Impaired deglutitive EGJ relaxation in clinical esophageal manometry: a quantitative analysis of 400 patients and 75 controls

Assessing deglutitive esophagogastric junction (EGJ) relaxation is an essential focus of clinical manometry. Our aim was to apply automated algorithmic analyses to high-resolution manometry (HRM) studies to ascertain the optimal method for discriminating normal from abnormal deglutitive EGJ relaxation. All 473 subjects (73 controls) were studied with a 36-channel solid-state HRM assembly during water swallows. Patients were classified as: 1) achalasia, 2) postfundoplication, 3) nonachalasia with normal deglutitive EGJ relaxation, or 4) functional obstruction (preserved peristalsis with incomplete EGJ relaxation). Automated computer programs assessed the adequacy of EGJ relaxation by using progressively complex analysis routines to compensate for esophageal shortening, crural diaphragm contraction, and catheter movement, all potential confounders. The single-sensor method of assessing EGJ relaxation had a sensitivity of only 52% for detecting achalasia. Of the automated HRM analysis paradigms tested, the 4-s integrated relaxation pressure using a cutoff of 15 mmHg performed optimally with 98% sensitivity and 96% specificity in the detection of achalasia. We also identified a heterogeneous group of 26 patients with functional EGJ obstruction attributed to variant achalasia and other diverse pathology. Although further clinical experience will ultimately judge, it is our expectation that applying rigorous methodology such as described herein to the analysis of HRM studies will improve the consistency in the interpretation of clinical manometry and prove useful in guiding clinical management.     

Quantifying EGJ morphology and relaxation with high-resolution manometry: a study of 75 asymptomatic volunteers

Our aim was to define normal esophagogastric junction (EGJ) morphology and relaxation characteristics using high-resolution manometry (HRM). To this end, 75 asymptomatic controls underwent HRM with a solid-state manometric assembly incorporating 36 circumferential sensors spaced at 1-cm intervals positioned to record from the hypopharynx to the stomach. Ten 5-ml water swallows were obtained. EGJ relaxation was quantified by 1) nadir pressure, 2) the lowest 3-s mean residual pressure after swallow (E-sleeve), and 3) the transsphincteric gradient 2-6 s after swallowing measured from 2 cm above to 2 cm below the EGJ. A new parameter, integrated relaxation resistance (IRR), was also calculated. The IRR calculation accounted for both the duration of EGJ relaxation and instantaneous E-sleeve-type relaxation pressures during the entire interval of relaxation. The means and ranges (5-95th percentile) for nadir lower esophageal sphincter relaxation pressure (mean: 3.9 mmHg, range: 0-10.1 mmHg) and E-sleeve relaxation pressure (mean: 8.1 mmHg, range: 4.1-15.1 mmHg) were consistent with previously reported values. The mean relaxation interval was 7.95 +/- 0.2 s (mean +/- SE), whereas the median relaxation pressure during that interval was 10.7 +/- 0.5 mmHg (mean +/- SE). Mean IRR was 1.3 mmHg/s (95th percentile: 3.0 mmHg/s). Mean EGJ length was 3.7 cm. In conclusion, HRM provides a seamless dynamic representation of pressure within and across the EGJ. In addition to providing conventional EGJ relaxation parameters, this technology also creates opportunities to quantify more precise measures of EGJ relaxation and morphology.     

Utilizing intraluminal pressure differences to predict esophageal bolus flow dynamics

Successful esophageal emptying depends on the generation of a sustained intrabolus pressure (IBP) sufficient to overcome esophagogastric junction (EGJ) obstruction. Our aim was to develop a manometric analysis paradigm that describes the bolus driving pressure difference and the flow permissive time for esophageal bolus transit. Twenty normal subjects were studied with a 36-channel manometry assembly (1-cm spacing) during two 5- and one 10-ml barium swallows and concurrent fluoroscopy. Bolus domain pressure plots were generated by plotting bolus domain pressure (BDP) and EGJ relaxation pressure. BDP was defined as the pressure midway between the peristaltic ramp-up and the proximal margin of the EGJ. The flow permissive time was defined as the period where the BDP was > or = EGJ relaxation pressure. The mean BDP was 11.7 +/- 1.0 mmHg (SE), and the mean flow permissive time was 3.9 +/- 0.4 s for 5-ml swallows in normal controls. The mean BDP difference during flow was 4.0 +/- 1.0 mmHg. There was no significant difference in the fluoroscopic transit time and the flow permissive time calculated from the BDP plots (5 ml: fluoroscopy 3.4 +/- 0.2 s; BDP 3.9 +/- 0.4 s, P > 0.05). BDP plots provide a reliable measurement of IBP and its relationship with EGJ relaxation. The time available for flow can be readily delineated from this analysis, and the driving pressure responsible for flow can be accurately described and quantified. This may help predict abnormal bolus transit and the underlying mechanical properties of the EGJ.     

Esophageal tone in patients with total aperistalsis: gastroesophageal reflux disease versus achalasia

We have evaluated esophageal tone in two different conditions that, in some cases, similarly impair phasic esophageal motility. Studies were performed in 14 healthy volunteers, 10 patients with total esophageal aperistalsis secondary to gastroesophageal reflux disease (GERD), and 25 untreated achalasia patients. We quantified esophageal compliance and relaxation induced by a nitric oxide donor using a barostat. Intraesophageal volume at a minimal distending pressure (2 mmHg) was not significantly different among all three groups (4.1 +/- 0.7, 3.8 +/- 0.7, and 4.2 +/- 1.2 ml for healthy, GERD, and achalasia groups, respectively). Esophageal compliance was significantly increased (P < 0.05 vs. healthy group) in the two groups of patients with aperistalsis (1.9 +/- 0.2, 3.0 +/- 0.2, and 3.1 +/- 0.3 ml/mmHg for healthy, GERD, and achalasia groups, respectively). Esophageal relaxation was decreased in GERD patients (Delta diameter: 0.4 +/- 0.1 cm) and increased in achalasia patients (Delta diameter: 1.3 +/- 0.4 cm) relative to healthy subjects (Delta diameter: 0.9 +/- 0.2 cm) (P < 0.05 for GERD vs. achalasia and healthy groups). Our results indicate that diseases that similarly impair phasic esophageal motility may affect esophageal tone differently.     

Evidence for a peripheral mechanism of esophagocrural diaphragm inhibitory reflex in cats

The esophagogastric junction (EGJ) is guarded by two sphincters, a smooth muscle lower esophageal sphincter (LES) and a skeletal muscle crural diaphragm. These two sphincters relax simultaneously under certain physiological conditions, i.e., swallowing, belching, vomiting, transient LES relaxation, and esophageal distension. Esophageal distension-induced crural diaphragm relaxation is mediated through vagal afferents that are thought to exert inhibitory influence on the central mechanism (brain stem) of crural diaphragm contraction. We conducted studies in 10 cats to determine whether a mechanism of crural diaphragm relaxation was located at the level of the neuromuscular junction and/or muscle. Stimulation of the crural diaphragm neuromuscular junction through 1) the electrodes implanted in the muscle and 2) the bilateral phrenic nerve resulted in an increase in EGJ pressure. Nicotinic receptor blockade (pancuronium, 0.2 mg/kg) abolished the EGJ pressure increase caused by electrical stimulation of the neuromuscular junction. Esophageal distension and bolus-induced secondary esophageal peristalsis caused relaxation of the EGJ during the stimulation of the neuromuscular junction. Bilateral phrenicotomy and vagotomy had no influence on this relaxation. These data suggest the existence of a peripheral mechanism of crural diaphragm inhibition. This peripheral inhibitory mechanism may reside at the level of either the neuromuscular junction or the skeletal muscle.     

Pressure morphology of the relaxed lower esophageal sphincter: the formation and collapse of the phrenic ampulla

This study aimed to apply novel high-resolution manometry with eight-sector radial pressure resolution (3D-HRM technology) to resolve the deglutitive pressure morphology at the esophagogastric junction (EGJ) before, during, and after bolus transit. A hybrid HRM assembly, including a 9-cm-long 3D-HRM array, was used to record EGJ pressure morphology in 15 normal subjects. Concurrent videofluoroscopy was used to relate bolus movement to pressure morphology and EGJ anatomy, aided by an endoclip marking the squamocolumnar junction (SCJ). The contractile deceleration point (CDP) marked the time at which luminal clearance slowed to 1.1 cm/s and the location (4 cm proximal to the elevated SCJ) at which peristalsis terminated. The phrenic ampulla spanned from the CDP to the SCJ. The subsequent radial and axial collapse of the ampulla coincided with the reconstitution of the effaced and elongated lower esophageal sphincter (LES). Following ampullary emptying, the stretched LES (maximum length 4.0 cm) progressively collapsed to its baseline length of 1.9 cm (P < 0.001). The phrenic ampulla is a transient structure comprised of the stretched, effaced, and axially displaced LES that serves as a "yield zone" to facilitate bolus transfer to the stomach. During ampullary emptying, the LES circular muscle contracts, and longitudinal muscle shortens while that of the adjacent esophagus reelongates. The likely LES elongation with the formation of the ampulla and shortening to its native length after ampullary emptying suggest that reduction in the resting tone of the longitudinal muscle within the LES segment is a previously unrecognized component of LES relaxation.     

Esophagogastric junction distensibility: a factor contributing to sphincter incompetence

To quantify the effect of hiatus hernia (HH) on esophagogastric junction (EGJ) distensibility, eight normal subjects and nine gastroesophageal reflux disease (GERD) patients with HH were studied with concurrent manometry, fluoroscopy, and stepwise controlled barostatic distention of the EGJ. The minimal barostatic pressure required to open the EGJ during the interswallow period was determined. Thereafter, barium swallows were imaged in 5-mmHg increments of intrabag pressure. EGJ diameter and length were measured at each pressure during deglutitive relaxation. The EGJ opening diameter was greater in hernia patients compared with normal subjects during deglutitive relaxation at all pressures, and EGJ length was 23% shorter. EGJ opening pressure among hernia patients was lower than normal subjects during the interswallow period. In conclusion, the EGJ of GERD patients with HH was more distensible and shorter than normal subjects. These findings partially explain why HH patients are predisposed to reflux by mechanisms other than transient lower esophageal sphincter relaxations, sustain greater volumes of refluxate, and have a reduced ability to discriminate gas from liquid reflux.     

The functional lumen imaging probe (FLIP) for evaluation of the esophagogastric junction

There is a need for new methods to study the dynamics of the esophagogastric junction (EGJ). The aims were to verify the efficacy and usefulness of a "functional lumen imaging probe" (FLIP) for the evaluation of the EGJ. Eight healthy volunteers (6 men), median age 26 (21-35) yr, and two achalasia patients underwent the FLIP procedure. The EGJ was located by manometry. The FLIP measured eight cross-sectional areas (CSAs) 4 mm apart together with the pressure inside a saline-filled cylindrical bag. The data showed the geometric profile of the EGJ reconstructed in a video animation of its dynamic activity. A plot of curve-fitted data for the smallest CSA vs. pressure after balloon distension indicated that the pressure increased from 18 cmH2O at a CSA of 38 mm2 to a pressure of 37 cmH2O at a CSA of 230 mm2 for the healthy controls. In one achalasia patient (unsuccessfully treated with dilations), the CSA never rose above the minimal measurable value despite the pressure increasing to 50 cmH2O. In another achalasia patient (successfully treated with dilations), the pressure only reached 15 cmH2O despite opening to a CSA of 250 mm2. In conclusion, FLIP represents the first dynamic technique to profile the function and anatomy of the EGJ. The method can be used practically to evaluate difficult cases of EGJ dysfunction and may provide a role in evaluating patients before and after therapies for diseases affecting the EGJ such as achalasia and gastroesophageal reflux disease.     

Calcitonin gene-related peptide: a sensory and motor neurotransmitter in the feline lower esophageal sphincter

The effect of calcitonin gene-related peptide (CGRP) on the feline lower esophageal sphincter (LES) was determined and correlated with its anatomic distribution as determined by immunohistochemistry. Intraluminal pressures of the esophagus and LES were recorded in anesthetized cats. In separate cats, gastroesophageal junctions were removed after locating the LES manometrically and stained for CGRP-like immunoreactivity (LI) and substance P-LI (SP-LI) by indirect immunohistochemistry. CGRP-LI in the LES was most prominent in large nerve fascicles between the circular and longitudinal muscle layers and only rarely seen in nerve fibers within the circular muscle. The myenteric plexus contained numerous CGRP-LI nerve fibers but cell bodies were not seen. Many CGRP-LI nerve fibers in the myenteric plexus and occasional varicose nerves in the circular muscle demonstrated colocalization with SP-LI. Colocalization of CGRP-LI with SP-LI was also seen in the perivascular nerves of the submucosal and intramural blood vessels and in varicose fibers in the lamina propria of the gastric fundic mucosa. In the esophagus, CGRP-LI nerves extended through the muscularis mucosa and penetrated the squamous epithelium to the lumen. CGRP, given intra-arterially caused a dose-dependent fall in basal LES pressure, with a threshold dose of 10(-8) g/kg (2.63 pmol/kg). At the maximal effective dose, 5 x 10(-6) g/kg (1.31 x 10(3) pmol/kg), CGRP produced 61.0 +/- 6.0% decrease in basal LES pressure. At this dose, mean systemic blood pressure fell by 40.9 +/- 7.8%. The LES relaxation induced by a submaximal dose of CGRP (10(-6) g/kg, 262.7 pmol/kg), 50.3 +/- 3.2% relaxation was partially inhibited by tetrodotoxin (26.9 +/- 10.8% relaxation, P less than 0.025). The inhibitory effect of CGRP was not affected by cervical vagotomy, hexamethonium, atropine, propranolol, or naloxone. The LES contractile response to the D90 of SP (5 x 10(-8) g/kg, 37.1 pmol/kg) was not altered by CGRP 10(-8) or 10(-6) g/kg and the CGRP relaxation effect was not altered by the threshold dose of substance P (5 X 10(-9) g/kg, 3.71 pmol/kg). CONCLUSIONS: (1) CGRP-LI is present at the feline LES and is primarily seen in large nerve fascicles which pass from the intermuscular plane and through the circular muscle layer to the submucosa and in mucosal nerves. (2) CGRP colocalizes with SP-LI in some varicose nerve fibers of the circular muscle of the esophagus, LES and fundus, in perivascular nerves of the submucosal and intramucosal blood vessels, and in nerves of the lamina propria of the gastric fundus. (3) The luminal penetration of CGRP-LI nerves in the squamous mucosa of the esophagus suggests a sensory func     

Axial stretch: A novel mechanism of the lower esophageal sphincter relaxation

Swallow and esophageal distension-induced relaxations of the lower esophageal sphincter (LES) are associated with an orad movement of the LES because of a concurrent esophageal longitudinal muscle contraction. We hypothesized that the esophageal longitudinal muscle contraction induces a cranially directed mechanical stretch on the LES and therefore studied the effects of a mechanical stretch on the LES pressure. In adult opossums, a silicon tube was placed via mouth into the esophagus and laparotomy was performed. Two needles with silk sutures were passed, 90 degrees apart, through the esophageal walls and silicon tube, 2 cm above the LES. The tube was withdrawn, and one end of each of the four sutures was anchored to the esophageal wall and the other end exited through the mouth to exert graded cranially directed stretch on the LES by using pulley and weights. A cranially directed stretch caused LES relaxation, and with the cessation of stretch there was recovery of the LES pressure. The degree an d duration of LES relaxation increased with the weight and the duration of stretch, respectively. The mean LES relaxation in all animals was 77.7 +/- 4.7%. The required weight to induce maximal LES relaxation differed in animals (714 +/- 348 g). N(G)-nitro-L-arginine, a nitric oxide inhibitor, blocked the axial stretch-induced LES relaxation almost completely (from 78 to 19%). Our data support the presence of an axial stretch-activated inhibitory mechanism in the LES. The role of axial stretch in the LES relaxation induced by swallow and esophageal distension requires further investigation.     

Patterns of esophageal inhibition during swallowing,pharyngeal stimulation,and transient LES relaxation. Lower esophageal sphincter

Lower esophageal sphincter (LES) relaxation and esophageal body inhibition co-occur during esophageal peristalsis but not necessarily during pharyngeal stimulation or transient LES relaxation (tLESR). This study examined these relationships and the impact on reflux. Nine young volunteers were studied. An artificial high-pressure zone (HPZ) was established, and pH was recorded 8 and 5 cm proximal to the LES. Pharyngeal stimulation was by water injection and gastric distension with liquid or gas. Peristalsis, pharyngeal stimulation, and spontaneous events were recorded. Swallowing relaxed the LES in 100% of trials (the HPZ in 80%) and caused no reflux. Pharyngeal stimulation relaxed the LES in two-thirds of trials, had no effect on the HPZ, and caused no reflux. Gastric distension was associated with 117 tLESRs, 48% with acid reflux, and 32% with gas reflux; there was no effect on the HPZ. We conclude that LES relaxation is a necessary but not sufficient condition for reflux. LES relaxation and esophageal body inhibition are independent events that may be concurrent (swallowing) or dissociated (tLESR).     

Dyschalasia: A Variant or Early Phase of Achalasia?: A Review of Motor Disturbances in Achalasia with Reference to Late Relaxation of the Lower Esophageal Sphincter

One of the characteristic motor abnormalities in achalasia of the esophagus is the lack of relaxation of the lower esophageal sphincter during swallowing. In a subject with a clinical history and radiologic evidence of early achalasia all the typical motor abnormalities of the disease were observed in the course of pressure studies, but the sphincter exhibited a fall of pressure in response to a contraction of the body of the esophagus. This relaxation occurred later than would be expected in the normal esophagus and, therefore, this unusual condition was named dyschalasia.The relationship of dyschalasia to classical achalasia is discussed and several theories are advanced. The authors believe that dyschalasia is possibly an early stage of achalasia.     

Effect of somatostatin on lower esophageal sphincter (les) pressure and serum gastrin in normal and achalasic subjects

Serum gastrin and lower esophageal sphincter (LES) responses to somatostatin infusion were evaluated in ten normal subjects and in nine achalasic patients in order to determine evidence of hormonal (presumably gastrin)control of LES pressure. After somatostatin infusion, a significant decrease of serum gastrin was observed in normal subjects at 30 min (81.6 +/- 3.2 versus 40.0 +/- 4.7 pg/ml; p less than 0.01) and a rapid increase of LES pressure was also observed (26.0 +/- 1.3 versus 34.1 +/- 1.6 mmHg; p less than 0.01). In achalasia no change was observed in serum gastrin concentration after somatostatin infusion. LES pressure at 20 min however significantly decreased (45.8 +/- 7.6 versus 31.6 +/- 2.3 mmHg; p less than 0.05). Endogenous gastrin is not a major control factor for LES pressure in either normal or achalasic subjects.     

Role of nitric oxide in lower esophageal sphincter relaxation to swallowing.

Studies were performed in the opossum to define the role of the L-arginine-nitric oxide (NO) pathway in lower esophageal sphincter (LES) relaxation to swallowing and vagal stimulation in viv and intramural nerve stimulation in vitro. In vivo, L-NAME, a water soluble NO synthase (NOS) inhibitor, caused antagonism of LES relaxation due to reflex-induced swallowing. L-NAME (20 mg/kg i.v.) reduced the amplitude of swallow induced relaxation from 88% to 28%. LES relaxation due to electrical stimulation of peripheral end of decentralized vagus nerve was also antagonized. The effects of L-NAME were reversed by L-arginine, but not by D-arginine. L-NAME treatment did not antagonize LES relaxation to intravenous administration of isoproterenol. In vitro, NO and sodium nitroprusside (SNP) caused a decrease in the sphincter tone. The relaxing effect caused by NO and SNP was not antagonized by tetrodotoxin or omega-conotoxin. Inhibitors of NO synthase, L-NMMA and L-NNA, caused slight increase in the spontaneous resting LES tone and concentration-dependent antagonism of electrical field stimulation (EFS) induced LES relaxation. L-NNA (10(-4)M) abolished EFS induced LES relaxation at low frequencies (less than 5 Hz) and antagonized the relaxation to a value 20% of the control at 20 Hz. The antagonistic action of L-NMMA and L-NNA was unaffected by D-arginine but was reversed by L-arginine. The inhibitory effect of NO, SNP, or two other putative inhibitory neurotransmitters (VIP and CGRP) on the LES was not antagonized by L-NNA. These studies show that inhibitors of NO synthase selectively antagonize LES relaxation to all three modes of intramural inhibitory nerve stimulation including physiological swallowing. These studies suggest that the L-arginine-nitric oxide pathway is involved in physiological relaxation of the LES.     

The impact of continuous positive airway pressure on the lower esophageal sphincter

The lower esophageal sphincter (LES) is the primary barrier to gastroesophageal reflux. Reflux is associated with periods of LES relaxation, as occurs during swallowing. Continuous positive airway pressure (CPAP) has been shown to reduce reflux in individuals with and without sleep apnea, by an unknown mechanism. The aim of this study was to determine the effect of CPAP on swallow-induced LES relaxation. Measurements were made in 10 healthy, awake, supine individuals. Esophageal (Pes), LES (Ples), gastric (Pg), and barrier pressure to reflux (Pb = Ples - Pg) were recorded using a sleeve catheter during five swallows of 5 ml of water. This was repeated at four levels of CPAP (0, 5, 10, and 15 cmH(2)O). Pressures were measured during quiet breathing and during the LES relaxation associated with a swallow. Duration of LES relaxation was also recorded. During quiet breathing, CPAP significantly increased end-expiratory Pes, Ples, Pg, and Pb (P < 0.05). The increase in Pb was due to a disproportionate increase in Ples compared with Pg (P < 0.05). During a swallow, CPAP increased nadir Ples, Pg, and Pb and decreased the duration of LES relaxation (4.1 s with 0-cmH(2)O CPAP to 1.6 s on 15-cmH(2)O CPAP, P < 0.001). Pb increased with CPAP by virtue of a disproportionate increase in Ples compared with Pg. This may be due to either reflex activation of LES smooth muscle, or nonspecific transmission of pressure to the LES. The findings suggest CPAP may make the LES less susceptible to reflux by increasing Pb and decreasing the duration of LES relaxation.     

A novel pattern of longitudinal muscle contraction with subthreshold pharyngeal stimulus: a possible mechanism of lower esophageal sphincter relaxation

A subthreshold pharyngeal stimulus induces lower esophageal sphincter (LES) relaxation and inhibits progression of ongoing peristaltic contraction in the esophagus. Recent studies show that longitudinal muscle contraction of the esophagus may play a role in LES relaxation. Our goal was to determine whether a subthreshold pharyngeal stimulus induces contraction of the longitudinal muscle of the esophagus and to determine the nature of this contraction. Studies were conducted in 16 healthy subjects. High resolution manometry (HRM) recorded pressures, and high frequency intraluminal ultrasound (HFIUS) images recorded longitudinal muscle contraction at various locations in the esophagus. Subthreshold pharyngeal stimulation was induced by injection of minute amounts of water in the pharynx. A subthreshold pharyngeal stimulus induced strong contraction and caudal descent of the upper esophageal sphincter (UES) along with relaxation of the LES. HFIUS identified longitudinal muscle contraction of the proximal (3-5 cm below the UES) but not the distal esophagus. Pharyngeal stimulus, following a dry swallow, blocked the progression of dry swallow-induced peristalsis; this was also associated with UES contraction and descent along with the contraction of longitudinal muscle of the proximal esophagus. We identify a unique pattern of longitudinal muscle contraction of the proximal esophagus in response to subthreshold pharyngeal stimulus, which we propose may be responsible for relaxation of the distal esophagus and LES through the stretch sensitive activation of myenteric inhibitory motor neurons.     

Effect of electrical stimulation of the LES on LES pressure in a canine model

Gastric electrical stimulation modulates lower esophageal sphincter pressure (LESP). High-frequency neural stimulation (NES) can induce gut smooth muscle contractions. To determine whether lower esophageal sphincter (LES) electrical stimulation (ES) can affect LESP, bipolar electrodes were implanted in the LES of four dogs. Esophageal manometry during sham or ES was performed randomly on separate days. Four stimuli were used: 1) low-frequency: 350-ms pulses at 6 cycles/min; 2) high-frequency-1: 1-ms pulses at 50 Hz; 3) high-frequency-2: 1-ms pulses at 20 Hz; and 4) NES: 20-ms bipolar pulses at 50 Hz. Recordings were obtained postprandially. Tests consisted of three 20-min periods: baseline, stimulation/sham, and poststimulation. The effect of NES was tested under anesthesia and following IV administration of l-NAME and atropine. Area under the curve (AUC) and LESP were compared among the three periods, by ANOVA and t-test, P < 0.05. Data are shown as means +/- SD. We found that low-frequency stimulation caused a sustained increase in LESP: 32.1 +/- 12.9 (prestimulation) vs. 43.2 +/- 18.0 (stimulation) vs. 50.1 +/- 23.8 (poststimulation), P < 0.05. AUC significantly increased during and after stimulation. There were no significant changes with other types of ES. With NES, LESP initially rose and then decreased below baseline (LES relaxation). During NES, N(G)-nitro-l-arginine methyl ester increased both resting LESP and the initial rise in LESP and markedly diminished the relaxation. Atropine lowered resting LESP and abolished the initial rise in LESP. In conclusion, low frequency ES of the LES increases LESP in conscious dogs. NES has dual effect on LESP: an initial stimulation, cholinergically mediated, followed by relaxation mediated by nitric oxide.     

Effect of hyperglycemia on triggering of transient lower esophageal sphincter relaxations

Acute changes in blood glucose concentration have major effects on gastrointestinal motor function. Patients with diabetes mellitus have an increased prevalence of gastroesophageal reflux. Transient lower esophageal sphincter (LES) relaxation (TLESR) is the most common sphincter mechanism underlying reflux. The aim of this study was to investigate the effect of acute hyperglycemia on triggering TLESRs evoked by gastric distension in healthy volunteers. TLESRs were stimulated by pressure-controlled and volume-controlled (500 ml) gastric distension using an electronic barostat and performed on separate days. On each day, esophageal manometry was performed in the sitting position during gastric distension for 1 h under euglycemia (5 mM), and either marked hyperglycemia (15 mM) or physiological hyperglycemia (8 mM) in randomized order was maintained by a glucose clamp. Marked hyperglycemia doubled the rate of TLESRs in response to both pressure-controlled [5 (3-10.5, median or interquartile range) to 10 (9.5-14.5) per hour, P < 0.02] and volume-controlled [4 (2.5-7.5) to 10.5 (7-12.5) per hour, P < 0.02] gastric distension but had no effect on basal LES pressure. Physiological hyperglycemia had no effect on the triggering of TLESRs or basal LES pressure. In healthy human subjects, marked hyperglycemia increases the rate of TLESRs. Increase in the rate of TLESRs is independent of proximal gastric wall tension. Mechanisms underlying the effect remain to be determined. Hyperglycemia may be an important factor contributing to the increased esophageal acid exposure in patients with diabetes mellitus.     

Effect of prolonged gastric distension on motor function of LES and of proximal stomach

Gastric distension is a potent stimulus of transient lower esophageal sphincter (LES) relaxation. To investigate the time effect of prolonged gastric distension on the rate of transient LES relaxations, LES pressure, and the motor and sensory functions of the proximal stomach, we performed a continuous isobaric distension of the proximal stomach at the 75% threshold pressure for discomfort for 2 h in seven healthy subjects. A multilumen assembly incorporating a sleeve and an electronic barostat was used. The rate of transient LES relaxations (n/30 min) was constant during the first hour [4.1 +/- 1.2 (0-30 min) and 5.4 +/- 1.1 (30-60 min)] but markedly decreased (P < 0.05) in the second hour [2.1 +/- 0.5 (60-90 min) and 2.3 +/- 0.9 (90-120 min)], whereas LES pressure, baseline volume and volume waves within the gastric bag, hunger, and fullness did not change throughout the experiment. It is concluded that the rate of transient LES relaxations decreases with time during prolonged gastric distension, thus suggesting that this type of stimulus should not be used in sequential experimental conditions.     

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.