Transient Lower Esophageal Sphincter (LES) Relaxations Research Articles

Circular and longitudinal muscles shortening indicates sliding patterns during peristalsis and transient lower esophageal sphincter relaxation.

Esophageal axial shortening is caused by longitudinal muscle (LM) contraction, but circular muscle (CM) may also contribute to axial shortening because of its spiral morphology. The goal of our study was to show patterns of contraction of CM and LM layers during peristalsis and transient lower esophageal sphincter (LES) relaxation (TLESR). In rats, esophageal and LES morphology was assessed by histology and immunohistochemistry, and function with the use of piezo-electric crystals and manometry. Electrical stimulation of the vagus nerve was used to induce esophageal contractions. In 18 healthy subjects, manometry and high frequency intraluminal ultrasound imaging during swallow-induced esophageal contractions and TLESR were evaluated. CM and LM thicknesses were measured (40 swallows and 30 TLESRs) as markers of axial shortening, before and at peak contraction, as well as during TLESRs. Animal studies revealed muscular connections between the LM and CM layers of the LES but not in the esophagus. During vagal stimulated esophageal contraction there was relative movement between the LM and CM. Human studies show that LM-to-CM (LM/CM) thickness ratio at baseline was 1. At the peak of swallow-induced contraction LM/CM ratio decreased significantly (<1), whereas the reverse was the case during TLESR (>2). The pattern of contraction of CM and LM suggests sliding of the two muscles. Furthermore, the sliding patterns are in the opposite direction during peristalsis and TLESR.

Mechanisms of Acid Reflux and How Refluxed Acid Extends Proximally in Patients with Non-Erosive Reflux Disease

Background/Aims: The mechanisms that cause acid reflux in patients with non-erosive reflux disease (NERD), including those that determine how acid extends proximally, are not yet clear. Methods: Concurrent esophageal manometry and pH monitoring were performed for 3 h after a meal in 13 patients with NERD, 12 with mild reflux esophagitis (RE), and 13 healthy subjects (HS). Results: Transient lower esophageal sphincter (LES) relaxation (TLESR) was the major mechanism of acid reflux in all three groups. LES pressure did not differ between the groups. At 2 cm above the LES, there were no differences between the three groups in the number of TLESR-related acid reflux episodes, rate of TLESRs and rate of acid reflux during TLESR. However, at 7 cm above the LES, the rate of acid reflux during TLESRs was significantly higher in patients with NERD (mean ± SEM 42.3 ± 4.8) than in those with mild RE (28.0 ± 3.8) and HS (10.8 ± 2.5). Conclusions: TLESRs are the sole motor events underlying acid reflux episodes in patients with NERD. Acid extends proximally more readily in patients with NERD than in HS and those with mild RE.

Relevance of position and movement of the gastroesophageal junction in gastroesophageal reflux disease.

TO THE EDITOR: Gastroesophageal reflux disease (GERD) and its complications are increasingly recognized in many parts of Asia, largely due to an increasing prevalence of obesity. Obese subjects are found to have frequent transient lower esophageal sphincter (LES) relaxations (TLESRs) and more likely to reflux 1 with underlying mechanisms being unclear. Besides the circular muscle, recent evidence suggests a role for longitudinal muscle in the opening of lower sphincter, 2 which may be relevant in the pathogenesis of GERD. Kim and colleagues 3 utilized high-resolution manometry to characterize TLESRs especially esophageal movement which they hypothesized to be different in patients with GERD from in controls. The study, however did not suggest a difference in degree of esophageal shortening using LES lift. There were a number of limitations which might explain the negative results, some that had been addressed in the paper. The study did not assess the presence of hiatus hernia which is an anatomical defect of the gastroesophageal junction (GEJ), commonly present in severe form of GERD. More recent evidence, using a novel Hall-effect technique that allows continuous measurement of the location of the GEJ without the need for fluoroscopy, indicates that TLESRs are a severe but transient form of hiatus herniation. 4,5 Furthermore, partial hiatus hernia is likely to be common especially in the presence of obesity and raised intra-abdominal pressure. 6 High-resolution manometry is able to discern the separation of pressure components of the LES 7 which is a sign of hiatus hernia but the sensitivity is poor. LES lift is a poor measure of esophageal shortening, not sensitive during complete TLESR or hiatus hernia and a small movement may not be detected. 8 A reliable knowledge of position of the GEJ is also relevant especially with regards to the acid pocket, which is an area of unbuffered postprandial gastric acidity, immediately distal to the GEJ. 9 Acid pocket is enlarged in hiatus hernia and it provides a reservoir of acid available to reflux whenever the intrinsic sphincter fails. 9

Transient Lower Esophageal Sphincter Relaxation and the Related Esophageal Motor Activities

Transient lower esophageal sphincter (LES) relaxation (TLESR) is defined as LES relaxation without a swallow. TLESRs are observed in both of the normal individuals and the patients with gastroesophageal reflux disorder (GERD). However, TLESR is widely considered as the major mechanism of the GERD. The new equipments such as high resolution manometry and impedance pH study is helped to understand of TLESR and the related esophageal motor activities. The strong longitudinal muscle contraction was observed during development of TLESR. Most of TLESRs are terminated by TLESR related motor events such as primary peristalsis and secondary contractions. The majority of TLESRs are associated with gastroesophageal reflux. Upper esophageal sphincter (UES) contraction is mainly associated with liquid reflux during recumbent position and UES relaxation predominantly related with air reflux during upright position. The frequency of TLESR in GERD patients seems to be not different compared to normal individuals, but the refluxate of GERD patients tend to be more acidic during TLESR.

775 Influence of the Cannabinoid Type 1 Receptor Antagonist Rimonabant On Esophageal Function in Man

Background: Cannabinoid type 1 (CB1) receptors have been implicated in the control of transient lower esophageal sphincter (LES) relaxations (TLESRs) in animals. In man, nonscpecific cannabinoid receptor agonism was found to inhibit TLESRS, but it is unclear whether CB1 receptors are involved in the control of esophageal function. Aim: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. Methods: Eleven healthy volunteers underwent two esophageal sleeve manometry studies after 3 days premedication with placebo or rimonabant 20 mg/ day. Drug was administered after 30 minutes and a standardized meal was administered after 90 minutes, with measurements continuing to 120 minutes postprandially. Throughout the study, 10 wet swallows were administered at 30-minute intervals. Results: Intragastric pressure was significantly enhanced by pretreatment with rimonabant (24.5±1.5 vs. 20.4±1.7 mmHg, p=0.01). Rimonabant did not significantly alter preprandial LES pressure (20.3±4.0 vs. 17.3±3.0 mmHg, NS), but postprandial LES pressures were significantly enhanced (ANOVA p<0.01), with post-hoc significant differences at 30, 60, 90, and 120 minutes after the end of the meal (respectively 17.1±2.7 vs. 10.0±1.7; 17.8±3.3 vs. 10.2±1.6; 19.3±3.6 vs. 10.4±1.3 mmHg and 19.6±3.1 vs. 8.6±3.0; all p<0.05). Swallow-induced relaxations (97±1 vs. 97±1%, NS) and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contraction waves at all time points (e.g. 5.0±0.3 vs. 8.0±0.3 sec preprandially and 5.0±0.2 vs. 8.2±0.3 sec at 30 min postprandially, both p<0.01). The tendency of a decreased number of TLESRs after rimonabant did not reach statistical significance (TLESRs total 2.3±0.8 vs. 3.3±0.5, p=0.08; preprandially 0.6±0.2 vs.1.3±0.3, p=0.14; postprandially 1.6±0.8 vs. 2.0±0.4, p=0.10). Conclusion: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and tends to decrease TLESRs in healthy subjects.

778 Cytokeratin Assisted Laser Scanning Cytometry (LSC) Permits Fully Automated Detection of Aneuploidy in Fixed Barrett's Biopsies

Background: Cannabinoid type 1 (CB1) receptors have been implicated in the control of transient lower esophageal sphincter (LES) relaxations (TLESRs) in animals. In man, nonscpecific cannabinoid receptor agonism was found to inhibit TLESRS, but it is unclear whether CB1 receptors are involved in the control of esophageal function. Aim: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. Methods: Eleven healthy volunteers underwent two esophageal sleeve manometry studies after 3 days premedication with placebo or rimonabant 20 mg/ day. Drug was administered after 30 minutes and a standardized meal was administered after 90 minutes, with measurements continuing to 120 minutes postprandially. Throughout the study, 10 wet swallows were administered at 30-minute intervals. Results: Intragastric pressure was significantly enhanced by pretreatment with rimonabant (24.5±1.5 vs. 20.4±1.7 mmHg, p=0.01). Rimonabant did not significantly alter preprandial LES pressure (20.3±4.0 vs. 17.3±3.0 mmHg, NS), but postprandial LES pressures were significantly enhanced (ANOVA p<0.01), with post-hoc significant differences at 30, 60, 90, and 120 minutes after the end of the meal (respectively 17.1±2.7 vs. 10.0±1.7; 17.8±3.3 vs. 10.2±1.6; 19.3±3.6 vs. 10.4±1.3 mmHg and 19.6±3.1 vs. 8.6±3.0; all p<0.05). Swallow-induced relaxations (97±1 vs. 97±1%, NS) and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contraction waves at all time points (e.g. 5.0±0.3 vs. 8.0±0.3 sec preprandially and 5.0±0.2 vs. 8.2±0.3 sec at 30 min postprandially, both p<0.01). The tendency of a decreased number of TLESRs after rimonabant did not reach statistical significance (TLESRs total 2.3±0.8 vs. 3.3±0.5, p=0.08; preprandially 0.6±0.2 vs.1.3±0.3, p=0.14; postprandially 1.6±0.8 vs. 2.0±0.4, p=0.10). Conclusion: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and tends to decrease TLESRs in healthy subjects.

776 Novel Fluorescence-Labeled Peptide for Targeting Intra-Epithelial Neoplasia in Barrett's Esophagus

Background: Cannabinoid type 1 (CB1) receptors have been implicated in the control of transient lower esophageal sphincter (LES) relaxations (TLESRs) in animals. In man, nonscpecific cannabinoid receptor agonism was found to inhibit TLESRS, but it is unclear whether CB1 receptors are involved in the control of esophageal function. Aim: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. Methods: Eleven healthy volunteers underwent two esophageal sleeve manometry studies after 3 days premedication with placebo or rimonabant 20 mg/ day. Drug was administered after 30 minutes and a standardized meal was administered after 90 minutes, with measurements continuing to 120 minutes postprandially. Throughout the study, 10 wet swallows were administered at 30-minute intervals. Results: Intragastric pressure was significantly enhanced by pretreatment with rimonabant (24.5±1.5 vs. 20.4±1.7 mmHg, p=0.01). Rimonabant did not significantly alter preprandial LES pressure (20.3±4.0 vs. 17.3±3.0 mmHg, NS), but postprandial LES pressures were significantly enhanced (ANOVA p<0.01), with post-hoc significant differences at 30, 60, 90, and 120 minutes after the end of the meal (respectively 17.1±2.7 vs. 10.0±1.7; 17.8±3.3 vs. 10.2±1.6; 19.3±3.6 vs. 10.4±1.3 mmHg and 19.6±3.1 vs. 8.6±3.0; all p<0.05). Swallow-induced relaxations (97±1 vs. 97±1%, NS) and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contraction waves at all time points (e.g. 5.0±0.3 vs. 8.0±0.3 sec preprandially and 5.0±0.2 vs. 8.2±0.3 sec at 30 min postprandially, both p<0.01). The tendency of a decreased number of TLESRs after rimonabant did not reach statistical significance (TLESRs total 2.3±0.8 vs. 3.3±0.5, p=0.08; preprandially 0.6±0.2 vs.1.3±0.3, p=0.14; postprandially 1.6±0.8 vs. 2.0±0.4, p=0.10). Conclusion: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and tends to decrease TLESRs in healthy subjects.

Inhibition of transient lower esophageal sphincter relaxations by electrical acupoint stimulation

Acupuncture has been shown to modulate visceral sensation and function. Traditionally, stimulation at the Neiguan (pericardial meridian) has been used to treat upper gastrointestinal symptoms. Some of the effects of acupuncture may be mediated through release of endogenous opioids and are reversed by naloxone. Gastric distension is the major trigger for transient lower esophageal sphincter (LES) relaxations (TLESRs). The aim of this study was to investigate the effect of electric stimulation at the Neiguan and naloxone on the TLESRs. In 14 healthy volunteers, electrical acupoint stimulation was applied at the Neiguan and a sham point on the hip in randomized order on the same day. In 12 healthy volunteers, the effects of naloxone (80 microg/kg iv bolus injection) and saline on electrical acupoint stimulation were compared on separate days at least 1 wk apart. Esophageal motility was measured during distension of the proximal stomach with 500 ml of air using a barostat balloon. Electric acupoint stimulation at the Neiguan decreased the rate of TLESRs by approximately 40% from a median of 6/h to 3.5/h (P < 0.02). Acupoint stimulation had no effect on basal LES pressure, the residual LES pressure during TLESRs, the duration of TLESRs, or gastrointestinal symptoms of fullness, bloating, discomfort, or nausea. The effect of acupoint stimulation was not inhibited by naloxone. Electric acupoint stimulation at the Neiguan significantly inhibits the frequency of TLESRs in response to gastric distention in healthy subjects. This effect does not appear to be mediated through mu-opioid receptors.

Baclofen blocks LES relaxation and crural diaphragm inhibition by esophageal and gastric distension in cats.

Esophageal distension and transient lower esophageal sphincter (LES) relaxation (TLESR) are accompanied by simultaneous relaxation of the LES and inhibition of crural diaphragm. Recent studies indicate that baclofen decreases the frequency of TLESR; however, its effect on the crural diaphragm is not known. We evaluated the effects of baclofen on LES relaxation and crural diaphragm inhibition induced by gastric distension and esophageal distension in cats. Five adult cats underwent surgical implantation of wire electrodes into the crural and costal diaphragm for measurement of their EMG activity, respectively. One week after the surgery, animals were lightly sedated and recordings were performed using a manometry catheter equipped with a 2.5-cm balloon. The effects of baclofen (10 micromol/kg iv) on the graded esophageal distension and gastric distension-induced LES and crural diaphragm responses were studied. Distension of the esophagus and stomach induces relaxation of the LES and inhibition of the crural diaphragm, simultaneously. Baclofen blocks both the esophageal and the gastric distension-induced relaxation of the LES and inhibition of the crural diaphragm. The magnitude of response to baclofen was significantly larger for the crural diaphragm inhibition than for the LES relaxation. Baclofen, a GABA(B) receptor agonist, blocks the reflex inhibitory pathway to the LES and crural diaphragm. The reflex inhibitory pathway to the crural diaphragm is more sensitive to blockade by baclofen than the reflex LES inhibitory pathway.

Effect of intragastric volume and osmolality on mechanisms of gastroesophageal reflux in children with gastroesophageal reflux disease

Both transient lower esophageal sphincter (LES) relaxations (TLESRs) and periods of low/absent LES pressure (LESP) are the main mechanisms of gastroesophageal reflux. These events are believed to be triggered by stimuli from different areas of the upper GI tract. We aimed at investigating the relationship between LESP profile and gastric emptying and distension after meals of different composition in 30 children with gastroesophageal reflux disease (median age 7.0 yr, range 12 months-12 yr). Recordings of LESP and intraesophageal pH for 1 h fasting and for 2 postprandial h were performed with a perfused sleeve catheter and flexible electrode, respectively; gastric emptying and distension of antral area were simultaneously recorded with real-time ultrasonography. Ten patients had a standard meal (group A), 10 had a high-volume meal (group B), and 10 had a high-volume and osmolality meal (group C). Postprandial esophageal acid exposure was significantly higher in patients of groups B and C than in patients of group A (p < 0.01); it was also more prolonged in patients of group C than in subjects of group B (p < 0.05). A higher postfeeding rate of reflux episodes caused by TLESRs was detected in patients of groups B and C as compared with patients of group A (p < 0.01). This increase did not statistically differ in patients of groups B and C. Patients of group C exhibited a higher postprandial rate of reflux episodes associated with low/absent tone of the LES as well as a more prolonged gastric emptying time and a higher postfeeding gastric distension as compared with patients of groups A and B (p < 0.01). Finally, a significant correlation was only found between the postprandial rate of reflux events resulting from low/absent LESP and the degree of antral distension in patients of group C (p < 0.01). Gastroesophageal reflux is worsened by increasing the volume and osmolality of meals through significant changes of LESP. Meals of high volume and meals with high volume and osmolality cause a comparable increase of reflux episodes as a result of TLESRs. However, meals with high volume and osmolality cause the higher degrees of esophageal acid exposure than meals with high volume resulting from a higher rate of reflux episodes associated with low/absent LESP. This finding correlates with a high postfeeding antral distension.

Effect of intragastric volume and osmolality on mechanisms of gastroesophageal reflux in children with gastroesophageal reflux disease

OBJECTIVE: Both transient lower esophageal sphincter (LES) relaxations (TLESRs) and periods of low/absent LES pressure (LESP) are the main mechanisms of gastroesophageal reflux. These events are believed to be triggered by stimuli from different areas of the upper GI tract. We aimed at investigating the relationship between LESP profile and gastric emptying and distension after meals of different composition in 30 children with gastroesophageal reflux disease (median age 7.0 yr, range 12 months–12 yr). METHODS: Recordings of LESP and intraesophageal pH for 1 h fasting and for 2 postprandial h were performed with a perfused sleeve catheter and flexible electrode, respectively; gastric emptying and distension of antral area were simultaneously recorded with real-time ultrasonography. Ten patients had a standard meal (group A), 10 had a high-volume meal (group B), and 10 had a high-volume and osmolality meal (group C). RESULTS: Postprandial esophageal acid exposure was significantly higher in patients of groups B and C than in patients of group A ( p < 0.01); it was also more prolonged in patients of group C than in subjects of group B ( p < 0.05). A higher postfeeding rate of reflux episodes caused by TLESRs was detected in patients of groups B and C as compared with patients of group A ( p < 0.01). This increase did not statistically differ in patients of groups B and C. Patients of group C exhibited a higher postprandial rate of reflux episodes associated with low/absent tone of the LES as well as a more prolonged gastric emptying time and a higher postfeeding gastric distension as compared with patients of groups A and B ( p < 0.01). Finally, a significant correlation was only found between the postprandial rate of reflux events resulting from low/absent LESP and the degree of antral distension in patients of group C ( p < 0.01). CONCLUSION: Gastroesophageal reflux is worsened by increasing the volume and osmolality of meals through significant changes of LESP. Meals of high volume and meals with high volume and osmolality cause a comparable increase of reflux episodes as a result of TLESRs. However, meals with high volume and osmolality cause the higher degrees of esophageal acid exposure than meals with high volume resulting from a higher rate of reflux episodes associated with low/absent LESP. This finding correlates with a high postfeeding antral distension.

Fasting and postprandial mechanisms of gastroesophageal reflux in children with gastroesophageal reflux disease

In order to define the mechanisms of gastroesophageal reflux (GER) in children, we performed simultaneous intraluminal esophageal motility and pH studies in 24 children with symptomatic reflux and abnormal prolonged pH probe study, ten (group A) without endoscopic and histologic esophagitis, 14 (group B) with endoscopic and histologic esophagitis. Median (ranges) age (years) was 5.0 (6 months-10 years) and 3.0 (6 months-12 years), respectively. Recordings were done for 1 hr before and 1 hr after feeding apple juice (15 ml/kg; pH 4.0). All episodes of GER in group A patients and 77.1% in group B patients were accounted for by abrupt transient lower esophageal sphincter (LES) relaxation (TLESR); 22.9% of reflux events in group B patients occurred during gradual drifts of LES pressure (LESP) to undetectable levels. Esophageal refluxate exposure (mean percentage time with esophageal pH < 4.0), the rate of TLESR (number of episodes/hr), and the percentage of TLESRs associated with reflux significantly increased in the fed period both in group A (18.5 +/- 5.4%, 6.2 +/- 2.65, 87.1%) and in group B (29.7 +/- 6.5, 7.8 +/- 3.05, 84.9%) as compared to the fasting state (group A: 10.8 +/- 3.9, 3.9 +/- 3.17, 46.1%; group B: 16.1 +/- 2.6, 4.14 +/- 3.06, 55.17%) (p < 0.01). The rate of LESP drifts (number of episodes/hr) was also significantly higher postprandially (4.85 +/- 1.24 vs 1.8 +/- 0.9, p < 0.01); furthermore there was a postfeeding increase of the LESP drift percentage associated with reflux (79.41% vs 46.15%, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)