Evidence for the presence of both D-1 and D-2 dopamine receptors in human esophagus.

Clinical and pharmacological evidence suggested that dopamine is involved in the control of esophageal motility. The present study was designed to determine whether or not dopamine receptors are present in human esophagus. With this aim we measured adenylate cyclase activity as a biochemical index of dopamine receptor function in esophageal specimens taken from five patients during surgery for upper esophageal carcinoma. The selective D-1 agonist fenoldopam stimulated cAMP formation in the lower esophageal sphincter, but not in the esophageal body; this effect was prevented by the selective D-1 antagonist SCH 23390 and by d-butaclamol. Bromocriptine, a selective D-2 stimulator, inhibited adenylate cyclase activity in the lower esophageal sphincter, an effect blocked by the D-2 antagonist (-)sulpiride. No effects of bromocriptine were found in the esophageal body. These data indicate that both D-1 and D-2 receptors are present in the lower esophageal sphincter, but not in esophageal body and emphasize the role of dopamine in the regulation of esophageal function.     

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.     

The effect of pitressin on esophageal blood flow of the dog.

In a previous study on canine esophagus, we reported that intravenous infusion of isoproterenol caused mucosal (i.e., mucosal + submucosal) vasodilation only in the lower esophageal sphincter (but not in the body) and muscularis vasodilation only in the body (not in the lower esophageal sphincter). In the present study, we have investigated in dogs whether these esophageal tissues also exhibit a similar difference in their vasoconstrictory response to intravenous infusion of pitressin. All measurements were made before (basal) and after infusion of 0.02 U pitressin.min-1.kg-1 for 15 min. Pitressin significantly decreased portal venous pressure and blood flow, and increased vascular resistance of all tissues of the esophagus. This vasoconstriction of the tissues, however, was higher in the squamous mucosa of the body than in the columnar mucosa of the lower esophageal sphincter. In contrast, it was higher in the smooth muscle of the lower esophageal sphincter than in the striated muscle of the body. These data together with those of our previous report on isoproterenol demonstrate that pitressin causes a pronounced vasoconstriction in those esophageal tissues where isoproterenol had no effect. Conversely, pitressin causes least vasoconstriction in those tissues where isoproterenol produced a significant vasodilation. These differences could be the result of partial agonist actions or differences in receptor density or in receptor-effector coupling mechanism.     

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.     

Peroral Endoscopic Myotomy Can Improve Esophageal Motility in Patients with Achalasia from a Large Sample Self-Control Research (66 Patients)

Background

Peroral endoscopic myotomy (POEM) as a new approach to achalasia attracts broad attention. The primary objective of this study was to evaluate the results with esophageal motility after POEM through the first large sample clinical research.

Patients and Methods

We have a self-control research with all patients (205 in total) who underwent POEM from 2010 to 2014 at our Digestive Endoscopic Center, 66 patients of which underwent high resolution manometry (HRM) before and after POEM in our motility laboratory. Follow-ups last for 5.6 months on average. Outcome variables analyzed included upper esophageal sphincter pressure (UESP), upper esophageal sphincter residual pressure (UESRP), lower esophageal sphincter pressure (LESP), lower esophageal sphincter residual pressure (LESRP) and esophageal body peristalsis. We have a statistical analysis to illustrate how POEM impacts on the change of esophageal motility.

Results

The symptoms related to dysphagia were relieved in 95% of patients in recent term after POEM. While HRM showed a statistically significant reduction of URSRP, LESP and LESRP (P<0.01), however, peristalsis was not consistently affected. There were 11 patients who had undergone other prior endoscopic treatment (endoscopic dilation or botulinum toxin injection) and 55 patients had not. The statistical difference (P>0.05) did not occur for these two groups on LESP and LESRP reduction.

Conclusions

POEM clearly relieved the symptoms related to dysphagia by lowering the pressure of upper esophageal sphincter (UES) and lower esophageal sphincter (LES),and other endoscopic treatment before POEM did not affect the improvement of LES pressure. These results are concluded from our short-term follow-up study, while the long-term efficacy remains to be further illustrated.

Trial Registration

Chinese Clinical Trial Register ChiCTR-TRC-12002204)     

Vasoactive intestinal peptide causes peristaltic contractions in the esophageal body

Vasoactive intestinal peptide (VIP) caused a dose-dependent fall in lower esophageal sphincter (LES) pressure and dose-dependent contractions in the body of the esophagus. The response to VIP in the esophagus or LES was not modified by atropine, phentolamine, haloperidol, pyrilamine, methysergide, indomethacin and tetrodotoxin, showing that it exerts direct action at the esophageal smooth muscle. These studies suggest that VIP causes contraction in the esophageal body and relaxation of the LES by a direct action on the smooth muscle. It is possible that VIP may be the common mediator of noncholinergic, nonadrenergic neurons that cause relaxation of the lower esophageal sphincter and contraction in the esophageal body.     

Lung volume dependence of esophageal pressure in the neck

There is conflicting evidence in the literature regarding tissue pressure in the neck. We studied esophageal pressure along cervical and intrathoracic esophageal segments in six healthy men to determine extramural pressure for the cervical and intrathoracic airways. A balloon catheter system with a 1.5-cm-long balloon was used to measure intraesophageal pressures. It was positioned at 2-cm intervals, starting 10 cm above the cardiac sphincter and ending at the cricopharyngeal sphincter. We found that esophageal pressures became more negative as the balloon catheter moved from intrathoracic to cervical segments, until the level of the cricopharyngeal sphincter was reached. At total lung capacity, esophageal pressures were -10.5 +/- 2.9 (SE) cmH2O in the lower esophagus, -18.9 +/- 3.0 just within the thorax, and -21.3 +/- 2.73 within 2 cm of the cricopharyngeal sphincter. The variation in mouth minus esophageal pressure with lung volume was similar in cervical and thoracic segments. We conclude that the subatmospheric tissue pressure applied to the posterior membrane of the cervical trachea results in part from transmission of apical pleural pressure into the neck. Transmural pressure for cervical and thoracic tracheal segments is therefore similar.     

Effect of galanin and galanin antagonists on peristalsis in esophageal smooth muscle in the opossum

Galanin, a neuropeptide that is widely distributed in the esophageal nerves, is known to exert a neuromodulatory action in the gut. These studies examined the effect of galanin and galanin antagonists on esophageal peristalsis in anesthetized opossums in vivo. Intraluminal esophageal pressures were recorded at 1, 3, 5, 7, and 9 cm above the lower esophageal sphincter. Esophageal peristaltic contractions were induced by swallow and short- (1-s) and long-train (10-s) vagal stimulation (VS). Galanin (1 nmol/kg) inhibited the amplitude of swallow-induced peristaltic contractions and increased peristaltic velocity by enlarging the latency periods in the upper part of the esophagus and reducing them in the lower part. Galinin nearly abolished esophageal contractions caused by short-train VS at 5 Hz and inhibited the contractions at 10 Hz. Galanin increased latency periods induced by short-train VS with little change in the velocity of peristalsis and reduced the amplitude of both A (cholinergic) and B (noncholinergic) contractions due to long-train VS. However, the decrease in amplitude of B contractions was more marked. Galantide (3 nmol/kg) antagonized the inhibitory action of exogenous galanin on esophageal contractions elicited by short-train VS, but by itself galantide had no significant effect on esophageal contractions. In conclusion, exogenous galanin inhibits the amplitude of swallow-induced peristaltic contractions and converts them into nonperistaltic contractions by inhibiting both the cholinergic and noncholinergic components.     

消化管括约肌部VIP免疫活性神经细胞分布

应用免疫组织化学方法研究了食管下部,幽门和回盲部肌间神经丛内ＶＩＰ免疫活性神经细胞的分布。ＶＩＰ免疫活性神经细胞在括约肌部比相邻部位数量多。并用Ｏｐｅｎ－ｔｉＰ法测量了刺激迷走神经后食管下段括约肌部压力的变化。用高阈值参数电刺激迷走神经引起预先投给阿托品的狗食管下段括约肌部压力的降低;这样条件下延长迷走神经刺激引起肌间神经丛内ＶＩＰ免疫活性神经细胞数量明显增加。由此结果提示含有或产生ＶＩＰ的神经细胞可能接受迷走神经的控制。由于刺激节前迷走神经纤维可能作用到这些细胞。     

Esophageal prostaglandins in guinea pigs and rats

The synthesis of prostaglandins (PGs) in the mucosa of the esophagus is studied in 20 albinotic adult guinea pigs and rats using the radioimmunoassay method. Both species investigated synthesize five PGs. The PG synthesis activity in the guinea pig's esophagus is higher than that in the rat's. PGE2 and PGF2 alpha might be involved in the regulation of lower esophagus sphincter pressure.     

The role of the superior laryngeal nerve in esophageal reflexes

The aim of this study was to determine the role of the superior laryngeal nerve (SLN) in the following esophageal reflexes: esophago-upper esophageal sphincter (UES) contractile reflex (EUCR), esophago-lower esophageal sphincter (LES) relaxation reflex (ELIR), secondary peristalsis, pharyngeal swallowing, and belch. Cats (N = 43) were decerebrated and instrumented to record EMG of the cricopharyngeus, thyrohyoideus, geniohyoideus, and cricothyroideus; esophageal pressure; and motility of LES. Reflexes were activated by stimulation of the esophagus via slow balloon or rapid air distension at 1 to 16 cm distal to the UES. Slow balloon distension consistently activated EUCR and ELIR from all areas of the esophagus, but the distal esophagus was more sensitive than the proximal esophagus. Transection of SLN or proximal recurrent laryngeal nerves (RLN) blocked EUCR and ELIR generated from the cervical esophagus. Distal RLN transection blocked EUCR from the distal cervical esophagus. Slow distension of all areas of the esophagus except the most proximal few centimeters activated secondary peristalsis, and SLN transection had no effect on secondary peristalsis. Slow distension of all areas of the esophagus inconsistently activated pharyngeal swallows, and SLN transection blocked generation of pharyngeal swallows from all levels of the esophagus. Slow distension of the esophagus inconsistently activated belching, but rapid air distension consistently activated belching from all areas of the esophagus. SLN transection did not block initiation of belch but blocked one aspect of belch, i.e., inhibition of cricopharyngeus EMG. Vagotomy blocked all aspects of belch generated from all areas of esophagus and blocked all responses of all reflexes not blocked by SLN or RLN transection. In conclusion, the SLN mediates all aspects of the pharyngeal swallow, no portion of the secondary peristalsis, and the EUCR and ELIR generated from the proximal esophagus. Considering that SLN is not a motor nerve for any of these reflexes, the role of the SLN in control of these reflexes is sensory in nature only.     

Role of endogenous prostaglandins in regulating the tone of opossum lower esophageal sphincter in vivo.

The role of prostaglandins in maintenance of basal myogenic tone of the lower esophageal sphincter (LES) of opossum has been studied in vivo. Intra-arterial infusion of arachidonic acid decreased LES tone, and this was inhibited by intravenous indomethacin (IDM) or intra-arterial 5,8,11,14-eicosatetraynoic acid (ETA). Alone these drugs did not reduce LES tone except transiently. In addition they did not affect relaxation of the LES to distention of a balloon located proximal to it or inhibit the "off" contractions of esophageal body and LES pressure which followed balloon deflation. Spontaneous oscillations of LES pressure were increased with IDM. Thus prostaglandin synthesis plays no essential role in maintenance of resting LES tone or in functioning of non-adrenergic inhibitory nerves in the esophagus in vivo. Endogenous inhibitory prostaglandins might reduce LES tone if synthesized in increased amounts.     

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.     

Protease-activated receptor-1 (PAR1) and PAR2 but not PAR4 mediate relaxations in lower esophageal sphincter

Protease-activated receptor-1 (PAR1), PAR2 and PAR4 activation can alter the gastrointestinal motility. To investigate effects mediated by PARs in the lower esophageal sphincter, we measured contraction or relaxation of transverse strips from the guinea-pig lower esophageal sphincter caused by PAR1 (TFLLR-NH2 and SFLLRN-NH2), PAR2 (SLIGKV-NH2 and SLIGRL-NH2) and PAR4 peptide agonists (GYPGKF-NH2, GYPGQV-NH2 and AYPGKF-NH2) as well as PAR protease activators (thrombin and trypsin). In resting lower esophageal sphincter strips, TFLLR-NH2 and SFLLRN-NH2 caused moderate concentration-dependent relaxation whereas thrombin did not cause any relaxation or contraction. Furthermore, in carbachol-contracted strips, TFLLR-NH2 and SFLLRN-NH2 caused marked whereas thrombin caused mild concentration-dependent relaxation. These indicate the existence of PAR1 mediating relaxation. Similarly, in resting lower esophageal sphincter strips, trypsin caused moderate concentration-dependent relaxation whereas SLIGRL-NH2 and SLIGKV-NH2 did not cause any relaxation or contraction. In addition, in carbachol-contracted strips, trypsin caused marked whereas SLIGRL-NH2 and SLIGKV-NH2 caused mild concentration-dependent relaxation. These indicate the existence of PAR2 mediating relaxation. The relaxant response of thrombin, TFLLR-NH2, trypsin and SLIGKV-NH2 was insensitive to atropine or tetrodotoxin, suggesting a direct effect. The relaxant response of trypsin was not affected by apamin, charybdotoxin, indomethacin and capsaicin but was attenuated by NG-nitro-L-arginine methyl ester, indicating involvement of NO. FSLLR-NH2, a PAR1 control peptide, and VKGILS-NH2, a PAR2 control peptide, as well as all three PAR4 peptide agonists, GYPGKF-NH2, GYPGQV-NH2 and AYPGKF-NH2, did not cause any relaxation or contraction. Taken together, these results demonstrate that PAR1 and PAR2 but not PAR4 mediate relaxations in the guinea-pig lower esophageal sphincter.     

Effect of repeated cycles of acute esophagitis and healing on esophageal peristalsis, tone, and length

Severe esophagitis is associated with motor abnormalities in the esophageal body and lower esophageal sphincter. Reflux disease involves repeated episodes of mucosal inflammation and spontaneous or treatment-induced healing. The aims of this study were 1) to further assess changes induced by acute esophagitis on esophageal peristalsis, tone, and shortening and 2) to assess the effect of repeated sequences of acute esophagitis-healing on these motor parameters. Experiments were performed on adult cats. Esophageal manometry and barostat were performed before, 24 h after, and every 7 days after intraesophageal acid perfusion (0.1 N HCl, 80 min). Esophageal length was measured during manometry, and compliance of the esophageal body was assessed with barostat. The identical protocol was performed 8 and 16 wk after the first acid perfusion. The degree of esophageal mucosal damage was evaluated by endoscopy, histopathology, and myeloperoxidase activity. Acid perfusion induced severe esophagitis. At 24 h, distal peristaltic contractions disappeared, lower esophageal sphincter pressure was reduced by 60%, the esophagus length was 1-2 cm shorter, and esophageal compliance was reduced by 30%. Most parameters recovered in 4 wk. Subsequent repeated acute injuries induced similar endoscopic esophagitis but a different pattern of inflammatory infiltration and fibrosis in the mucosa and muscle layers, resulting in milder motor disturbances. Acute experimental esophagitis provokes severe but reversible hypomotility. Spaced repeated acute injuries provoke milder motor effects, suggesting an adaptive response.     

IL-1beta signaling in cat lower esophageal sphincter circular muscle

In a cat model of acute experimental esophagitis, resting in vivo lower esophageal sphincter (LES) pressure and in vitro tone are lower than in normal LES, and the LES circular smooth muscle layer contains elevated levels of IL-1beta that decrease the LES tone of normal cats. We now examined the mechanisms of IL-1beta-induced reduction in LES tone. IL-1beta significantly reduced acetylcholine-induced Ca(2+) release in Ca(2+)-free medium, and this effect was partially reversed by catalase, demonstrating a role of H(2)O(2) in these changes. IL-1beta significantly increased the production of H(2)O(2), and the increase was blocked by the p38 MAPK inhibitor SB-203580, by the cytosolic phospholipase A(2) (cPLA(2)) inhibitor AACOCF3, and by the NADPH oxidase inhibitor apocynin, but not by the MEK1 inhibitor PD-98059. IL-1beta significantly increased the phosphorylation of p38 MAPK and cPLA(2). IL-1beta-induced cPLA(2) phosphorylation was blocked by SB-203580 but not by AACOCF3, suggesting sequential activation of p38 MAPK-phosphorylating cPLA(2). The IL-1beta-induced reduction in LES tone was partially reversed by AACOCF3 and by the Ca(2+)-insensitive PLA(2) inhibitor bromoenol lactone (BEL). IL-1beta significantly increased cyclooxygenase (COX)-2 and PGE(2) levels. The increase in PGE(2) was blocked by SB-203580, AACOCF3, BEL, and the COX-2 inhibitor NS-398 but not by PD-98059 or the COX-1 inhibitor valeryl salicylate. The data suggested that IL-1beta reduces LES tone by producing H(2)O(2), which may affect Ca(2+)-release mechanisms and increase the synthesis of COX-2 and PGE(2). Both H(2)O(2) and PGE(2) production depend on sequential activation of p38 MAPK and cPLA(2). cPLA(2) activates NADPH oxidases, producing H(2)O(2), and may produce arachidonic acid, converted to PGE(2) via COX-2.     

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.     

Role of endogenous prostaglandins in regulating the tone of opossum lower esophageal sphincter in vivo

The role of prostaglandins in maintenance of basal myogenic tone of the lower esophageal sphincter (LES) of opossum has been studied $\text{in vivo}$. Intra-arterial infusion of arachidonic acid decreased LES tone, and this was inhibited by intravenous indomethacin (IDM) or intra-arterial 5,8,11,14-eicosatetraynoic acid (ETA). Alone these drugs did not reduce LES tone except transiently. In addition they did not affect relaxation of the LES to distention of a balloon located proximal to it or inhibit the “off” contractions of esophageal body and LES pressure which followed balloon deflation. Spontaneous oscillations of LES pressure were increased with IDM. Thus prostaglandin synthesis plays no essential role in maintenance of resting LES tone or in functioning of non-adrenergic inhibitory nerves in the esophagus $\text{in vivo}$. Endogenous inhibitory prostaglandins might reduce LES tone if synthesized in increased amounts.     

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.     

Inflammation induced changes in arachidonic acid metabolism in cat LES circular muscle

Myogenic lower esophageal sphincter (LES) tone is maintained by arachidonic acid metabolites, such as PGF(2alpha) and thromboxane A(2)/B(2). Experimental esophagitis in cat reduces LES in vivo pressure and in vitro tone. Because IL-1beta may mediate esophagitis-associated reduction in ACh release in esophagus, we examined whether IL-1beta may also play a role in esophagitis-induced reduction of LES tone. A cat model of experimental esophagitis was obtained by repeated esophageal perfusion with HCl (Biancani P, Barwick K, Selling J, and McCallum R. Gastreonterology 87: 8-16, 1984 and Sohn UD, Harnett KM, Cao W, Rich H, Kim N, Behar J, and Biancani P. J Pharmacol Exp Ther 283: 1293-1304, 1997.). LES circular muscle strips were examined in muscle chambers as previously described (Biancani P, Billett G, Hillemeier C, Nissenshon M, Rhim BY, Sweczack S, and Behar J. Gastroenterology 103: 1199-1206, 1992). Levels of inflammatory mediators were measured. IL-1beta levels were higher in esophagitis than in normal LES. IL-1beta reduced normal LES tone, and the reduction was reversed by catalase, suggesting a role of H(2)O(2). This was confirmed by IL-1beta-induced production of H(2)O(2) in normal LES and elevated H(2)O(2) levels in esophagitis. H(2)O(2) by itself is sufficient to explain the changes that occur in the muscle, reducing its ability to contract. H(2)O(2) increased PGE(2) in normal LES, and PGE(2) levels were elevated in esophagitis LES, whereas PGF(2alpha) levels were unchanged. H(2)O(2) also increased levels of 8-isoprostanes, stable prostaglandin-like compounds formed by free radical-induced peroxidation of arachidonic acid, and 8-isoprostane levels were elevated in esophagitis. The PGF(2alpha) analog 8-iso-PGF(2alpha) caused little contraction of LES strips but reduced PGF(2alpha) binding and contraction of normal LES. In esophagitis, PGF(2alpha) binding and contraction were reduced in LES, suggesting that isoprostanes may contribute to reduction in tone in esophagitis. The data suggest that, in esophagitis, IL-1beta causes production of H(2)O(2). H(2)O(2) increases PGE(2), which relaxes the LES, and 8-iso-F(2alpha), which blocks PGF(2alpha)-mediated contraction.