The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers.

BACKGROUND: Selective metabotropic glutamate receptor 5 (mGluR5) antagonists inhibit transient lower oesophageal sphincter relaxations (TLESRs) in animals and acid reflux in humans. AIM: To assess the effect of single doses of the mGluR5 antagonist AZD2066 on TLESRs and reflux in humans. METHODS: Healthy male volunteers received AZD2066 13 mg and placebo (part A), or AZD2066 2 mg and AZD2066 6 mg and placebo (part B), in a randomised crossover study. Postprandial manometry/pH-impedance measurements were taken after each dose. RESULTS: A total of 13 individuals completed part A of the study and 19 individuals completed part B. There was a significant reduction in the geometric mean number of TLESRs (27%; P = 0.02) and the geometric mean number of reflux episodes (51%; P = 0.01) in subjects receiving AZD2066 13 mg compared with placebo. Adverse events in participants receiving AZD2066 13 mg were mostly related to the nervous system [dizziness (3/13); disturbance in attention (3/13)]. Adverse events were reversible and of mild intensity. There were no serious adverse events. The effects of AZD2066 appeared dose-dependent, with smaller reductions in TLESRs and reflux episodes (relative to placebo) and fewer adverse events observed for AZD2066 2 mg and AZD2066 6 mg compared with AZD2066 13 mg. CONCLUSION: The mGluR5-mediated inhibition of TLESRs may be a useful approach for inhibiting gastro-oesophageal reflux.

Effect of azithromycin on acid reflux, hiatus hernia and proximal acid pocket in the postprandial period.

BACKGROUND: The risk for acidic reflux is mainly determined by the position of the gastric acid pocket. It was hypothesised that compounds affecting proximal stomach tone might reduce gastro-oesophageal reflux by changing the acid pocket position. OBJECTIVE: To study the effect of azithromycin (Azi) on acid pocket position and acid exposure in patients with gastro-oesophageal reflux disease (GORD). METHODS: Nineteen patients with GORD were included, of whom seven had a large hiatal hernia (≥3 cm) (L-HH) and 12 had a small or no hiatal hernia (S-HH). Patients were randomised to Azi 250 mg/day or placebo during 3 days in a crossover manner. On each study day, reflux episodes were detected using concurrent high-resolution manometry and pH-impedance monitoring after a standardised meal. The acid pocket was visualised using scintigraphy, and its position was determined relative to the diaphragm. RESULTS: Azi reduced the number of acid reflux events (placebo 8.0±2.2 vs Azi 5.6±1.8, p<0.01) and postprandial acid exposure (placebo 10.5±3.8% vs Azi 5.9±2.5%, p<0.05) in all patients without affecting the total number of reflux episodes. Acid reflux occurred mainly when the acid pocket was located above, or at the level of, the diaphragm, rather than below the diaphragm. Treatment with Azi reduced hiatal hernia size and resulted in a more distal position of the acid pocket compared with placebo (below the diaphragm 39% vs 29%, p=0.03). Azi reduced the rate of acid reflux episodes in patients with S-HH (38% to 17%) to a greater extent than in patients with L-HH (69% to 62%, p=0.04). CONCLUSION: Azi reduces acid reflux episodes and oesophageal acid exposure. This effect was associated with a smaller hiatal hernia size and a more distal position of the acid pocket, further indicating the importance of the acid pocket in the pathogenesis of GORD. CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1970 NTR1970.

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.

A discussion of airway and respiratory complications along with general considerations in obese patients.

Obesity is defined as the degree of excess weight associated with adverse health consequences. Within Great Britain, it is reported that a quarter of men and women are obese; these rates have trebled over the past 20 years. In 2001, it was estimated that obesity cost the National Health Service at least half a billion pounds, with a further two billion pounds lost on lower productivity and lost output. Obesity poses a significant risk factor for diseases, such as coronary heart disease, diabetes mellitus and certain forms of cancer, amongst others. Obese individuals pose significant problems to the clinician because of airway and respiratory complications. Sleep apnoea, obesity-hypoventilation syndrome, pulmonary atelectasis are associated with obesity and tracheostomy insertion is made all the more difficult in these patients. This article aims to discuss some of these issues relevant to the clinician and examine present strategies for dealing with them.

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.

Reproducibility of meal-induced transient lower oesophageal sphincter relaxations in patients with gastro-oesophageal reflux disease.

AIM: To calculate the number of subjects required in trials investigating drugs reducing the number of transient lower oesophageal sphincter relaxations (TLOSRs), the inter- and intra-individual variability of TLOSRs were determined, using meal ingestion as a trigger of TLOSRs and reflux. METHODS: A total of 23 gastro-oesophageal reflux disease (GORD) patients with no to grade B oesophagitis and a hiatal hernia < or =3 cm underwent oesophageal manometry and pHmetry 1 h before and 3 h after ingestion of a solid meal on two separate days approximately 4 weeks apart. Reflux episodes and the underlying mechanisms and the number of TLOSRs were evaluated. RESULTS: The number of TLOSRs, reflux episodes and % time with pH < 4 after meal ingestion did not differ significantly between the two sessions. The intra-individual variation of TLOSRs in the 3 h postprandial period (24.4) was smaller compared with the inter-individual variation (47.5). Transient lower oesophageal sphincter relaxations were the predominant cause of reflux accounting for 61 +/- 7 and 70 +/- 5% of the reflux episodes in visits 1 and 2, respectively. CONCLUSIONS: These data for the first time provide information on the variability of TLOSRs and reflux evoked by meal ingestion, which is of crucial importance for the design and power calculations of future clinical studies evaluating the efficacy of new drugs targeting TLOSRs.

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.

Long term results of pneumatic dilation in achalasia followed for more than 5 years.

OBJECTIVE: We aimed to evaluate the long term therapeutic outcome in achalasia patients treated with pneumatic dilation, specifically focusing on those patients treated more than 15 yr ago. METHODS: All patients treated in our center whose records were available for review were asked to fill out a questionnaire assessing their degree of dysphagia, retrosternal pain, regurgitation, weight loss, and coughing during the night. The number of dilations was collected from the clinical records. The results of the treatment were classified into four different classes (excellent, good, moderate, poor). For those patients who had died, the cause of death was ascertained from the medical records or from the general practitioner. RESULTS: The questionnaires were distributed to 249 patients, 32 of whom had died. Of the 125 patients who completed the questionnaire, 81 (45 male and 36 female) were treated more than 5 yr ago. The mean follow-up was 12+/-1 yr. The therapeutic success rate was 50%, obtained after a median of four dilations (interquartile range = 3-6). Of this cohort, 25 patients (18 male and seven female, aged 35-84 yr) were treated more than 15 yr ago (mean follow-up = 20.5+/-0.5 yr). The median number of dilations was four (interquartile range = 3-7), with a therapeutic success rate of 40%. Two patients experienced a perforation, and seven were referred for surgery. Six patients out of 32 (19%) died of esophageal cancer. CONCLUSIONS: The long term success rate of pneumatic dilation is rather low, resulting in permanent successful treatment of achalasia in only 40-50% of patients. Achalasia is a risk factor for esophageal cancer.

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.

Laryngeal gout.

A review of the literature reveals only 12 reported cases of laryngeal gout. We describe three further cases of laryngeal gout, the largest series ever published. The first case is previously undescribed acute gouty cricoarytenoiditis resulting in acute airway embarrassment requiring tracheotomy, and then we describe two cases of chronic tophaceous involvement of the thyroid lamina with computed tomography (CT) images of this process. The paucity of literature on this subject may not only be due to rarity but also lack of clinical awareness. Gouty involvement of the larynx must be considered in any patient with a history of gout who presents with hoarseness, odynophagia, dysphagia, stridor or neck lump. Acute airway compromise may require tracheotomy, whereas chronic airway problems may necessitate endoscopic tophi removal, lateralization procedures or even permanent tracheostomy.

The proximal stomach and postprandial symptoms in functional dyspeptics.

OBJECTIVES: It remains unclear whether postprandial symptom profiles in patients with visceral hypersensitivity and in those with impaired fundic accommodation differ. Therefore, we evaluated the postprandial symptoms in functional dyspepsia (FD) patients classified according to proximal stomach function. In addition, the effect of gastric relaxation induced by sumatriptan on postprandial symptoms was studied in FD patients with impaired fundic accommodation. METHODS: Twenty-five healthy volunteers (HVs) and 44 FD patients filled out a disease-specific questionnaire (Nepean Dyspepsia Index) and underwent a gastric barostat study to evaluate visceral sensitivity, meal-induced fundic relaxation, and postprandial symptoms. Postprandial symptoms evoked by a drink test or reported during the barostat study were compared between FD patients subdivided according to the underlying pathophysiological mechanism. Finally, the effect of sumatriptan on postprandial symptoms evoked by a drink test was investigated in HVs and in FD patients with impaired fundic accommodation. RESULTS: There was no clear relationship between any of the 15 Nepean Dyspepsia Index symptoms and proximal stomach function. Postprandial symptoms evoked during the barostat study or after the drink tests were significantly higher in FD patients than in HVs; however, no clear differences in symptom profile could be demonstrated between the different subclasses of FD. Sumatriptan did not affect the maximal ingested volume or the postprandial symptoms in HVs or FD patients after a drink test. CONCLUSIONS: No clear relationship could be demonstrated between postprandial symptoms and proximal stomach function.

Impaired drinking capacity in patients with functional dyspepsia: relationship with proximal stomach function.

BACKGROUND & AIMS: Impaired fundic accommodation to a meal and hypersensitivity to distention are increasingly recognized as important mechanisms underlying functional dyspepsia (FD). In the present study, we evaluated whether a drink test can predict such abnormalities and thus represent a noninvasive tool to study proximal stomach motor function. METHODS: Healthy volunteers (HV), nonconsulters with mild dyspeptic symptoms (MS), and patients with FD filled out a disease-specific questionnaire and underwent a drink test with either water or with a high calorie fluid. The maximal ingested volume and the subsequent symptoms were meticulously recorded. In addition, all subjects underwent a gastric barostat study assessing meal-induced relaxation and sensation to distention. RESULTS: Drinking capacity was not significantly related to any particular dyspeptic symptom. FD were able to consume less water (893 +/- 70 mL) and caloric liquid (767 +/- 50 mL) compared with HV (water, 1764 +/- 120 mL; caloric liquid, 1308 +/- 96 mL) or MS (water, 1645 +/- 120 mL; caloric liquid, 973 +/- 45 mL). Approximately half of the FD had an abnormal water or Nutridrink test compared with 9% of MS and 4% of HV. Furthermore, FD developed significantly more symptoms than MS or HV after both drink tests. The drinking capacity did not predict impaired fundic accommodation or visceral hypersensitivity. CONCLUSIONS: FD, but not MS, have an impaired drinking capacity to both water and a nutrient liquid. The drinking capacity is not related to a specific dyspeptic symptom and does not predict proximal stomach motor function.

Primary sinonasal amyloidosis.

Primary amyloidosis localized to the sinonasal tract is extremely rare with only 20 reported cases in the English literature. We describe a further case and review the literature.

Effect of L-NMMA on postprandial transient lower esophageal sphincter relaxations in healthy volunteers.

In a previous study we showed that nitric oxide (NO) synthesis inhibition by NG-monomethyl-L-arginine (L-NMMA) reduced the number of transient lower esophageal sphincter relaxations (TLESRs) triggered by gastric balloon distention. The role of NO in postprandial TLESRs and gastroesophageal reflux, however, is unknown. Therefore, we studied the effect of L-NMMA on meal-induced TLESRs and reflux episodes with simultaneous recording of esophageal peristalsis, intraesophageal and intragastric pH, and gastric emptying in healthy volunteers. Ingestion of a solid meal resulted in an increase in TLESRs [8.5 (6.3-11.0) 60 min] which was significantly inhibited by L-NMMA [6.0 (4.0-8.8) 60 min, P < 0.05]. In addition, the total number of reflux episodes was reduced. L-NMMA had no effect on intragastric meal distribution and gastric emptying, but attenuated the postprandial increase in intragastric pH. These results confirm the involvement of NO in the neurocircuitry underlying the triggering of TLESRs. The reduction in reflux by L-NMMA has to be confirmed in patients with gastroesophageal reflux disease. NO may be involved in the regulation of gastric acid secretion.

Nasal pH and saccharin clearance are unrelated in the physiologically normal nose.

A group of 56 asymptomatic non-smoking men was prospectively recruited to study the relationship between nasal mucosal pH and saccharin clearance rate. No significant relationship was found between the two variables (Pearson correlation coefficient = -.105, p = 0.44). This finding suggests that in vivo mucociliary flow rates are resistant to change within the pH range of the physiologically normal nose.

Olfactory groove meningiomas.

Olfactory groove meningioma is a rare clinical entity. The principal symptoms associated with olfactory groove meningiomas are anosmia and headache which lead the patient to the ENT specialist. Frontal sinusitis, migraine and neuralgia are most frequent incorrect diagnoses. This retrospective study of 13 consecutive patients who underwent excision of Olfactory Groove meningiomas in the North Staffordshire Royal Infirmary, Department of Neurosurgery over a 20-year period was undertaken to study the presenting features, duration of symptoms, results of surgery, and long-term follow-up. Symptoms were present for less than 6 months to 3 years. Although excision was thought to be complete reoccurrences occurred in four patients. The morbidity of surgery was significant.

Activation of an adrenergic and vagally-mediated NANC pathway in surgery-induced fundic relaxation in the rat.

The aim of this study was to pharmacologically characterize and investigate the possible contribution of adrenergic and nonadrenergic noncholinergic (NANC) pathways involved in the relaxation of the rat gastric fundus following abdominal surgery. Using an intragastric balloon, the effect of skin incision (SI), laparotomy (LT) and manipulation of the small intestine followed by caecal resection (M + R) on fundic pressure was evaluated. SI resulted in a brief relaxation of the gastric fundus abolished by guanethidine and blocked by hexamethonium and the combination of phentolamine, propranolol and atropine (PPA). LT induced a longer lasting relaxation which was abolished by guanethidine and hexamethonium. It was blocked by PPA and the combination of ganglionectomy and vagotomy, but unaffected by atropine, vagotomy or ganglionectomy. M + R induced a long-lasting relaxation which was only partly blocked by guanethidine or PPA, illustrating an inhibitory NANC component. Vagotomy combined with guanethidine completely abolished the relaxation following M + R, whereas it was significantly blocked by hexamethonium and the combination of ganglionectomy with vagotomy. These results indicate that SI, LT and M + R induce inhibition of fundic motility via an adrenergic mechanism. During M + R, an additional vagally mediated inhibitory NANC pathway is activated. Finally, we suggest that LT and M + R inhibit the gastric fundus via both a splanchnic and a vagal reflex pathway.

Involvement of nitric oxide in human transient lower esophageal sphincter relaxations and esophageal primary peristalsis.

BACKGROUND & AIMS: Nitric oxide (NO) is well accepted as an inhibitory neurotransmitter in the gastrointestinal tract; however, its role in the triggering of transient lower esophageal sphincter relaxations (TLESRs) in humans remains to be determined. Therefore, the effect of NG-monomethyl-L-arginine (L-NMMA), a specific NO synthase blocker, on gastric distention-induced TLESRs was investigated. METHODS: Esophageal manometry was performed using a perfused sleeve assembly. The effect of L-NMMA was evaluated on water swallow-evoked primary peristalsis (n = 8; single-blind, placebo-controlled) and on the rate of TLESRs during gastric distention (n = 8; double-blind, placebo-controlled). RESULTS: L-NMMA increased the amplitude of peristaltic pressure waves in the distal esophagus and increased peristaltic velocity in the proximal esophagus. In contrast, L-NMMA had no effect on basal lower esophageal sphincter pressure, nadir pressure, duration, and area under the curve of lower esophageal sphincter relaxation. L-NMMA significantly inhibited the increase in TLESRs during gastric distention. L-NMMA also increased the intraballoon pressure during distention. CONCLUSIONS: NO is one of the neurotransmitters involved in the reflex arc mediating the triggering of TLESRs. NO is involved in the timing of human esophageal peristalsis and may exert a tonic inhibition on the proximal stomach.