depending on the transmitter released by cholecystokinin. Based on mimicry by infusion of cholecystokinin to postprandial levels and the ability of specific cholecystokinin receptor antagonists to abolish effects of endogenous cholecystokinin released in response to a meal, three physiological effects of cholecystokinin, all of which are neurally-mediated, have been identified: contraction of the gallbladder mediated by cholecystokinin-induced release of acetylcholine, relaxation of the sphincter of Oddi mediated by cholecystokinin-induced release of vasoactive intestinal peptide and inhibition of gastric emptying mediated by cholecystokinin-induced activation of an inhibitory vago-vagal reflex involving vasoactive intestinal peptide-induced relaxation of the gastric fundus. Gallbladder contraction and relaxation of the sphincter of Oddi regulate the flow of bile, and inhibition of gastric emptying regulates the flow of chyme into the duodenum. Combined with the potent stimulation of pancreatic enzyme secretion by cholecystokinin, these effects insure optimal conditions for digestion and absorption of nutrients by the intestine.

Animals↗

Gastrointestinal motility stimulating drugs and 5-HT receptors on myenteric neurons.

5-HT3 receptor antagonists may have both antiemetic and gastric and intestinal motility stimulating properties, but they differ in their relative potencies and efficacies for these two activities. Since the 5-HT3 receptor is present on enteric neurons, intracellular recordings of myenteric neuronal transmembrane potential were used to assess the actions of four proposed motility stimulating drugs, metoclopramide, BRL 24924, ICS 205-930 and cisapride. BRL 24924 (10(-6) M), ICS 205-930 (10(-7) M) and cisapride (5 x 10(-6) M) each antagonized the 5-HT3-mediated fast depolarization of myenteric neurons. Metoclopramide (10(-5) M) was less consistent in its ability to antagonize this response, and the response often returned in the continued presence of metoclopramide. In the present study, BRL 24924 (10(-6) M) and, as previously shown, cisapride (5 x 10(-6) M) antagonized the slow depolarization of myenteric neurons induced by 5-HT. Metoclopramide (10(-5) M), BRL 24924 (10(-6) M) and cisapride (5 x 10(-6) M), but not ICS 205-930 (10(-7) M) depolarized myenteric neurons within the first 2 min of contact with myenteric neurons. These data support the view that there are separate receptors that may be responsible for the prokinetic actions of these drugs and a series of 5-HT3-mediated actions which include antiemesis.

Animals↗

Octreotide in gastrointestinal motility disorders.

The effects of octreotide on six normal subjects and five patients with scleroderma were investigated. Changes in intestinal motility and in plasma motilin were examined after a single injection of octreotide. Octreotide stimulated intense intestinal motor activity in normal subjects. Motility patterns in the scleroderma patients were chaotic and non-propagative, but, after octreotide was given, became well coordinated, aborally directed, and nearly as intense as in normal volunteers. Clinical responses and changes in breath hydrogen were also evaluated in the five scleroderma patients who had further treatment with octreotide at a dose of 50 micrograms/day subcutaneously for three weeks. A reduction in symptoms of abdominal pain, nausea, vomiting, and bloating was seen. Additionally, there was an improvement in bacterial overgrowth as objectively measured by breath hydrogen testing. The effects of octreotide (100 micrograms/day subcutaneously) on the perception of rectal distension were investigated in a double blind, placebo controlled study in healthy volunteers. Octreotide was shown to reduce the perception of rectal distension without affecting motor pathways or local rectal reflexes. This enhanced tolerance to volume distension seems to result from inhibition of sensory afferent pathways as shown by electroencephalographic studies showing diminished evoked spinal and cortical potentials after octreotide. In irritable bowel syndrome patients with rectal urgency, octreotide reduces rectal pressures and perception after rectal distension to near normal values.

Breath Tests↗

A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis.

Peptide hormones exert unique actions via specific G protein-coupled receptors; however, the therapeutic potential of regulatory peptides is frequently compromised by rapid enzymatic inactivation and clearance from the circulation. In contrast, recombinant or covalent coupling of smaller peptides to serum albumin represents an emerging strategy for extending the circulating t(1/2) of the target peptide. However, whether larger peptide-albumin derivatives will exhibit the full spectrum of biological activities encompassed by the native peptide remains to be demonstrated. We report that Albugon, a human glucagon-like peptide (GLP)-1-albumin recombinant protein, activates GLP-1 receptor (GLP-1R)-dependent cAMP formation in BHK-GLP-1R cells, albeit with a reduced half-maximal concentration (EC(50)) (0.2 vs. 20 nmol/l) relative to the GLP-1R agonist exendin-4. Albugon decreased glycemic excursion and stimulated insulin secretion in wild-type but not GLP-1R(-/-) mice and reduced food intake after both intracerebroventricular and intraperitoneal administration. Moreover, intraperitoneal injection of Albugon inhibited gastric emptying and activated c-FOS expression in the area postrema, the nucleus of the solitary tract, the central nucleus of the amygdala, the parabrachial, and the paraventricular nuclei. These findings illustrate that peripheral administration of a larger peptide-albumin recombinant protein mimics GLP-1R-dependent activation of central and peripheral pathways regulating energy intake and glucose homeostasis in vivo.

Albumins↗

The association between enteric bacterial overgrowth and gastrointestinal motility after subtotal liver resection or portal vein obstruction in rats.

OBJECTIVE: To test the hypothesis that intestinal motility is delayed after hepatectomy, which alters the ecology of the enteric microflora and contributes to the development of bacterial translocation from the gut. DESIGN: Open experimental study. SETTING: University department of surgery. MATERIAL: Adult male Sprague-Dawley rats (n = 6 in each group at each time point). INTERVENTIONS: Sham operation, 90% hepatectomy, and portal venous obstruction. MAIN OUTCOME MEASURES: Intestinal morphology, immunocytochemistry of the enteric nervous system, enteric bacterial growth in the small intestine and colon, and intestinal transit time. RESULTS: Intestinal transit was already delayed one hour after 90% hepatectomy, and histopathological alterations and overgrowth by Escherichia Coli had developed after two hours. There were significant differences in intestinal transit time between sham operated rats and those subjected to portal venous obstruction on the one hand, and those that underwent 90% hepatectomy on the other. There was no difference in intestinal transit time between rats with portal venous obstruction and the sham operated animals. CONCLUSION: Delayed intestinal transit after 90% hepatectomy may contribute to enteric bacterial overgrowth and thereby contribute to the development of bacterial translocation from the gut.

Animals↗

Dose-related effects of motilin on proximal gastrointestinal motility.

AIM: To assess non-invasively the dose-response relations for the effects of exogenous motilin on antrum contraction frequency, gall-bladder volume and gastric myoelectrical activity. METHODS: In a double-blind, randomized, placebo-controlled, five-way crossover study, 10 fasted healthy volunteers were infused intravenously with synthetic human motilin (0.5, 1, 2 and 4 pmol x min/kg) or placebo for 60 min. Gall-bladder volume and antrum contractions were assessed by ultrasonography and gastric myoelectrical activity by electrogastrography. Motilin concentrations were measured using a radioimmunoassay. RESULTS: Baseline plasma motilin levels (60 pmol/L) were similar for all treatments. Motilin levels increased upon the start of infusion and rapidly returned to baseline after cessation of the infusion. At motilin doses of 2 and 4 pmol.min/kg, the antrum contraction frequency was significantly augmented, with maximum differences of two contractions per 2-min interval compared to placebo, while no changes in gastric myoelectrical activity were observed. Changes in gall-bladder volume were not significantly different for any of the motilin doses compared to placebo. CONCLUSIONS: Motilin increased antrum contraction frequency, whereas no effect on gastric myoelectrical activity was observed. Antrum contraction frequency appears to be a useful biomarker for motilin efficacy, and motilin doses of 2 and 4 pmol x min/kg were equally effective.

Adolescent↗

Domperidone should not be considered a no-risk alternative to cisapride in the treatment of gastrointestinal motility disorders.

BACKGROUND: Several cases of QT prolongation and ventricular tachyarrhythmia have been reported with domperidone, a gastrokinetic and antiemetic agent available worldwide but still under investigation in the United States. Although electrolyte disturbances such as hypokalemia could account for some of these events, we hypothesized that domperidone may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. METHODS AND RESULTS: Studies were undertaken in 9 isolated guinea pig hearts, which demonstrated reverse use-dependent prolongation of cardiac repolarization by 100 nmol/L domperidone. Action potential duration increased 27% from baseline with domperidone (from 114+/-3 to 145+/-2 ms) during pacing at a cycle length of 250 ms, and a 9% increase (from 97+/-2 to 106+/-3 ms) was seen with pacing at a cycle length of 150 ms. Experiments in human ether-a-go-go-related gene (HERG)-transfected Chinese hamster ovary cells (n=32) demonstrated a concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current. The tail current decreased by 50% at 162 nmol/L domperidone. CONCLUSIONS: Domperidone possesses cardiac electrophysiological effects similar to those of cisapride and class III antiarrhythmic drugs. These effects are observed at clinically relevant concentrations of the drug. Therefore, domperidone should not be considered a no-risk alternative to cisapride, a drug that was recently withdrawn from the US market.

Action Potentials↗

[Networks of pacemaker cells for gastrointestinal motility].

In the wall of the digestive tract, there are pacemaker and conduction systems which can be compared with those in the heart. The introduction of c-Kit as a specific marker of the cells, ICCs, have dramatically clarified morphological and functional understanding of the cells. Mutant animals that lack c-Kit lose or decrease intestinal motility. Four classes of ICCs have been identified and these are distributed along the digestive tract in an organ- and tissue-specific manner: 1) IC-MY locate along the myenteric plexus; 2) IC-DMP, along the deep muscular plexus of small intestine; 3) IC-SMP, along the interface between the submucosa and circular muscle layer of large intestine; and 4) IC-IM, within the muscular layer of the stomach and large intestine. Basically, IC-MY and IC-SMP have pacemaker functions, whereas IC-DMP and IC-IM link signals between the enteric nervous system and smooth muscle cells (SMC). All classes of the cells are connected by gap junctions. Immunocytochemical observations using specific antibodies against various gap junction proteins, connexins (Cx), revealed that Cx43 was localized in the gap junctions between SMC and ICCs, whereas Cx45 was specifically expressed in IC-DMP as it is in the cardiac conduction systems. Mutant animals that we produced enabled us to show cells expressing Cx45 mRNA by replacing the Cx45 locus with a LacZ reporter gene and revealed that most of SMC express Cx45, where so far gap junctions were not demonstrated by electron microscopy or immunocytochemistry, probably due to their small size.

Animals↗

Gastrointestinal motility in patients with ulcerative colitis.

In the first study 62 patients with ulcerative colitis and 20 healthy controls were fed a test meal of mashed potatoes and baked beans containing transit markers. Mouth-to-caecum transit was significantly slower in the patients than in controls; gastric emptying, however, was similar. Patients with active colitis had proximal colonic stasis, with rapid transit through the rectosigmoid region. In the patients with quiescent colitis the colonic distribution of markers was normal. Stool weight and frequency were significantly higher in the patients with active colitis. In the second study anorectal function was assessed in 29 patients with ulcerative colitis and in 12 healthy controls by measuring interluminal pressures at multiple sites in the anus and rectum before and during serial distention of a rectal balloon. Overall, resting and maximum squeeze sphincter pressures did not differ in patients with active or quiescent colitis and controls; however, in six patients with moderately severe colitis and incontinence, maximum squeeze pressure was significantly lower than in controls. The rectal volumes required to induce sensations of wind, a desire to defaecate, and pain were significantly lower in the patients with active colitis than patients with quiescent colitis and controls. Rectal pressures in response to rectal distention were higher in patients with active colitis. During disease remission rectal sensitivity decreased and rectal compliance increased. In the third study integrated pressure activity of the sigmoid colon, rectum, and anus was studied in patients with ulcerative colitis and healthy controls before and during provocation by rectal infusion of 1500 ml of warm saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Colitis, Ulcerative↗

The newborn piglet: a model of neonatal gastrointestinal motility.

Small intestinal myoelectric activity has been studied extensively in adult humans and in many animal models. However, little is known about gut myoelectrical activity in newborns, a population susceptible to primary and secondary motility disorders. We report the development of a chronic neonatal piglet model for assessment of gastric and small intestinal myoelectric activity. Six piglets aged 12 to 27 days and weighing 2.3 to 4 kg underwent laparotomy and implantation of four to six bipolar serosal electrodes along the small intestine; and selectively on the gastric antrum. Myoelectric records were obtained daily after operation in awake animals using low (0.16 Hz) and high (30 Hz) frequency filters. Electrical control activity (ECA) was observed in the stomach (4 to 5 cycles per minute) and in the duodenum (14 to 15 cycles per minute) on postoperative day 1; along with random bursts of spiking activity. The migrating myoelectric complex (MMC) appeared on postoperative day 2 or 3. In piglets followed for a week or more, the MMC cycle duration and phase III duration (period of maximal spiking activity) were longer in the proximal small intestine than at the terminal ileum (80 +/- 5 versus 47 +/- 3 minutes and 5.1 +/- 0.3 versus 3.7 +/- 0.1 minutes, respectively; mean +/- SEM, P less than .005), suggesting that some MMCs arise spontaneously in the distal small bowel without traversing the upper intestine. The antral and duodenal ECA frequencies are similar to values reported in human adults; the MMC cycle duration is slightly shorter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Relationships between dyspeptic symptoms and gastrointestinal motility in patients with type 1 (insulin-dependent) diabetes mellitus.

Reports on motor abnormalities in Type 1 (insulin-dependent) diabetes mellitus are inconsistent. In 20 Type 1 diabetic patients and in 11 control subjects antroduodenojejunal manometry was performed under euglycaemic conditions in order to examine the prevalence of gastric and small intestinal motor abnormalities in relation to dyspeptic symptoms and the degree of cardiac autonomic neuropathy. In diabetic patients compared to control subjects phase III (regular, high-amplitude contractile activity at maximal frequency) involved the gastric antrum less often (12 vs 35%, p < 0.05), the duration of phase I (motor quiescence) was shorter (6 +/- 1 vs 21 +/- 4 min, p < 0.002) and in phase II (irregular motor activity) the frequency of duodenal and jejunal contractions was higher. After a meal the duration of the fed state was shorter in diabetic patients with symptoms during the study than in diabetic patients without symptoms and than in control subjects (57 +/- 27 vs 157 +/- 11 and 140 +/- 13 min, p < 0.02). Postprandial antral hypomotility was seen in diabetic patients with symptoms only in the first 30 min after the meal. One hour after the meal the frequency of duodenal and jejunal contractions was again higher in diabetic patients. In diabetic patients compared to control subjects more burst activity (clusters of non-propagated high-amplitude contractile activity at maximal frequency) was seen (7.9 +/- 1.6 vs 0.8 +/- 0.5% of the total time of study, p < 0.002). No correlation was found between manometric parameters and the degree of cardiac autonomic neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Standards for non-invasive methods for gastrointestinal motility: scintigraphy. A position statement from the Gruppo Italiano di Studio Motilità Apparato Digerente (GISMAD).

Scintigraphic techniques are well established methods to assess gastrointestinal transit patterns. The main advantages are represented by the possibility to evaluate, in a relatively non-invasive manner, the transit time of specific components of physiological meals as well as of some digestive secretions. These techniques are generally well accepted by the patients and results are largely not operator dependent. Their main limitation is the use of a radioisotope, that prevents repeated applications in all subjects and immediate exclusion of women of childbearing potential. Due to the high costs of these tests and the limited availability of Nuclear Medicine Departments, scintigraphic techniques should be reserved for well-selected patients. A review is made of the technical requirements and indications for scintigraphic tests currently available for clinical purposes (gastric emptying study, oesophageal transit time, evaluation of gastro-oesophageal reflux, intestinal and colonic transit time, evaluation of biliary motility and of duodenogastric reflux).

Colon↗