Esophagitis-related esophageal shortening in opossum is associated with longitudinal muscle hyperresponsiveness

Acute intraluminal acid perfusion induces esophageal shortening in humans and opossums. Lower esophageal sphincter (LES) hypotension and peristaltic dysfunction occur in patients and animal models of reflux esophagitis. This study examined whether similar shortening and motor dysfunction occur in anesthetized opossums after repeated esophageal acid exposure and whether this is associated with longitudinal muscle (LM) hyperresponsiveness. Manometry used before and after 3 consecutive days of 45-min perfusion with 100 mmol/l HCl or normal saline measured esophageal length and motor responses to induced swallows. LM electrical and mechanical responses were assessed using standard isometric tension and intracellular recording techniques. Compared with controls, repeated acid perfusion induced erosive esophagitis and significant esophageal shortening, associated with enhanced LM responses to carbachol, a significantly depolarized resting membrane potential, and abnormal spike patterns. LES resting pressure and swallow-induced peristalsis were unaffected. In this model of reflux esophagitis, marked persistent esophageal shortening and associated LM hyperresponsiveness occur before significant LES or peristaltic dysfunction, suggesting that esophageal shortening is the earliest motor disorder induced by acid injury.     

Pepsin and the esophagus

Esophagitis results from excessive exposure of the esophagus to gastric juice through an ineffective or dysfunctional lower esophageal sphincter mechanism. A possible role of pepsin in damaging the esophageal mucosa with consequent esophagitis may be examined directly by testing pepsin under various conditions in experimental models of esophagitis. Since gastric juice contains both acid and pepsin, all experiments examine separately effects of perfusion of the esophagus by acid without and with pepsin in various combinations. Acid perfusion alone at concentrations represented by pH 1.3 or above does not produce esophagitis. The addition of pepsin to acid between pH 1 and 3.5 causes considerable acute esophageal damage. Outside the proteolytic range, i.e., higher than pH 3.5, pepsin does not damage the esophagus. The damage caused by acidified pepsin may be made much worse by the further addition of aspirin or other NSAIDs, presumably by further breaking down mucosal barriers.     

BPC 157 therapy to detriment sphincters failure-esophagitis-pancreatitis in rat and acute pancreatitis patients low sphincters pressure

Possibly, acute esophagitis and pancreatitis cause each other, and we focused on sphincteric failure as the common causative key able to induce either esophagitis and acute pancreatitis or both of them, and thereby investigate the presence of a common therapy nominator. This may be an anti-ulcer pentadecapeptide BPC 157 (tested for inflammatory bowel disease, wound treatment) affecting esophagitis, lower esophageal and pyloric sphincters failure and acute pancreatitis (10 μg/kg, 10 ng/kg intraperitoneally or in drinking water). The esophagitis-sphincter failure procedure (i.e., insertion of the tubes into the sphincters, lower esophageal and pyloric) and acute pancreatitis procedure (i.e., bile duct ligation) were combined in rats. Esophageal manometry was done in acute pancreatitis patients. In rats acute pancreatitis procedure produced also esophagitis and both sphincter failure, decreased pressure 24 h post-surgery. Furthermore, bile duct ligation alone immediately declines the pressure in both sphincters. Vice versa, the esophagitis-sphincter failure procedure alone produced acute pancreatitis. What's more, these lesions (esophagitis, sphincter failure, acute pancreatitis when combined) aggravate each other (tubes into sphincters and ligated bile duct). Counteraction occurred by BPC 157 therapies. In acute pancreatitis patients lower pressure at rest was in both esophageal sphincters in acute pancreatitis patients. We conclude that BPC 157 could cure esophagitis/sphincter/acute pancreatitis healing failure.     

The upper esophageal sphincter in the cat: the role of central innervation assessed by transient vagal blockade

Studies were performed on four cats to assess the role of extrinsic innervation via the cervical nerve trunks in the control of upper esophageal sphincter function. Transient vagal nerve blockade was accomplished by cooling the cervical vagosympathetic nerve trunks previously isolated in skin loops on each side of the neck. Upper esophageal sphincter pressure was measured using a multilumen oval manometry tube and a rapid pull-through technique. The upper esophageal sphincter response to cervical intraesophageal balloon distention and acid perfusion was assessed. The feline upper esophageal sphincter has a distinct asymmetric pressure profile, whereby anterior pressure greater than posterior pressure greater than left pressure greater than right pressure. Bilateral vagal nerve blockade lowered the mean upper esophageal sphincter pressure from 18.5 +/- 1.5 to 12.0 +/- 2.8 mmHg (1 mmHg = 133.3 Pa) (p less than 0.001), with a significant reduction in pressure in all four quadrants. Intraesophageal balloon distention and acid perfusion both produced a significant increase in upper esophageal sphincter pressure. Bilateral vagal nerve blockade completely abolished the response of the upper esophageal sphincter to balloon distention and acid perfusion. We conclude that normal upper esophageal sphincter tone in the cat is partially mediated by excitatory neural input via the cervical nerve trunks, presumably via the recurrent laryngeal nerves; and cervical intraesophageal balloon distention and acid perfusion produce reflex contraction of the upper esophageal sphincter, which is dependent on neural pathways via the cervical vagal nerve trunks, but the relative contribution of afferent and efferent pathways remains unknown.     

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.     

Achalasia in a sixty-four-year-old man.

Achalasia is an esophageal motility disorder characterized by increased lower esophageal sphincter pressure and absence of peristalsis in the lower esophagus. Patients typically present with complaints of progressive difficulty swallowing over a period of several years. Diagnosis is confirmed by esophageal manometry. Complications of achalasia include esophagitis, aspiration and possibly an increased risk of esophageal carcinoma. Medical treatment options include pneumatic dilatation, esophageal bougienage, nitrates, calcium channel blockers and botulinum toxin injections. The primary method of surgical treatment is the Heller myotomy, in which longitudinal incisions are made in the muscle fibers of the lower esophageal sphincter to reduce sphincter pressure. Frequently, a fundoplication is performed in addition to the myotomy to decrease the likelihood of development of gastroesophageal reflux. In recent years, the Heller myotomy has been performed both thoracoscopically and laparoscopically. An additional development has been the placement of an endoscope in the esophagus to provide transillumination during surgery; intraoperative endoscopy allows improved assessment of the depth of myotomy incisions and reduces the risk of esophageal perforation. The case report below describes a 64-year-old-man with achalasia who presented with persistent dysphagia despite multiple attempts at medical treatment. A laparoscopic Heller myotomy with Toupet fundoplication was performed with subsequent eradication of symptoms. A discussion of the epidemiology, etiology, clinical presentation, diagnosis and treatment of achalasia follows the case report.     

Prostaglandin E1 effects on resting and cholinergically stimulated lower esophageal sphincter pressure in cats

Intraluminal esophageal manometry with a sleeve catheter was used to compare the magnitude of decrease in lower esophageal sphincter (LES) pressure produced by an arterial or venous infusion of prostaglandin E1 in cats. Arterial PGE1 produced significantly lower LES pressures than venous PGE1 (p less than 0.05). Maximal decrease of 75% in basal LES pressure occurred with an associated 15% decrease in systolic blood pressure. The site of action of PGE1 in producing LES hypotension was studied by injection of either edrophonium, or bethanechol during the maximal PGE1 effect. Bethanechol, which acts directly on sphincteric smooth muscle, produced an increase in LES pressure during both saline and PGE1 infusion, while the increases in LES pressure seen with edrophonium during saline infusion were blocked during the PGE1 infusion. From these studies, we conclude that PGE1 produces LES hypotension in the cat by an inhibitory effect on the cholinergic pathway responsible for maintaining LES tone. These studies pharmacologically reproduce the LES pressure abnormality previously reported in the cat during acid-induced esophagitis and support the hypothesis that PGE1 may be involved in the pathogenesis of acute acid-induced lower esophageal sphincter abnormalities.     

Failure of capsaicin-containing red pepper sauce suspension to induce esophageal motility response in patients with Barrett's esophagus.

The physiologic importance of afferent sensory pathways in the esophageal motor functions has been recently recognised. Capsaicin-sensitive sensory afferents were shown to play a role in the maintenance of mucosal integrity of the GI tract, and regulation of human esophageal motility. The aim of this study was to investigate the effect of topical application of capsaicin-containing red pepper sauce (Tabasco, 25%v/v, pH:7.0) suspension on the phasic activity of the human esophagus of healthy volunteers and patients with Barrett's esophagus. METHODS: The diagnosis of Barrett's esophagus was based on the findings of esophagoscopy and histology taken from the squamocolumnar junction of the esophagus. Esophageal motility was measured by perfusion manometry before and after application of red pepper sauce. RESULTS: Capsaicin containing red pepper sauce increases the motility response (LES tone, contraction amplitude, propagation velocity) of the human esophagus in healthy volunteers. This response failed in patients with Barrett's esophagus. CONCLUSION: Impaired esophageal sensory motor function may serve as one etiologic role in the development of Barrett's esophagus.     

Diminished mechanosensitivity and chemosensitivity in patients with achalasia

The pathogenesis of achalasia involves the degeneration of enteric and autonomic nervous systems with resultant effects on esophageal motility. The neural degeneration could affect visceral sensation in achalasia. The aim of this study was to examine mechanosensitivity and chemosensitivity in patients with achalasia. Perceptual responses to esophageal distension and acid perfusion were assessed in nine achalasia patients and nine healthy subjects. Mechanosensitivity was evaluated using a barostat with a double-random staircase distension protocol. Responses were graded as follows: 0, no sensation; 1, initial sensation; 2, mild discomfort; 3, moderate discomfort; and 4, pain. Chemosensitivity was graded along a visual analog scale after perfusion of saline and 0.1 N HCl. Barostat pressure-volume relationships were used to report esophageal body compliance. Barostat pressures for initial sensation and mild discomfort were not significantly different for patients and controls. The pressures for moderate discomfort (37.9 +/- 3.5 vs. 25.7 +/- 2.4 mmHg; P < 0.05) and pain (47.8 +/- 2.3 vs. 32.2 +/- 3.5 mmHg; P = 0.002) were significantly higher in achalasics than controls. Seven of the eight achalasia patients never reached pain thresholds at the maximum distension pressure (50 mmHg). Sensation to acid perfusion was significantly lower in achalasics compared with controls (2.2 +/- 1.2 vs. 6.7 +/- 1.7 cm; P < 0.05). Compliance was significantly increased in patients with achalasia compared with controls. We conclude that both mechanosensitivity and chemosensitivity are significantly diminished in achalasia patients compared with controls. Also, initial sensation and pain sensation are differentially affected in achalasics. These findings suggest that neuropathic defects in achalasia may manifest themselves in visceral sensory and motor dysfunction.     

Cytoprotective Effects of Hydrogen Sulfide in Novel Rat Models of Non-Erosive Esophagitis

Non-erosive esophagitis is a chronic inflammatory condition of the esophagus and is a form of gastroesophageal reflux disease. There are limited treatment options for non-erosive esophagitis, and it often progresses to Barrett’s esophagus and esophageal carcinoma. Hydrogen sulfide has been demonstrated to be a critical mediator of gastric and intestinal mucosal protection and repair. However, roles for H₂S in esophageal mucosal defence, inflammation and responses to injury have not been reported. We therefore examined the effects of endogenous and exogenous H₂S in rat models of non-erosive esophagitis. Mild- and moderate-severity non-erosive esophagitis was induced in rats through supplementation of drinking water with fructose, plus or minus exposure to water-immersion stress. The effects of inhibitors of H₂S synthesis or of an H₂S donor on severity of esophagitis was then examined, along with changes in serum levels of a pro- and an anti-inflammatory cytokine (IL-17 and IL-10, respectively). Exposure to water-immersion stress after consumption of the fructose-supplemented water for 28 days resulted in submucosal esophageal edema and neutrophil infiltration and the development of lesions in the muscular lamina and basal cell hyperplasia. Inhibition of H₂S synthesis resulted in significant exacerbation of inflammation and injury. Serum levels of IL-17 were significantly elevated, while serum IL-10 levels were reduced. Treatment with an H₂S donor significantly reduced the severity of esophageal injury and inflammation and normalized the serum cytokine levels. The rat models used in this study provide novel tools for studying non-erosive esophagitis with a range of severity. H₂S contributes significantly to mucosal defence in the esophagus, and H₂S donors may have therapeutic value in treating esophageal inflammation and injury.     

Esophageal sensation in premature human neonates: temporal relationships and implications of aerodigestive reflexes and electrocortical arousals

Electrocortical arousal (ECA) as an effect of visceral provocation or of its temporal relationships with aerodigestive reflexes in premature neonates is not known. We tested the hypothesis that esophageal provocation results in both esophageal reflex responses and ECAs during sleep and that ECAs are dependent on the frequency characteristics of esophageal neuromotor responses. We defined the spatiotemporal relationship of ECAs in relation to 1) spontaneous pharyngoesophageal swallow sequences and gastroesophageal reflux (GER) events and 2) sensory-motor characteristics of esophageal reflexes. Sixteen healthy premature neonates born at 27.9 ± 3.4 wk were tested at 36.8 ± 1.9 wk postmenstrual age. Ninety-five midesophageal and 31 sham stimuli were given in sleep during concurrent manometry and videopolysomnography. With stimulus onset as reference point, we scored the response latency, frequency occurrence and duration of arousals, peristaltic reflex, and upper esophageal sphincter contractile reflex (UESCR). Changes in polysomnography-respiratory patterns and esophageal sensory-motor parameters were scored by blinded observers. Significantly (for each characteristic listed, P < 0.05), swallow sequences were associated with arousals and sleep state changes, and arousals were associated with incomplete peristalsis, response delays to lower esophageal sphincter relaxation, and prolonged esophageal clearance. GER events (73.5%) provoked arousals, and arousals were associated with response delays to peristaltic reflexes or clearance, sleep state modification, and prolonged respiratory arousal. Midesophageal stimuli (54%) provoked arousals and were associated with increased frequency, prolonged latency, prolonged response duration of peristaltic reflexes and UESCR, and increased frequency of sleep state changes and respiratory arousals. In human neonates, ECAs are provoked upon esophageal stimulation; the sensory-motor characteristics of esophageal reflexes are distinct when accompanied by arousals. Aerodigestive homeostasis is defended by multiple tiers of aerodigestive safety mechanisms, and when esophageal reflexes are delayed, cortical hypervigilance (ECAs) occurs.     

Esophageal wall blood perfusion during contraction and transient lower esophageal sphincter relaxation in humans

We recently reported that esophageal contraction reduces esophageal wall perfusion in an animal study. Our aim was to determine esophageal wall blood perfusion (EWBP) during esophageal contraction and transient lower esophageal sphincter relaxations (TLESRs) in humans. We studied 12 healthy volunteers. A custom-designed laser Doppler probe was anchored to the esophageal wall, 4-6 cm above the LES, by use of the Bravo pH system so that the laser light beam stay directed toward the esophageal mucosa. A high-resolution manometry equipped with impedance electrodes recorded esophageal pressures and reflux events. Synchronized pressure, impedance, pH, and EWBP recordings were obtained during dry and wet swallows and following a meal. Stable recordings of laser Doppler EWBP were only recorded when the laser Doppler probe was firmly anchored to the esophageal wall. Esophageal contractions induced by dry and wet swallows resulted in 46 ± 9% and 60 ± 10% reduction in the EWBP, respectively (compared to baseline). Reduction in EWBP was directly related to the amplitude (curvilinear fit) and duration of esophageal contraction. Atropine reduced the esophageal contraction amplitude and decreased the EWBP reduction associated with esophageal contraction. TLESRs were also associated with reduction in the EWBP, albeit of smaller amplitude (29 ± 3%) but longer duration (19 ± 2 s) compared with swallow-induced esophageal contractions. We report 1) an innovative technique to record EWBP for extended time periods in humans and 2) contraction of circular and longitudinal muscle during peristalsis and selective longitudinal muscle contraction during TLESR causes reduction in the EWBP; 3) using our innovative technique, future studies may determine whether esophageal wall ischemia is the cause of esophageal pain/heartburn.     

Evaluation of multiple-point measurement of sphincter of Oddi motility in the Australian brush-tailed possum

Manometric assembly diameter is a major limitation on the number of perfused manometric recording points for recordings from the sphincter of Oddi (SO). We evaluated novel polyimide manometric assemblies whereby four recording channels were incorporated in an overall assembly diameter of 0.8 mm. Over the very low range of perfusion rates tested (0.005-0.04 ml/min), the assemblies had pressure offsets attributable to water perfusion from 2 to 23 mmHg and pressure rise rates from 20 to 163 mmHg/s. In six anesthetized Australian brush-tailed possums, manometric recordings from the SO showed a significant reduction in the recorded peak amplitude of pressure waves with perfusion rates below 0.02 ml/min. The pressure profile of the sphincter was found to be asymmetric, and phasic wave propagation patterns were complex (antegrade 35.6%, "mixed" 64.4%). In conclusion, accurate multipoint SO manometry in the possum can be performed with micromanometric assemblies at very low perfusion rates to give a more complete understanding of SO mechanics. These methods are also potentially applicable to perfusion manometry in other small laboratory animals such as mice.     

The alteration of intracellular signaling on the smooth muscle cells contraction in cat esophagitis

We investigated the alteration of signal transduction after acute esophagitis in cat lower esophageal sphincter (LES). Acute esophagitis (AE) was induced by perfusion with 0.1N HCl at a rate of 1 ml/min for 45 min over three consecutive days. Acetylcholine (ACh)-induced contraction was inhibited by M3> M1 or M2 antagonists in normal LES. In AE, inhibition by M2 antagonists increased significantly, so that contraction was inhibited by M3> M2> M1 antagonists and the expression of M2 and M3 receptors were increased when compared to normal LES. In normal cells, ACh-induced contractions were antagonized by antibody against G(q/11) and the phosphatidylinositol-specific phospholipase C (PI-PLC) antagonist, U73122. The phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor, D609, or the phospholipase D inhibitor, propranolol had no effects on contraction in normal LES. However, in AE, G(q/11), and G(i3) antibodies reduced ACh-induced contraction and U73122, propranolol and D609 also reduced the contraction. In AE, we found that the expressions of G protein subtypes were increased but the expression of PLCbeta1, and PLCgamma1 were decreased when compared to normal LES. In conclusion, experimental esophagitis may alter the signal transduction by ACh in LES. ACh-induced contraction is mediated by M3 receptor, G(q/11) and PI-PLC in normal LES. However, in AE, the contractions are mediated by M2, M3 receptor, G(q/11) and G(i3). PC-PLC and PLD as PI-PLC are also involved in ACh-induced cell contraction in AE.     

Failure of capsaicin-containing red pepper sauce suspension to induce esophageal motility response in patients with Barrett’s esophagus

The physiologic importance of afferent sensory pathways in the esophageal motor functions has been recently recognised. Capsaicin-sensitive sensory afferents were shown to play a role in the maintenance of mucosal integrity of the GI tract, and regulation of human esophageal motility. The aim of this study was to investigate the effect of topical application of capsaicin-containing red pepper sauce (Tabasco, 25%v/v, pH:7.0) suspension on the phasic activity of the human esophagus of healthy volunteers and patients with Barrett’s esophagus. Methods: The diagnosis of Barrett’s esophagus was based on the findings of esophagoscopy and histology taken from the squamocolumnar junction of the esophagus. Esophageal motility was measured by perfusion manometry before and after application of red pepper sauce. Results: Capsaicin containing red pepper sauce increases the motility response (LES tone, contraction amplitude, propagation velocity) of the human esophagus in healthy volunteers. This response failed in patients with Barrett’s esophagus. Conclusion: Impaired esophageal sensorymotor function may serve as one etiologic role in the development of Barrett’s esophagus.     

Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum

Although exercise usually improves motor performance, the underlying cellular changes in the cerebellum remain to be elucidated. This study aimed to investigate whether and how chronic treadmill exercise in young rats induced Purkinje cell changes to improve motor performance and rendered the cerebellum less vulnerable to toxin insults. After 1-wk familiarization of treadmill running, 6-wk-old male Wistar rats were divided into exercise and sedentary groups. The exercise group was then subjected to 8 wk of exercise training at moderate intensity. The rotarod test was carried out to evaluate motor performance. Purkinje cells in cerebellar slices were visualized by lucifer yellow labeling in single neurons and by calbindin immunostaining in groups of neurons. Compared with sedentary control rats, exercised rats not only performed better in the rotarod task, but also showed finer Purkinje cell structure (higher dendritic volume and spine density with the same dendritic field). The exercise-improved cerebellar functions were further evaluated by monitoring the long-lasting effects of intraventricular application of OX7-saporin. In the sedentary group, OX7-saporin treatment retarded the rotarod performance and induced ～60% Purkinje cell loss in 3 wk. As a comparison, the exercise group showed much milder injuries in the cerebellum by the same toxin treatment. In conclusion, exercise training in young rats increased the dendritic density of Purkinje cells, which might play an important role in improving the motor performance. Furthermore, as Purkinje cells in the exercise group were relatively toxin resistant, the exercised rats showed good motor performance, even under toxin-treated conditions.     

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.     

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.     

Relationship between esophageal muscle thickness and intraluminal pressure in patients with esophageal spasm

We previously showed, in normal subjects, a positive correlation between the esophageal contraction amplitude and peak muscle thickness. The goal of this study was to determine the relationship between esophageal muscle thickness and contraction amplitude in patients with high-amplitude peristaltic and simultaneous contractions. Eleven patients with high-amplitude peristaltic contractions, 8 with diffuse esophageal spasm (DES), 7 with nonspecific (NS) motor disorder of the esophagus, and 10 normal subjects were studied using simultaneous pressure and ultrasound imaging. Pressure was recorded by manometry and ultrasound imaging with a high-frequency ultrasound probe catheter. Recordings were performed in the lower esophageal sphincter (LES) and at 2, 4, 6, 8, and 10 cm above the LES during resting state and swallow-induced contractions. Baseline esophageal muscle was thicker in the distal, compared with the proximal esophagus both in normal subjects and patient groups. Patients with DES and nutcracker esophagus (NC) have a higher baseline muscle thickness compared with normal and NS patients. Correlation between the peak pressure and the peak muscle thickness was weaker in patients with NC and DES compared with normal subjects and patients with NS. Whereas normal subjects have good correlation between delta (difference between peak and baseline) muscle thickness and peak pressures, this relationship was absent in patients with NC and DES. Increase in contraction amplitude in patients with NC and DES was associated with an increase in baseline thickness of esophageal muscularis propria. Increase in baseline thickness was specific to patients with spastic motor disorders and was not seen in patients with NS.     

Prostaglandin E1 effects on resting and cholinergically stimulated lower esophageal sphincter pressure in cats

Intraluminal esophageal manometry with a sleeve catheter was used to compare the magnitude of decrease in lower esophageal spincter (LES) pressure produced by an arterial or venous infusion of prostaglandin E₁ in cats. Arterial PGE₁ produced significantly lower LES pressures than venous PGE₁ (p < 0.05). Maximal decrease of 75% in basal LES pressure occurred with an associated 15% decrease in systolic blood pressure. The site of action of PGE₁ in producing LES hypotension was studied by injection of either edrophonium, or bethanechol during the maximal PGE₁ effects. Bethanechol, which acts directly on sphincteric smooth muscle, produced an increase in LES pressure during both saline and PGE₁ infusion, while the increases in LES pressure seen with edrophonium during saline infusion were blocked during the PGE₁ infusion. From these studies, we conclude that PGE₁ produces LES hypotension in the cat by an inhibitory effect on the cholinergic pathway responsible for maintaining LES tone. These studies pharmacologically reproduce the LES pressure abnormality previously reported in the cat during acid-induced esophagitis and support the hypothesis that PGE₁ may be involved in the pathogenesis of acute acid-induced lower esophageal sphincter abnormalities.