Intolerance to visceral distension in functional dyspepsia or irritable bowel syndrome: an organ specific defect or a pan intestinal dysregulation?

Functional gastrointestinal disorders (FGID) are characterized by visceral hypersensitivity that could be specific to a region of the gut or reflect a diffuse pan-intestinal disorder. Sensory thresholds to distension at two visceral sites in patients with different FGIDs were determined. According to Rome II criteria, 30 patients from three groups were studied: patients with (i) functional dyspepsia (FD) or (ii) irritable bowel syndrome (IBS), and (iii) patients with concomitant symptoms of FD and IBS. Pain thresholds to balloon distension were determined in stomach and rectum. In FD patients, gastric intolerance to balloon distension was found in 91% patients; rectal hypersensitivity was documented in 18% patients. In IBS patients, rectal hypersensitivity was seen in 75% patients; while gastric hypersensitivity was never found. In patients with concomitant symptoms of FD + IBS, gastric and rectal intolerance to distension were present respectively in 82 and 91% patients. In the whole group, visceral intolerance to distension was documented at one site in 90% patients and at both sites, i.e. stomach and rectum, in 33% patients. Visceral intolerance to distension can be pan-intestinal in patients with multiple sites of symptoms, but appears organ-specific in patients exhibiting a specific site of symptoms.

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.

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.

Review article: acid suppression in non-variceal acute upper gastrointestinal bleeding.

Despite a decreased incidence of ulcer disease and improvements in the management of acute upper gastrointestinal (GI) bleeding, mortality remains at about 6-7%. Although endoscopic haemostatic therapy has been demonstrated to be the mainstay of management, the search continues for less invasive medical modalities that might also improve patient outcome. In vitro data have indicated the important role of acid in impairing haemostasis and causing clot digestion. Therefore, theoretically, maintenance of a high intragastric pH (above 6.0) during management of upper GI bleeding is warranted. Until recently, available agents did not permit such a sustained elevation in gastric pH. Early studies with H2-receptor antagonists have not demonstrated significant improvements in important patient outcomes, such as rebleeding, surgery or mortality. With the availability of intravenous formulations of proton pump inhibitors, it is now possible to aim at maintaining gastric pH above 6.0 for 24 h per day. Recent clinical trial data would appear to support the use of proton pump inhibitors to decrease the rate of rebleeding and the need for surgery. This paper provides a review of non-variceal acute GI bleeding, with special reference to the role of proton pump inhibitors in this clinical setting.

Stress-induced changes in the gastrointestinal motor system.

Several autonomic, hormonal, behavioural and neuropeptidergic bodily responses to stressful stimuli have been described over the past few decades. Both animal models and human paradigms have been explored. It is acknowledged that stress modulates gastrointestinal (GI) motility through central mechanisms including corticotropin-releasing-factor. This process requires the integrity of autonomic neural pathways. It has become evident that the effects of stress on GI motility vary according to the stressful stimulus, its intensity, the animal species under study and the time course of the study. Recent evidence suggests that chronic or possibly permanent changes develop in enteric smooth muscle properties in response to stress. In animals, the most consistent findings include retardation of gastric emptying in response to various stressors; acceleration of gastric emptying upon cold stress, presumably through the secretion of brain thyroglobulin-hormone; acceleration of intestinal transit; and stimulation of colonic transit and fecal output. In humans, the cold water immersion test has been associated with an inhibition of gastric emptying, while labyrinthine stimulation induces the transition from postprandial to fasting motor patterns in the stomach and the small bowel. Psychological stress has been shown to induce a reduction in the number and amplitude of intestinal migrating motor complexes and to neither affect nor stimulate colonic motility. These various responses to stress are presumably attributed to the preferential activation of specific neuronal pathways under the influence of a given stimulus or its intensity. The significance of these findings and the directions of further studies are discussed.

The economic burden of irritable bowel syndrome in Canada.

In the treatment of irritable bowel syndrome (IBS), medical practitioners and policymakers face the task of providing both high quality and cost effective medical care for a condition with no certain cure. To date, studies have examined only total medical costs to patients with symptoms consistent with an IBS diagnosis. However, these studies have not examined the direct and indirect costs incurred in the course of treatment for IBS, excluding the costs of unrelated medical conditions. Because patients with IBS have been shown to differ significantly from non-IBS patients in their desire to seek medical care, one cannot consider solely the cost differential in medical costs for IBS and non-IBS patients. The present study examines a set of patients who have been diagnosed with IBS and seek medical care for IBS.

Evaluation of gastric emptying function in clinical practice.

In this retrospective analysis, we compared different methods to evaluate gastric emptying function, aiming to improve the sensitivity and the clinical availability of our diagnostic testing. In the first study, we compared, in 72 patients clinically suspected of gastroparesis, the emptying of a meal containing two solid nutrients with different disintegration rates: 111In-labeled scrambled eggs and 99Tc-labeled liver cubes. Gastric emptying of 111In-labeled egg was delayed in 12 of our patients and the evacuation of the 99Tc-labeled liver was prolonged in 19 patients. The choice of the nutrient was not important for the identification of diabetic gastroparesis (43% vs 57%; NS), but it was determinant in the case of patients suspected of idiopathic gastroparesis (12% were positive with the egg and 25% with the liver; P < 0.05). In the second study, we compared two different diagnostic methods in 46 patients: a simple radiological detection of the gastric emptying of radiopaque pellets, and the scintigraphic emptying of a solid meal containing 99Tc-labeled liver cubes. Both tests correlated perfectly in 78% of our patients. In 15% of the population (six of these seven patients were diabetics suspected of gastroparesis) the scintigraphic method was normal, while the evacuation of radiopaque pellets was delayed. For clinical purposes, we therefore propose: (1) the scintigraphic method should use liver rather than egg as a radiolabeled tracer in order to improve the sensitivity of the test for detection of gastroparesis; and (2) the radiological detection of radiopaque markers is a reliable and convenient method for the detection of gastroparesis in clinical practice. It is possibly more sensitive than scintigraphy.

Calcitonin gene-related peptide in viscerosensitive response to colorectal distension in rats.

The role of calcitonin gene-related peptide (CGRP) on colorectal distension-induced visceral pain was investigated in conscious rats. Intracolonic administration of acetic acid (0.6%) resulted in a significantly increased number of abdominal contractions in response to colorectal balloon distension from 5.8 +/- 1.2 in controls to 16.6 +/- 1.0 in acetic acid-treated animals (P < 0.05), evidencing sensitization of visceral afferent pathways and subsequently visceral hyperalgesia. This sensitization phenomenon was not observed in animals previously treated with systemic capsaicin. Likewise, in animals not treated with capsaicin, use of an intravenous antagonist for CGRP [human CGRP-(8-37)], completely reversed the sensitizing effects of acetic acid. Furthermore, intravenous administration of CGRP dose dependently increased the number of abdominal contractions in response to colorectal distension from 3.0 +/- 1.1 (CGRP 250 ng) to 17.0 +/- 1.2 (CGRP 500 ng, P < 0.05), as previously observed in acetic acid-treated animals. Finally, intrathecal administration of hCGRP-(8-37) (mid-lumbar) also resulted in a total dose-dependent reversal of CGRP (500 ng) or acetic acid-induced visceral hypersensitivity. These results demonstrate that CGRP plays a major role in this model of visceral afferent nerve sensitization from gastrointestinal origin.

Effects of the corticotropin-releasing factor (CRF) on rectal afferent nerves in humans.

Corticotropin-releasing factor (CRF) released in the gastrointestinal mucosa from immune cells or enterochromaffin cells may play a role in the modulation of rectal afferent function. In the current study we evaluated the effects of peripherally administered CRF on afferent mechanisms in the human rectum. We used rectal balloon distention in seven healthy volunteers to evaluate the effect of CRF (1 microgram/kg) on visceral afferents originating in the rectum which are involved in the following functions: thresholds and intensity of conscious perception, receptive relaxation, reflex inhibition of internal anal sphincter and a viscerosomatic reflex. Rectal mechanoreceptors were stimulated either by distending the rectum using a volume ramp (40 and 400 mL/min), or by intermittent phasic distention. CRF decreased the thresholds and increased the intensity for the sensation of discomfort in response to both ramp and phasic distention. During slow ramp distention, CRF also lowered the stool threshold. CRF increased rectal compliance during slow ramp distention without affecting the rate of receptive relaxation or the inflection point of the compliance curve. CRF had no effect on viscerosomatic referral patterns, or on the rectoanal inhibitory reflex. These findings are consistent with a dual effect of CRF on afferent pathways mediating perception of aversive rectal sensations, and on rectal smooth muscle.

Abdominal surgery-induced inhibition of gastric emptying is mediated in part by interleukin-1 beta.

The role of interleukin-1 beta (IL-1 beta) in abdominal surgery-induced inhibition of gastric emptying was investigated. Abdominal surgery was performed under halothane anesthesia, and 5 min later, the 20-min rate of gastric emptying was measured by the phenol red method in conscious animals. In nonoperated animals, intravenous IL-1 beta dose dependently decreased gastric emptying from 55.1 +/- 1.7% in controls to 8.0 +/- 3.5% (P < 0.05) after treatment with 1 microgram IL-1 beta. Prior administration of IL-1 beta receptor antagonist (IL-1 beta ra; 200 micrograms) completely abolished the inhibitory effects of IL-1 beta. Surgery inhibited gastric emptying by 83.4% compared with rats receiving anesthesia alone. IL-1 beta ra (200 micrograms) reversed the inhibition of gastric emptying by 34.8% (P < 0.05) in the early (30 min) postoperative period and by 32.3% (P < 0.05) in the late (120 min) postoperative period. Use of calcitonin gene-related peptide-(8-37) [CGRP-(8-37)] in combination with IL-1 beta ra in operated animals resulted in no further reversal in the inhibition of gastric emptying: CGRP-(8-37)-treated animals = 42.1 +/- 4.1%; CGRP-(8-37) + IL-1 beta ra = 38.0 +/- 4.4% (not significant). Moreover, in nonoperated animals, CGRP-(8-37) completely abolished the effects of intravenous IL-1 beta on gastric emptying: IL-1 beta-treated animals = 11.1 +/- 2.0%; IL-1 beta + CGRP-(8-37) = 40.6 +/- 6.4% (P < 0.05). These results suggest that IL-1 beta is mediating part of the gastric ileus observed after abdominal surgery through the release of CGRP from the visceral afferents.

Intravenous interleukin-1-beta-induced inhibition of gastric emptying: involvement of central corticotrophin-releasing factor and prostaglandin pathways in rats.

The role of corticotrophin-releasing factor (CRF) and prostaglandin in interleukin-1 beta (IL-1 beta)-induced delayed gastric emptying was investigated. Gastric emptying was monitored 20 min after orogastric delivery of a methylcellulose phenol red solution in fasted rats injected intravenously with IL-1 beta at the ED50 dose (3 ng/rat) 30 min before the non-caloric solution. The IL-1 receptor antagonist (IL-1ra) injected intravenously (3 micrograms/rat) or intracisternally (100 ng/rat) reversed the IL-1 beta-induced 47% inhibition of gastric emptying by 100% and 62%, respectively. The new CRF antagonist [DPhe12, Nle21,38, C alpha MeLeu37]-CRF12-41 (20 micrograms/rat), injected intracisternally, or indomethacin (5 mg/kg i.p.) completely abolished IL-1 beta (3 ng/rat i.v.)-induced gastric stasis. The CRF antagonist injected intravenously (20 micrograms/rat) did not influence the IL-1 beta inhibitory action. None of the pretreatments given alone influenced basal gastric emptying. These data suggest that peripheral IL-1 beta-induced inhibition of gastric emptying is mediated by specific IL-1 receptor interactions and brain CRF pathways requiring the integrity of eicosanoid-cyclooxygenase pathways.

Abdominal surgery induces Fos immunoreactivity in the rat brain.

Previous neuropharmacological studies indicate that brain peptides are involved in mediating gastric stasis induced by abdominal surgery. Central pathways activated by abdominal surgery were investigated in the rat by using Fos protein as a marker of neuronal activation. Abdominal surgery (laparotomy alone or combined with cecal manipulation) was performed under brief enflurane anesthesia (7-8 minutes), and 1 hour later rats were killed and brains processed for Fos immunoreactivity. Double labeling with Fos and arginine vasopressin, oxytocin, or tyrosine hydroxylase antibodies was also performed. Abdominal surgery induced Fos staining in the nucleus tractus solitarii, paraventricular and supraoptic nuclei of the hypothalamus, locus coeruleus, and ventrolateral medulla. After abdominal surgery, 18-25% of vasopressin and 18-33% of oxytocin-labeled cells were found to be Fos positive in the paraventricular nucleus and 15% of activated cells in the nucleus tractus solitarii were positive for tyrosine hydroxylase immunoreactivity. Enflurane alone induced c-fos expression in the same brain area; however, the number of Fos-positive cells and double-labeled cells were decreased two- to fivefold and three- to eightfold, respectively, compared with the abdominal surgery groups. These data show that abdominal surgery induced activation of specific hypothalamic, pontine, and medullary neurons. These findings may have implications for the understanding of central mechanisms involved in mediating gastric ileus following abdominal surgery.

Gastric emptying of solids but not liquids is decreased in rats with chronic renal failure.

Severe gastric complications occur in uremic patients, yet few studies have addressed the effect of chronic renal failure (RF) on gastric physiology. In the present study, we investigated: (1) the effect of RF on gastric emptying of liquids and solids in awake rats, (2) the motor function in the gastric corpus, and (3) the role of nitric oxide in any alterations in gastric motor function in uremic rats. RF was induced by partial kidney infarction. RF had no effect on gastric emptying of liquids but significantly inhibited gastric emptying of solids by 68%. N-Nitro-L-arginine, an inhibitor of nitric oxide (NO) synthesis, had no effect on the reduced gastric emptying of solids in RF rats. RF rats showed an altered pattern of gastric motility compared to sham-operated rats. These data suggest that RF induced an inhibition of gastric emptying of solids, but not liquids. However, NO does not seem to play a role in this inhibition.

Delayed gastric emptying induced by inhibitors of nitric oxide synthase in rats.

The effect of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester, on gastric emptying of a non-nutrient solution was investigated in conscious rats. NG-Monomethyl-L-arginine (10 mg/kg i.v.) and NG-nitro-L-arginine methyl ester (3 or 10 mg/kg i.v.) inhibited the 20-min rate of gastric emptying of liquids by 34%, 69% and 84% respectively, whereas the 0.3 mg/kg of NG-nitro-L-arginine methyl ester or 3 mg/kg of NG-monomethyl-L-arginine had no effect. The inhibitory effect of NG-nitro-L-arginine methyl ester (3 mg/kg) was prevented by L-arginine (300 mg/kg i.v.), but not by D-arginine (300 mg/kg i.v.). NG-Nitro-L-arginine methyl ester (0.3-10 mg/kg) induced a dose-related increase in mean blood pressure up to 161 +/- 10 mm Hg. Spontaneous hypertensive rats with a mean blood pressure of 180 +/- 5 mm Hg had a gastric emptying rate of 51.9 +/- 6.1%. These data indicate that NO synthase inhibitors given i.v. at doses that inhibit NO synthase, delay gastric emptying through mechanisms which are unrelated to changes in arterial blood pressure.

Role of spinal afferents and calcitonin gene-related peptide in the postoperative gastric ileus in anesthetized rats.

OBJECTIVE: The object of this study was to investigate the mechanisms of postoperative gastric ileus in an experimental model of abdominal surgery in anesthetized rats. SUMMARY BACKGROUND DATA: Sensory neurons partly mediate postoperative gastric ileus. Among other neuropeptides, sensory neurons contain calcitonin gene-related peptide (CGRP) and release CGRP in response to noxious stimulation. Because CGRP inhibits gastric motility, it was hypothesized that abdominal surgery stimulates sensory neurons, which then releases CGRP, thereby inhibiting gastric motility. METHODS: Postoperative ileus was induced by abdominal surgery. Gastric corpus motility was measured by an intragastric catheter. CGRP action was blocked by CGRP immunoneutralization or by a CGRP receptor antagonist. Spinal sensory neurons were ablated by application of a sensory neurotoxin (capsaicin) to the celiac and superior mesenteric ganglia. RESULTS: Abdominal surgery decreased gastric corpus motility in the first 5 minutes after abdominal surgery by 59 +/- 5% and by 24 +/- 4% during the 1st postoperative hour. Capsaicin pretreatment of the celiac and superior mesenteric ganglia, CGRP immunoneutralization, or CGRP receptor antagonism reversed the postoperative decrease in gastric corpus motility during the 1st postoperative hour by 50%, 100%, and 59%, respectively. CONCLUSIONS: These data indicate that spinal sensory neurons and CGRP partly mediate postoperative gastric ileus. CGRP may be released from spinal sensory neuron terminals in the celiac and superior mesenteric ganglia as part of an extraspinal intestinogastric inhibitory reflex activated by abdominal surgery.

CGRP antagonists and capsaicin on celiac ganglia partly prevent postoperative gastric ileus.

The role of capsaicin-sensitive pathways and CGRP in postoperative gastric ileus was investigated. Abdominal surgery was performed under enflurane anesthesia, and 5 min later, the 20-min rate of gastric emptying was measured by the phenol red method in conscious rats. Surgery inhibited gastric emptying by 76-83% compared with rats receiving anesthesia alone. Capsaicin on the celiac/mesenteric ganglia (10-21 days before) reduced gastric ileus by 33 +/- 8%, whereas perivagal capsaicin had no effect. The IV CGRP-induced inhibition of gastric emptying was completely reversed by the CGRP antagonist, CGRP(8-37) (30 micrograms, IV); CGRP(8-37) (15, 30, or 60 micrograms) or CGRP monoclonal antibody #4901 (2 mg protein) decreased the inhibition of gastric emptying by 11 +/- 7%, 51 +/- 13%, 47 +/- 3%, and 45 +/- 17%, respectively. These results indicate that CGRP and splanchnic capsaicin-sensitive afferents are involved in mediating part of the gastric ileus observed immediately after abdominal surgery.

Effects of the somatostatin analogue octreotide on rectal afferent nerves in humans.

Somatostatin (Som) administered intrathecally to humans has been shown to exert potent analgesic effects on somatic pain, and anecdotal evidence suggests that Som may also relieve visceral pain. In the current study, we used rectal balloon distension in seven healthy volunteers to evaluate the effect of the Som analogue octreotide (Oct; 1.25 microgram/kg sc) on four pathways mediated by different visceral afferents that originate in the rectum: conscious perception, receptive relaxation, reflex inhibition of internal anal sphincter, and a viscerosomatic reflex. Rectal mechanoreceptors were stimulated either by distending the rectum tonically (volume ramp at 20-40 and 400 ml/min) or phasically (intermittent pressure steps of 60 s duration). Pressure thresholds for nonnoxious and noxious sensations in response to slow tonic distension were increased in the presence of rectal lidocaine (20 ml of 2% solution), whereas those to phasic distension were unaffected. Oct significantly increased pressure and volume thresholds for nonnoxious and noxious sensations in response to slow tonic distension but did not further increase thresholds in the presence of intrarectal lidocaine. In contrast, no effect of Oct on rectal sensations was observed during rapid tonic or phasic distension. Oct had no effect on any of the monitored reflex responses. The effect of Oct on rectal sensation in the concentration used in this study was not associated with changes in the rectal wall pressure-volume relationship during any distension protocol. These findings indicate that the inhibitory effect of Oct on rectal sensation is likely to represent a direct effect on a subset of extrinsic primary afferent neurons, with receptive fields in the mucosa.

CGRP 8-37[correction of 8-27] blocks the inhibition of gastric emptying induced by intravenous injection of alpha-CGRP in rats.

The receptor subtype mediating rat alpha-calcitonin gene-related peptide (alpha-CGRP)-induced inhibition of gastric emptying of a non nutrient solution was tested in conscious rats using the CGRP1 receptor antagonist, CGRP 8-37, and the CCK antagonist, MK-329. Intravenous injection of alpha-CGRP (0.5 micrograms) decreased gastric emptying to 26.5 +/- 5.8% from 46.4 +/- 3.9% in vehicle-treated group. Intravenous injection of CGRP 8-37 (15 micrograms) did not influence gastric emptying but completely prevented alpha-CGRP inhibitory effect whereas the 47% delay in gastric emptying induced by intravenous cholecystokinin-8 (CCK, 0.25 microgram) was not modified. The CCK antagonist, MK-329 (1 mg) reversed CCK- but not alpha-CGRP-induced delay in gastric emptying. These results demonstrate that CGRP 8-37 is a specific tool to block alpha-CGRP inhibitory action on gastric motor function and suggest that gastric stasis elicited by peripheral injection of alpha-CGRP may involve an interaction with a CGRP1 receptor subtype.