Systemic inflammation with enhanced brain activation contributes to more severe delay in postoperative ileus.

BACKGROUND: The severity of postoperative ileus (POI) has been reported to result from decreased contractility of the muscularis inversely related to the number of infiltrating leukocytes. However, we previously observed that the severity of POI is independent of the number of infiltrating leukocytes, indicating that different mechanisms must be involved. Here, we hypothesize that the degree of tissue damage in response to intestinal handling determines the upregulation of local cytokine production and correlates with the severity of POI. METHODS: Intestinal transit, the inflammatory response, I-FABP (marker for tissue damage) levels and brain activation were determined after different intensities of intestinal handling. KEY RESULTS: Intense handling induced a more pronounced ileus compared with gentle intestinal manipulation (IM). No difference in leukocytic infiltrates in the handled and non-handled parts of the gut was observed between the two intensities of intestinal handling. However, intense handling resulted in significantly more tissue damage and was accompanied by a systemic inflammation with increased plasma levels of pro-inflammatory cytokines. In addition, intense but not gentle handling triggered enhanced c-Fos expression in the nucleus of the solitary tract (NTS) and area postrema (AP). In patients, plasma levels of I-FABP and inflammatory cytokines were significantly higher after open compared with laparoscopic surgery, and were associated with more severe POI. CONCLUSIONS & INFERENCES: Not the influx of leukocytes, rather the manipulation-induced damage and subsequent inflammatory response determine the severity of POI. The release of tissue damage mediators and pro-inflammatory cytokines into the systemic circulation most likely contribute to the impaired motility of non-manipulated intestine.

Objective definition and detection of transient lower esophageal sphincter relaxation revisited: is there room for improvement?

BACKGROUND: The advent of drugs that inhibit transient lower esophageal sphincter relaxation (TLESR) necessitates accurate identification and scoring. We assessed the intra- and inter-assessor variability of the existing objective criteria for TLESR, improving them where necessary. METHODS: Two 3-h postprandial esophageal manometric and pH recordings were performed in 20 healthy volunteers. Each recording was duplicated. The recordings were analyzed by five experienced observers for TLESRs based on their expert opinion. TLESRs were also analyzed for the presence of the original four criteria as well as inhibition of the crural diaphragm (ID), a prominent after-contraction (AC), acid reflux and an esophageal common cavity. KEY RESULTS: The overall inter- and intra-observer agreements for TLESRs scored, according to observer's expert opinion, were 59% (range 56-67%) and 74% (60-89%), respectively. When TLESRs were restricted to those fulfilling the original criteria, these agreements fell to 46% (40-53%) and 60% (44-67%), respectively. Cleaning the recordings by removal of technically flawed sections improved agreements by 5%. Inclusion of additional criteria (ID and AC) resulted in inter- and intra-observer agreements of 62% (52-70%) and 69% (53-79%), respectively. A consensus analysis performed collectively by three observers and based on the new criteria (original ± ID and AC) resulted in 84% agreement between the paired recordings. CONCLUSIONS & INFERENCES: The original criteria for the definition of TLESRs allows for substantial inter- and intra-observer variability, which can be reduced by incorporation of additional objective criteria. However, the highest level of intra-observer agreement can be achieved by consensus analysis.

High-resolution esophageal pressure topography is superior to conventional sleeve manometry for the detection of transient lower esophageal sphincter relaxations associated with a reflux event.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-esophageal reflux and are detected during manometric studies using well defined criteria. Recently, high-resolution esophageal pressure topography (HREPT) has been introduced and is now considered as the new standard to study esophageal and lower esophageal sphincter (LES) function. In this study we performed a head-to-head comparison between HREPT and conventional sleeve manometry for the detection of TLESRs. METHODS: A setup with two synchronized MMS-solar systems was used. A solid state HREPT catheter, a water-perfused sleeve catheter, and a multi intraluminal impedance pH (MII-pH) catheter were introduced in 10 healthy volunteers (M6F4, age 19-56). Subjects were studied 0.5 h before and 3 h after ingestion of a standardized meal. Tracings were blinded and analyzed by the three authors according to the TLESR criteria. KEY RESULTS: In the HREPT mode 156 TLESRs were scored, vs 143 during sleeve manometry (P = 0.10). Hundred and twenty-three TLESRs were scored by both techniques. Of all TLESRs (177), 138 were associated with reflux (78%). High-resolution esophageal pressure topography detected significantly more TLESRs associated with a reflux event (132 vs 119, P = 0.015) resulting in a sensitivity for detection of TLESRs with reflux of 96% compared to 86% respectively. Analysis of the discordant TLESRs associated with reflux showed that TLESRs were missed by sleeve manometry due to low basal LES pressure (N = 5), unstable pharyngeal signal (N = 4), and residual sleeve pressure >2 mmHg (N = 10). CONCLUSIONS & INFERENCES: The HREPT is superior to sleeve manometry for the detection of TLESRs associated with reflux. However, rigid HREPT criteria are awaited.

The cannabinoid receptor agonist delta-9-tetrahydrocannabinol does not affect visceral sensitivity to rectal distension in healthy volunteers and IBS patients.

BACKGROUND: Visceral hypersensitivity to distension is thought to play an important role in the pathophysiology of the irritable bowel syndrome (IBS). Cannabinoids are known to decrease somatic pain perception, but their effect on visceral sensitivity in IBS remains unclear. Therefore, we evaluated the effect of the mixed CB(1) /CB(2) receptor agonist delta-9-tetrahydrocannabinol (Δ(9) -THC, dronabinol) on rectal sensitivity. METHODS: Ten IBS patients and 12 healthy volunteers (HV) underwent a barostat study to assess rectal sensitivity using an intermittent pressure-controlled distension protocol before and after sigmoid stimulation. Repetitive sigmoid stimulation is a validated method to increase visceral perception in IBS patients, consisting of a 10-min period of 30 s stimuli (60 mmHg), separated by 30 s of rest (5 mmHg). The effect of placebo and Δ(9) -THC (5 and 10 mg in healthy volunteers and 10 mg in IBS patients) on rectal sensitivity was evaluated on respectively three and two separate days in a double blind, randomized, crossover fashion. KEY RESULTS: All participants (HV and IBS) reported central side effects during the highest dose of Δ(9) -THC, most frequently increased awareness of the surrounding, light-headedness and sleepiness, whereas no side effects where reported during placebo. Although blood pressure was not affected, heart rate increased in both HV and IBS, but was most pronounced in IBS patients. The cannabinoid agonist Δ(9) -THC did not alter baseline rectal perception to distension compared to placebo in HV or IBS patients. Similarly, after sigmoid stimulation there were no significant differences between placebo and Δ(9) -THC in sensory thresholds of discomfort. CONCLUSIONS & INFERENCES: These findings imply that Δ(9) -THC does not modify visceral perception to rectal distension and argue against (centrally acting) CB agonists as tool to decrease visceral hypersensitivity in IBS patients.

Pathophysiology and management of gastroesophageal reflux disease.

Gastroesophageal reflux is a physiological phenomenon but becomes pathological if troublesome symptoms and/or complications occur. Gastroesophageal reflux disease (GERD) has different phenotypes ranging from non-erosive reflux disease (NERD), through reflux esophagitis and Barrett's esophagus, and can present with either typical symptoms such as regurgitation and heartburn, or extra-esophageal symptoms such as cough and laryngitis. In the diagnosis of GERD endoscopy, empirical PPI test, and pH impedance testing all have their own position. Although proton pump inhibitors (PPIs) are very effective in the treatment of esophagitis, a significant proportion of patients have persistent symptoms even during high dosing of PPIs. Therefore, insight into the multifactorial pathophysiology of GERD is needed to develop new anti-reflux therapies. The predominant mechanism underlying reflux is the transient lower esophageal sphincter relaxation (TLESR). Hiatal hernia, impaired esophageal clearance and reduced lower esophageal sphincter pressure play a significant role in patients with moderate to severe reflux disease. Refluxate containing acid, pepsin and bile can cause epithelial injury when epithelial barrier of the esophagus fails to defend. In the majority of patients there is histopathological evidence of epithelial injury, even with NERD where there are more dilated intercellular spaces. The perception of heartburn can be enhanced due to visceral hypersensitivity, leading to more and more severe symptoms. Anti-reflux surgery is as effective as PPI therapy, but has higher morbidity and results decline in the long term. Therefore, new pharmacological, endoscopic and surgical interventions are being developed for these patients.

Morphological changes of the enteric nervous system, interstitial cells of cajal, and smooth muscle in children with colonic motility disorders.

OBJECTIVES: To evaluate the relation between colonic manometry findings and the colonic enteric nervous system, interstitial cells of Cajal, and smooth muscle morphology. PATIENTS AND METHODS: Colonic specimens from surgical resections or full-thickness biopsy specimens were assessed from a cohort of children who underwent colonic manometry before surgery. Colonic manometric patterns were subdivided into high-amplitude propagating contractions, low-amplitude propagating contractions, absence of contractions, and low-amplitude simultaneous contractions. Immunohistochemistry was performed to identify abnormalities in the enteric nervous system, interstitial cells of Cajal, and smooth muscle layers. RESULTS: Study participants included patients with Hirschsprung disease (n = 4), chronic intestinal pseudo-obstruction (n = 1), and idiopathic intractable constipation (n = 8). Thirty-seven ganglionic segments were studied. Abnormalities in myenteric plexus were recognized in segments of all manometry groups, and no differences could be identified when they were compared with segments with high-amplitude propagating contractions. All of the segments showed an abnormal interstitial cells of Cajal plexus, and no statistical difference could be identified between the 4 groups (n = 0.08). Homogeneous expression of smooth muscle actin was observed in all of the segments. CONCLUSIONS: In this cohort we were unable to classify specific manometric findings as reflective of myopathic or neuropathic abnormalities in patients with motility disorders. Caution should be used when predicting the type of neuromuscular disorder based on colonic manometry.

Gastric hypersensitivity induced by oesophageal acid infusion in healthy volunteers.

Distal oesophageal acid exposure has been shown to increase visceral sensitivity of the proximal oesophagus via central sensitization. Here we evaluated whether acidification of the distal oesophagus also affects the sensorimotor function of the proximal stomach. A gastric barostat study combined with a 30-min acid (HCl 0.15 mol L(-1)) or saline infusion in the distal oesophagus was performed in 18 healthy volunteers. Gastric and cutaneous sensitivity was assessed before and up to 2 h after the start of infusion. Directly after acid infusion, but not after saline, the threshold for discomfort decreased (-6.4 +/- 1.7 vs 0.4 +/- 0.4 mmHg; P = 0.028) and distension-induced symptoms increased significantly compared with the baseline (122 +/- 49% vs -3 +/- 9%). Cutaneous sensitivity remained unaffected by acid infusion. In contrast, when the infused liquid was aspirated 3 cm more distally, at the level of the lower oesophageal sphincter, the effect of acid infusion on gastric sensitivity was abolished and the increase in distension-induced symptoms was reduced (61 +/- 24%). Distal oesophageal acid infusion induces visceral hypersensitivity without affecting somatic sensitivity arguing against a similar mechanism of central sensitization as observed in non-cardiac chest pain. As reduction of the acid load to the stomach prevented this effect, our findings indicate that either gastric and/or duodenal acidification is involved. It should be emphasized though that aspiration from distal oesophagus may have attenuated the effect by reducing the acid-exposed area or by reducing the contact time.

Can the outcome of pelvic-floor rehabilitation in patients with fecal incontinence be predicted?

PURPOSE: Pelvic-floor rehabilitation does not provide the same degree of relief in all fecal incontinent patients. We aimed at studying prospectively the ability of tests to predict the outcome of pelvic-floor rehabilitation in patients with fecal incontinence. MATERIALS AND METHODS: Two hundred fifty consecutive patients (228 women) underwent medical history and a standardized series of tests, including physical examination, anal manometry, pudendal nerve latency testing, anal sensitivity testing, rectal capacity measurement, defecography, endoanal sonography, and endoanal magnetic resonance imaging. Subsequently, patients were referred for pelvic-floor rehabilitation. Outcome of pelvic-floor rehabilitation was quantified by the Vaizey incontinence score. Linear regression analyses were used to identify candidate predictors and to construct a multivariable prediction model for the posttreatment Vaizey score. RESULTS: After pelvic-floor rehabilitation, the mean baseline Vaizey score (18, SD+/-3) was reduced with 3.2 points (p<0.001). In addition to the baseline Vaizey score, three elements from medical history were significantly associated with the posttreatment Vaizey score (presence of passive incontinence, thin stool consistency, primary repair of a rupture after vaginal delivery at childbed) (R2, 0.18). The predictive value was significantly but marginally improved by adding the following test results: perineal and/or perianal scar tissue (physical examination), and maximal squeeze pressure (anal manometry; R2, 0.20; p=0.05). CONCLUSION: Additional tests have a limited role in predicting success of pelvic-floor rehabilitation in patients with fecal incontinence.

Achalasia.

Achalasia is a rare motor disorder of the oesophagus, characterised by the absence of peristalsis and impaired swallow-induced relaxation. These motor abnormalities result in stasis of ingested food in the oesophagus, leading to clinical symptoms, such as dysphagia, regurgitation of food, retrosternal pain and weight loss. Although it is well demonstrated that loss of myenteric oesophageal neurons is the underlying problem, it still remains unclear why these neurons are preferentially attacked and destroyed by the immune system. This limited insight into pathophysiology explains the fact that treatment is limited to interventions aimed at reducing the pressure of the lower oesophageal sphincter. The most successful therapies are clearly pneumatic dilatation and Heller myotomy with short-term success rates of 70-90%, declining to 50-65% after more than 15 years. The challenge for the coming years will undoubtedly be to get more insight into the underlying disease mechanisms and to develop a treatment to restore function.

Review article: the pathophysiology of gastro-oesophageal reflux disease.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is a common condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. AIM: To review the current knowledge on the underlying factors contributing to GERD, with particular emphasis on the most recent research. METHODS: Literature searches were conducted in Medline and EMBASE. The abstracts from recent large congresses were also reviewed to ensure coverage of the latest findings. RESULTS: The pathophysiological factors causing GERD can be split into those inducing greater exposure of the oesophagus to stomach contents, and those that provide increased perception of reflux or increased mucosal damage. Transient lower oesophageal sphincter relaxations, which are likely to be triggered by gastric distension, appear to be a key physiological cause of GERD. Excessive reflux may also be provoked by impaired oesophageal or gastric clearance mechanisms. Pre-epithelial, epithelial and post-epithelial defences all normally protect the oesophagus from injury, and may be compromised in individuals with GERD. Heartburn could also be caused by oesophageal hypersensitivity as a result of visceral neural pathway dysfunction. CONCLUSION: The pathophysiology of GERD is multifactorial, and abnormalities in the gastro-oesophageal junction, the stomach, the oesophagus and the nervous system may all contribute to this disease state.

Electrical stimulation and pelvic floor muscle training with biofeedback in patients with fecal incontinence: a cohort study of 281 patients.

PURPOSE: Pelvic floor rehabilitation is an appealing treatment for patients with fecal incontinence but reported results vary. This study was designed to assess the outcome of pelvic floor rehabilitation in a large series of consecutive patients with fecal incontinence caused by different etiologies. METHODS: A total of 281 patients (252 females) were included. Data about medical history, anal manometry, rectal capacity measurement, and endoanal sonography were collected. Subgroups of patients were defined by anal sphincter complex integrity, and nature and possible underlying causes of fecal incontinence. Subsequently patients were referred for pelvic floor rehabilitation, comprising nine sessions of electric stimulation and pelvic floor muscle training with biofeedback. Pelvic floor rehabilitation outcome was documented with Vaizey score, anal manometry, and rectal capacity measurement findings. RESULTS: Vaizey score improved from baseline in 143 of 239 patients (60 percent), remained unchanged in 56 patients (23 percent), and deteriorated in 40 patients (17 percent). Mean Vaizey score reduced with 3.2 points (P < 0.001). A Vaizey score reduction of >or= 50 percent was observed in 32 patients (13 percent). Mean squeeze pressure (+5.1 mmHg; P = 0.04) and maximal tolerated volume (+11 ml; P = 0.01) improved from baseline. Resting pressure (P = 0.22), sensory threshold (P = 0.52), and urge sensation (P = 0.06) remained unchanged. Subgroup analyses did not show substantial differences in effects of pelvic floor rehabilitation between subgroups. CONCLUSIONS: Pelvic floor rehabilitation leads overall to a modest improvement in severity of fecal incontinence, squeeze pressure, and maximal tolerated volume. Only in a few patients, a substantial improvement of the baseline Vaizey score was observed. Further studies are needed to identify patients who most likely will benefit from pelvic floor rehabilitation.

Review article: a critical view on impaired accommodation as therapeutic target for functional dyspepsia.

Several important pathophysiological mechanisms have been identified in functional dyspepsia, however a complete understanding of these mechanisms and beneficial therapeutic strategies are still lacking. Based on the currently available literature we aimed at providing a critical view on one of these pathophysiological mechanisms, impaired accommodation. Although impaired gastric accommodation is identified as a major pathophysiological mechanism, the clinical evidence supporting its role as an important therapeutic target is currently still lacking. Treatment with fundic relaxant drugs has shown conflicting results and has been rather disappointing in general. These negative findings could be explained by the fact that impaired fundic accommodation is part of a more complex disorder involving other regions of the proximal gut or by the increasing insight that central mechanisms may play an important role. Future studies of impaired accommodation should take these considerations into account.

Fundic accommodation assessed by SPECT scanning: comparison with the gastric barostat.

BACKGROUND: Recently, single photon emission computed tomography (SPECT) scanning was described as a non-invasive technique to assess fundic accommodation. However, in contrast with the barostat, no intragastric distending force is applied during SPECT scanning. We hypothesised that in the absence of a barostat balloon, SPECT scanning largely detects the volume effect of the ingested meal and is a rather insensitive tool to detect fundic relaxation. METHODS: After an overnight fast, healthy volunteers underwent a barostat study and SPECT scanning on two separate days to assess: (1) meal induced fundic accommodation (Nutridrink, 200 ml, 300 kcal); and (2) gastric relaxation to 1 mg intravenous glucagon. RESULTS: Fasting fundic volumes (145 (8) v 280 (32) ml; p=0.001) and average postprandial volume (329 (10) v 571 (53) ml; p=0.001) were significantly lower measured with SPECT compared with the barostat study. Meal induced fundic relaxation (183 (10) v 289 (46) ml; p=0.050) and the postprandial/fasting volume ratio (2.32 (0.10) v 2.27 (0.29); p=0.892) did not differ significantly between SPECT scanning and the barostat. However, no correlation could be determined between accommodation volumes measured by both techniques. In contrast with meal induced relaxation, the glucagon induced increase in fundic volume (19 (5) v 406 (56) ml; p=0.007) and post/pre glucagon ratio (1.16 (0.03) v 3.02 (0.54); p=0.046) were significantly lower when measured by SPECT scanning compared with the barostat. CONCLUSION: SPECT scanning detects changes in postprandial volume but is less suitable than the gastric barostat in detecting changes in gastric tone. Our study therefore questions its role as a tool to detect impaired accommodation and warrants further validation of this technique.

Effect of prolonged gastric distention on lower esophageal sphincter function and gastroesophageal reflux.

OBJECTIVES: Morbidly obese patients treated with an intragastric balloon report a transient increase in gastroesophageal reflux (GER) symptoms. In the present study, we evaluated the underlying mechanisms of GER and examined the effect of prolonged gastric distention on lower esophageal sphincter function. METHODS: Fasting and postprandial manometric studies were performed in obese subjects (n = 15) before, immediately after, and 10 and 20 wk after placement of a 500-ml water-filled balloon. RESULTS: Residual lower esophageal sphincter (LES) pressure after water swallows was not affected after balloon placement, excluding mechanical interaction with sleeve function. Postprandial LES pressure was significantly increased after 10 and 20 wk. GER was increased in the right recumbent position until 10 wk after balloon placement, mainly because of an increased percentage of transient lower esophageal sphincter relaxations (TLESRs) accompanied by GER. TLESRs were the main mechanisms underlying reflux both before and after balloon placement. The rate of TLESRs was increased significantly immediately after introduction of the balloon, returning to baseline values after 20 wk. After balloon placement, reflux episodes were evoked by gastric contractions that were not inhibited by meals. CONCLUSIONS: Chronic distention by an intragastric balloon increased reflux up to 10 wk after placement because of an increase in the percentage of TLESRs accompanied by a reflux episode. In addition, prolonged balloon distention increased the rate of TLESRs and created a postprandial state even 10 wk after balloon placement. After 20 wk these effects largely resolved, illustrating adaptation to this artificial situation.

Role of CCK(A) receptors in postprandial lower esophageal sphincter function in morbidly obese subjects.

To reduce weight, some morbidly obese patients are treated with an intragastric balloon, often resulting in increased reflux symptoms. As transient lower esophageal sphincter relaxations (TLESRs) are the major mechanism underlying reflux and can be reduced by cholecystokinin-A (CCK(A)) blockade, we hypothesized that the CCK(A)-receptor antagonist loxiglumide could reduce gastroesophageal reflux in these subjects. Postprandial manometric studies were performed in 12 obese subjects during infusion of placebo or loxiglumide. Before balloon placement, loxiglumide did not significantly reduce the rate of TLESRs but attenuated the postprandial decrease in LES pressure. After 10 weeks of balloon treatment, loxiglumide significantly reduced the rate of TLESRs. Postprandial LES pressure was significantly increased, whereas the meal-induced decrease in LES pressure was absent. Neither loxiglumide nor balloon placement affected gastroesophageal reflux. In conclusion, CCK(A) receptors play an important role in post-prandial LES pressure decrease and are involved in the reflex pathway underlying the triggering of TLESRs, at least after balloon placement.

Prospective evaluation of anorectal function after total mesorectal excision for rectal carcinoma with or without preoperative radiotherapy.

OBJECTIVE: Anorectal function is greatly disturbed after rectal surgery with or without radiotherapy (RT). To clarify the underlying mechanisms, we designed a prospective study to evaluate the effect of RT and surgery on anorectal function and clinical outcome of patients with a rectal carcinoma. METHODS: Thirty-four patients with a rectal carcinoma participated in this study. They filled out a symptom questionnaire and underwent anal manometry, anal and rectal mucosal electrosensitivity testing, and a rectal barostat, before surgery, 4 and 12 months postoperatively. Thirteen patients were lost to follow-up, 14 underwent surgery alone (total mesorectal excision [TME]), and seven also received RT (RT + TME). RESULTS: Functional outcome was disappointing in both groups, with at 4 months a significantly higher defecation frequency after RT + TME as compared with TME. Anal sphincter function and rectal sensitivity to pressure-controlled distention were not affected by either treatment. Rectal compliance, however, was significantly reduced after RT + TME at 4 and 1 2 months, resulting in lower rectal volumes at the thresholds for first sensation and desire to defecate. Rectal but not anal mucosal electrosensitivity was higher after TME + RT. CONCLUSIONS: Anorectal function after rectal surgery with or without RT is greatly hampered because of a decreased rectal compliance. After 12 months, partial improvement is shown, especially in the absence of RT.

Effect of the low-affinity, noncompetitive N-methyl-d-aspartate receptor antagonist dextromethorphan on visceral perception in healthy volunteers.

BACKGROUND: The use of N-methyl-d-aspartate (NMDA) receptor antagonists may hold promise for the treatment of pain of visceral origin, in particular in conditions characterized by visceral hypersensitivity. AIM: To study the effect of dextromethorphan, a low affinity, non-competitive NMDA receptor antagonist, on visceral perception in healthy volunteers. METHODS: Nine healthy volunteers (5 female, median age 22 years) underwent a gastric barostat study after oral administration of placebo, dextromethorphan 10 mg or dextromethorphan 30 mg, on three separate days in a double-blind, randomised order. Sensations induced by step-wise isobaric gastric distension (2 mmHg/2 min) were studied during fasting and 30 min after a meal. In addition, proximal gastric tone was measured during fasting and postprandially. RESULTS: Compared to placebo, dextromethorphan 30 mg significantly increased the distension-evoked sensation scores for nausea (P=0.004) and satiation (P=0.004) during fasting; and for bloating (P= 0.001), nausea (P=0.000) and satiation (P=0.01) 30 min postprandially. Dextromethorphan did not alter pain scores, proximal gastric tone or gastric compliance. CONCLUSIONS: Dextromethorphan increases the perception of non-painful sensations during gastric distension, without altering the perception of pain. Therefore, application of dextromethorphan as a visceral analgesic is questionable. Future studies with more specific NMDA receptor antagonist are warranted.

Role of nitric oxide in gastric motor and sensory functions in healthy subjects.

BACKGROUND AND AIMS: Impaired accommodation and hypersensitivity to distension of the proximal stomach are considered to be important factors in the pathogenesis of dyspeptic complaints. As fundus relaxing agents may be effective in the treatment of these symptoms, insight into the mediators involved in fundic accommodation and associated perceptual responses is important. Therefore, we studied the effect of nitric oxide (NO) synthase inhibition by N(G)-monomethyl-L-arginine (L-NMMA) on fundic tone, postprandial sensations, and gastric perception in healthy volunteers. SUBJECTS AND METHODS: Eighteen healthy volunteers participated in a double blind, placebo controlled, randomised study. They underwent a gastric barostat study to evaluate the effect of L-NMMA on meal and distension induced sensations and on fundic relaxation in response to oral meal intake, intraduodenal lipid, and glucagon administration. RESULTS: Compared with placebo, L-NMMA decreased fundic volume after oral meal intake (438 (55) v 304 (67) ml; n=8; p<0.05) and during intraduodenal lipid infusion (384 (37) v 257 (43) ml; n=10; p<0.05) but not after glucagon injection (570 (62) v 540 (52) ml; n=4; p=0.4). In addition, basal fundic volume was significantly reduced by L-NMMA. Scores for nausea and satiation were decreased by L-NMMA after oral meal intake but not during intraduodenal lipid infusion. Perception scores to gastric distension were not altered by L-NMMA. CONCLUSIONS: NO is involved in maintaining basal fundic tone and in meal induced fundic relaxation in humans, but not in visceral perception.

Is glutamate involved in transient lower esophageal sphincter relaxations?

Glutamate is an important excitatory amino acid and plays a major role in brain stem neurotransmission. Although the effect of glutamate on esophageal motility is well studied, its role in the triggering of transient lower esophageal sphincter relaxations (TLESRs) remains to be determined. Esophageal manometry was performed in 10 healthy volunteers using a perfused sleeve assembly. The effect of intragastric instillation of the nonspecific N-methyl-D-aspartate receptor antagonist dextromethorphan (30 mg) and the glutamate-release inhibitor riluzole (100 mg) was evaluated on esophageal motility and on the rate of TLESRs during isovolumetric gastric distension (500 ml). Dextromethorphan and riluzole had no effect on the amplitude or peristaltic velocity of esophageal pressure waves, basal LES pressure, or LES relaxation after water swallowing. Gastric distension increased the rate of TLESRs from 2.0 (1.0-3.5)/45 min to 5.0 (4.0-7.0)/45 min during placebo (P < 0.05). In contrast, the rate of TLESRs during gastric distension was significantly reduced with riluzole [4.0 (2.5-6.0)/45 min], but not with dextromethorphan. In conclusion, riluzole had no effect on swallow-induced LES relaxation, esophageal peristalsis, or gastric tone, but it reduced the number of TLESRs evoked by gastric distension. These findings suggest that glutamate may be involved in the neurocircuitry underlying TLESRs. However, as the effect was only marginal, additional studies are required to confirm our observations.

Transient lower oesophageal sphincter relaxations--a pharmacological target for gastro-oesophageal reflux disease?

The oesophago-gastric junction functions as an anti-reflux barrier preventing increased exposure of the oesophageal mucosa to gastric contents. Failure of this anti-reflux barrier results in gastro-oesophageal reflux disease, and may lead to complications such as oesophagitis, Barrett's oesophagus and eventually oesophageal carcinoma. Recent studies have suggested that transient lower oesophageal sphincter relaxation is the main mechanism underlying gastro-oesophageal reflux. It involves a prolonged relaxation of the lower oesophageal sphincter, mediated by a vago-vagal neural pathway, synapsing in the brainstem. Several drugs, such as atropine, baclofen and loxiglumide, have been shown to reduce the rate of transient lower oesophageal sphincter relaxations and concomitantly the number of reflux episodes. These findings illustrate that transient lower oesophageal sphincter relaxations may represent a potential new target for the pharmacological treatment of gastro-oesophageal reflux disease. It is possible that the reduction in the number of transient lower oesophageal sphincter relaxations may also contribute to the beneficial effect of fundoplication and new endoscopic anti-reflux procedures. It should be emphasized, however, that other factors, such as low lower oesophageal sphincter pressure, the presence of a hiatal hernia and impaired oesophageal peristalsis, are also of great importance. Therefore, whether the targeting of transient lower oesophageal sphincter relaxations is the 'golden bullet' in anti-reflux therapy remains to be proven, as evidence of an effective control of gastro-oesophageal reflux in reflux patients is still lacking.