pH, healing rate, and symptom relief in patients with GERD

Gastroesophageal reflux symptoms are common and occur in all of us from time to time. In others, reflux may be associated with ulcerative esophagitis. The symptoms may be aggravated by large meals, coffee, smoking and position. Physiological and pathological reflux can be separated by the frequency and duration of the exposure of the lower esophagus to acid. Pathological reflux results in symptoms and also esophagitis and ulceration in some patients. Although gastroesophageal reflux disease (GERD) is considered to result from a disorder of motility in the esophagus, gastric acid and peptic activity are deemed pivotal to the initiation and continuation of the esophageal damage and the development of symptoms. Acid exposure in the esophagus is normally less than 4 percent of the 24 hours with a pH below 4. An increase over 4 percent of the time with a pH less than 4 is considered pathological. Hence, antisecretory drugs have become the principle approach to the treatment of reflux symptoms and esophagitis since they reduce the acidity, of gastric juice and the activity of pepsin. Importantly, they also reduce the volume of gastric juice available for reflux into the esophagus. There is a clear relationship between the degree and duration of acid suppression and the relief of heartburn and healing of esophagitis. Pharmacodynamic studies with different dose regimens of the H2-receptor antagonists and the proton pump inhibitors show a difference in the degree and duration of the antisecretory effect, and this correlates closely with the results of clinical trials with respect to the healing of esophagitis and the relief of symptoms. Proton pump inhibitors achieve healing rates by week four, which are not achieved by H2-receptor antagonists even after 12 weeks of treatment. The advantage of proton pump inhibitors over H2-receptor antagonists is due to the greater degree, longer duration of effect and more complete inhibition of acid secretion that maintains intragastric pH above 4 for a maximal duration. Although there is no significant difference between proton pump inhibitors with respect to healing of esophagitis, symptom relief occurs earlier with lansoprazole than omeprazole, and this is probably due to the greater oral bioavailability and faster onset of action of lansoprazole when compared to omeprazole.     

Does Helicobacter pylori infection contribute to gastroesophageal reflux disease?

Helicobacter pylori organisms that infect the stomach conceivably could contribute to esophageal inflammation in patients with gastroesophageal reflux disease (GERD) through any of at least three potential mechanisms: 1) by causing an increase in gastric acid secretion; 2) by spreading to infect the gastric-type columnar epithelium that occasionally can line the distal esophagus; and/or 3) by secreting noxious bacterial products into the gastric juice. Studies regarding these potential mechanisms are discussed in this report. Most investigations have found no apparent association between H. pylori infection and reflux esophagitis. Presently, infection with H. pylori does not appear to play an important role in the pathogenesis of GERD.     

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.     

The enzymatic digestion of elastin at acidic pH

The enzymatic degradation of insoluble elastin has been studied at several pH values using purified pepsin and cathepsin D, and neutrophil extracts. Pepsin degraded elastin throughout the pH range of 1.2-4.0 with the optimum pH below 2.0. Molecular sieve chromatography and gel electrophoresis indicated that a spectrum of molecular weight degradation products was produced. The degradation by pepsin was inhibited by sodium dodecyl sulfate (SDS), NaCl and pepstatin. Cathepsin D, which, like pepsin, degrades hemoglobin at acid pH and is inhibited by pepstatin, had no activity against insoluble elastin in the pH range of 3.2-7.2. Extracts of neutrophils degraded elastin above pH 4.0. The pH profile of elastin degradation by neutrophil extracts generally followed that of purified human leukocyte elastase. Our results suggest that during alimentation or pulmonary aspiration of gastric contents, extracellular elastin may be digested by gastric juice at acid pH. Inflammatory cells would not appear to be capable of contributing to such actions until local pH approaches neutrality. Cathepsin D, a major constituent of inflammatory cells, does not digest all types of connective tissue proteins.     

Lumen-to-surface pH gradients in opossum and rabbit esophagi: role of submucosal glands

The opossum esophagus, like that of humans, contains a network of submucosal glands with the capacity to secrete bicarbonate ions into the esophageal lumen. To evaluate the role of these glands in protecting the epithelial surface from acid insult, we measured the lumen-to-surface pH gradient in opossum esophagus at different luminal pH and compared it to that of rabbit esophagus, an organ devoid of submucosal glands. Sections of opossum and rabbit esophageal epithelium were mounted luminal side up in a modified Ussing chamber. pH-sensitive microelectrodes, positioned within 5 microm of the epithelial cell surface, were used to monitor surface pH during perfusion with solutions of different pH. At luminal pH 7. 5, the pH(s) of both opossum and rabbit were similar (pH(s) = 7.5). Lowering luminal pH from 7.5 to 3.5 in opossum decreased pH(s) to 4.2+/-0.16, a value significantly higher than pH of perfusate, whereas in rabbit this maneuver decreased pH(s) to 3.69+/-0.08, a value not significantly different from pH of perfusate. In opossum but not in rabbit, addition of carbachol to the serosal solution increased basal pH(s) to 7.8+/- 0.1 and significantly blunted the decline in pH(s) on perfusion with acidic Ringer solution (pH 3.5), with pH(s) falling to 5.6+/-0.45. The effect of carbachol on surface buffering was inhibited by prior treatment with atropine. Luminal acidification to pH 2.0 in opossum (as in rabbit) abolished the lumen-to-surface pH gradient even after addition of serosal carbachol. We conclude that the presence of submucosal glands in esophagus contributes through bicarbonate secretion to creation of a lumen-to-surface pH gradient. Although this gradient can be modulated by carbachol, its capacity to buffer (and therefore to protect) the epithelial surface against back-diffusing H(+) is limited and dissipated at pH 2.0.     

Gastric secretion in dogs following three day fasting and resumed feeding

The investigation into the influence of a three-day starvation on the gastric secretion in dogs with Pavlov pouches stimulated by meat, histamine and pentagastrin, was carried out. A 72-hour starvation did not change the summary volume of the gastric juice, debit of the gastric acid, and quantity of pepsin. At the same time the starvation decreased the average rate of gastric juice secretion, gastric acid and pepsin secretion in response to histamine and decreased the pepsin secretion in response to pentagastrin. In this way re-feeding enhanced the average rate of gastric juice secretion and gastric acid secretion on 3-day and pepsin on 5-day in response to meat. The average rate of gastric juice secretion increased on the 5-day after refeeding in response to histamine and the average rate of gastric juice, gastric acid and pepsin secretion in response to pentagastrin.     

Comparative pepstatin inhibition studies on individual human pepsins and pepsinogens 1,3 and 5(gastricsin) and pig pepsin A

Human gastric juice contains 3 major proteolytic components (pepsins1,3 and 5 or gastricsin). Pepsin 1 is increased in peptic ulcer and it's properties are relatively poorly understood. Studies with pepstatin the highly specific aspartic-protease inhibitor have therefore been carried out on individual active and proenzymes to assess any enzymic similarities. Human pepsin 1 was inhibited with high affinity similar to pepsin 3, whereas pepsin 5(gastricsin) was at least 40 times less sensitive. Inhibition of human pepsinogens 1,3 and 5 and pig pepsinogen A showed similar trends to the active enzymes. Studies using Sephadex gel filtration showed that pepstatin does not bind to pepsinogens and inhibition arises from pepstatin binding the pepsins released upon activation. Pepstatin inhibition was shown to be relatively independent of pH between 1.5 and 3.8 although at higher pH inhibition was less effective. The evidence suggests that pepsin 1 is similar to pepsin 3 and pepstatin inhibits by a one to one molecular binding to the active site. The explanation for the reduced affinity of pepstatin to pepsin 5(gastricsin) needs further study by co-crystallisation X-ray analysis.     

Effect of synthetic cationic protein on mechanoexcitability of vagal afferent nerve subtypes in guinea pig esophagus

Eosinophilic esophagitis is characterized by increased infiltration and degranulation of eosinophils in the esophagus. Whether eosinophil-derived cationic proteins regulate esophageal sensory nerve function is still unknown. Using synthetic cationic protein to investigate such effect, we performed extracellular recordings from vagal nodose or jugular neurons in ex vivo esophageal-vagal preparations with intact nerve endings in the esophagus. Nerve excitabilities were determined by comparing action potentials evoked by esophageal distensions before and after perfusion of synthetic cationic protein poly-L-lysine (PLL) with or without pretreatment with poly-L-glutamic acid (PLGA), which neutralized cationic charges of PLL. Perfusion with PLL did not evoke action potentials in esophageal nodose C fibers but increased their responses to esophageal distension. This potentiation effect lasted for 30 min after washing out of PLL. Pretreatment with PLGA significantly inhibited PLL-induced mechanohyperexcitability of esophageal nodose C fibers. In esophageal nodose Aδ fibers, perfusion with PLL did not evoke action potentials. In contrast to nodose C fibers, both the spontaneous discharges and the responses to esophageal distension in nodose Aδ fibers were decreased by perfusion with PLL, which can be restored after washing out PLL for 30-60 min. Pretreatment with PLGA attenuated PLL-induced decrease in spontaneous discharge and mechanoexcitability of esophageal nodose Aδ fibers. In esophageal jugular C fibers, PLL neither evoked action potentials nor changed their responses to esophageal distension. Collectively, these data demonstrated that synthetic cationic protein did not evoke action potential discharges of esophageal vagal afferents but had distinctive sensitization effects on their responses to esophageal distension.     

Comparative Pepstatin Inhibition Studies on Individual Human Pepsins and Pepsinogens 1,3 and 5(gastricsin) and Pig Pepsin A

Human gastric juice contains 3 major proteolytic components (pepsins1,3 and 5 or gastricsin). Pepsin 1 is increased in peptic ulcer and it's properties are relatively poorly understood. Studies with pepstatin the highly specific aspartic-protease inhibitor have therefore been carried out on individual active and proenzymes to assess any enzymic similarities. Human pepsin 1 was inhibited with high affinity similar to pepsin 3, whereas pepsin 5(gastricsin) was at least 40 times less sensitive. Inhibition of human pepsinogens 1,3 and 5 and pig pepsinogen A showed similar trends to the active enzymes. Studies using Sephadex gel filtration showed that pepstatin does not bind to pepsinogens and inhibition arises from pepstatin binding the pepsins released upon activation. Pepstatin inhibition was shown to be relatively independent of pH between 1.5 and 3.8 although at higher pH inhibition was less effective. The evidence suggests that pepsin 1 is similar to pepsin 3 and pepstatin inhibits by a one to one molecular binding to the active site. The explanation for the reduced affinity of pepstatin to pepsin 5(gastricsin) needs further study by co-crystallisation X-ray analysis.     

Phytohaemagglutinin inhibits gastric acid but not pepsin secretion in conscious rats

Phytohaemagglutinin (PHA), a kidney bean lectin, is known for its binding capability to the small intestinal surface. There has been no data available, however, on the biological activity of PHA in the stomach. Recent observations indicate that PHA is able to attach to gastric mucosal and parietal cells. Therefore, we examined whether PHA affects gastric acid and pepsin secretion in rats. Rats were surgically prepared with chronic stainless steel gastric cannula and with indwelling polyethylene jugular vein catheter. During experiments, animals were slightly restrained. Gastric acid secretion was collected in 30 min periods. Acid secretion was determined by titration of the collected gastric juice with 0.02 N NaOH to pH 7.0. Pepsin activity was estimated by measuring enzymatic activity. Saline, pentagastrin and histamine were infused intravenously. PHA or bovine serum albumin (BSA) were dissolved in saline and given intragastrically through the gastric cannula. PHA significantly inhibited basal acid secretion. Inhibition of acid output reached 72% during the first collection period following PHA administration when compared, then gradually disappeared. Pentagastrin-stimulated acid secretion was repressed dose-dependently by PHA as well. Maximal inhibition was observed during the first 30 min following application of PHA. Histamine-stimulated acid secretion was inhibited by PHA in a similar manner. Pepsin secretion was not affected by PHA under either basal or stimulated conditions. These results provide evidence that PHA is a potent inhibitor of gastric acid secretion in conscious rats, but it does not affect pepsin output from the stomach.     

Physiological and morphological effects of alendronate on rabbit esophageal epithelium

Alendronate, an aminobisphosphonate, produces as a side effect a topical (pill induced) esophagitis. To gain insight into this phenomenon, we assessed the effects of luminal alendronate on both esophageal epithelial structure and function. Sections of rabbit esophageal epithelium were exposed to luminal alendronate at neutral or acidic pH while mounted in Ussing chambers to monitor transmural electrical potential difference (PD), short-circuit current (I(sc)), and resistance (R). Morphological changes were sought by light microscopy in hematoxylin and eosin-stained sections. Impedance analysis was used for localization of alendronate-induced effects on ion transport. Luminal, but not serosal, alendronate (pH 6.9-7.2), increased PD and I(sc) in a dose- and time-dependent manner, with little change in R and mild edema of surface cell layers. The changes in I(sc) (and PD) were reversible with drug washout and could be prevented either by inhibition of Na,K-ATPase activity with serosal ouabain or by inhibition of apical Na channels with luminal acidification to pH 2.0 with HCl. An effect on apical Na channel activity was also supported by impedance analysis. Luminal alendronate at acidic pH was more damaging than either alendronate at neutral pH or acidic pH alone. These data suggest that alendronate stimulates net ion (Na) transport in esophageal epithelium by increasing apical membrane sodium channel activity and that this occurs with limited morphological change and no alteration in barrier function. Also alendronate is far more damaging at acidic than at neutral pH, suggesting its association with esophagitis requires gastric acid for expression. This expression may occur either by potentiation between the damaging effects of (refluxed) gastric acid and drug or by acid-induced conversion of the drug to a more toxic form.     

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.     

Bile salts disrupt human esophageal squamous epithelial barrier function by modulating tight junction proteins

Reflux of acid and bile acids contributes to epithelial tissue injury in gastro-esophageal reflux disease. However, the influence of refluxed material on human esophageal stratified epithelial barrier function and tight junction (TJ) proteins has not been fully elucidated. Here, we investigated the influence of acid and bile acids on barrier function and TJ protein distribution using a newly developed air-liquid interface (ALI) in vitro culture model of stratified squamous epithelium based on primary human esophageal epithelial cells (HEECs). Under ALI conditions, HEECs formed distinct epithelial layers on Transwell inserts after 7 days of culture. The epithelial layers formed TJ, and the presence of claudin-1, claudin-4, and occludin were detected by immunofluorescent staining. The NP-40-insoluble fraction of these TJ proteins was significantly higher by day 7 of ALI culture. Exposure of HEECs to pH 2, and taurocholic acid (TCA) and glycocholic acid (GCA) at pH 3, but not pH 4, for 1 h decreased transepithelial electrical resistance (TEER) and increased paracellular permeability. Exposure of cell layers to GCA (pH 3) and TCA (pH 3) for 1 h also markedly reduced the insoluble fractions of claudin-1 and -4. We found that deoxycholic acid (pH 7.4 or 6, 1 h) and pepsin (pH 3, 24 h) significantly decreased TEER and increased permeability. Based on these findings, ALI-cultured HEECs represent a new in vitro model of human esophageal stratified epithelium and are suitable for studying esophageal epithelial barrier functions. Using this model, we demonstrated that acid, bile acids, and pepsin disrupt squamous epithelial barrier function partly by modulating TJ proteins. These results provide new insights into understanding the role of TJ proteins in esophagitis.     

Esophageal mucosal protection--why do we need a special approach?

The epidemiology and natural history of reflux induced peptic esophageal diseases remain incompletely understood. That is why it is easy to explain that the traditional therapeutic efforts were mostly restricted to the use of acid-reducing or neutralizing drogs. The author tries to survey--mainly on theoretical bases--a new approach of the maintenance treatment of peptic esophagitis and consequential columnar metaplasia. The mechanism of the esophageal antireflux barrier is composed by the (a) lower esophageal sphincter tone, (b) upper esophageal sphincter tone, (c) esophageal acid clearance and (d) esophageal epithelial resistance. The data of a 100-patient-group of gastroesophageal reflux disease cases were retrospectively evaluated principally considering the efficacy of antisecretory treatment relating to the accompanying diseases, recurrence of symptoms and prevention the development of Barrett's columnar lined esophagus and Barrett's ulceration. The decrease of exposure by damaging factors is an essential criterion of antisecretory therapy, having several disadvantages. Based only to logically well established arguments the author believes that gastroesophageal reflux disease and consecutive conditions might be an ideal model for studying and introducing esophageal cyto (-mucosal, -tissue) protection, considering that in the esophagus--in contradiction to the stomach--the cell and tissue injury, induced by several pathogenic agents, does not develop rapidly, and when the organ damage develops gradually, interventions may be possible to protect esophageal cell and the mucosa directly.     

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.     

Drugs, bugs, and esophageal pH profiles

Until relatively recently, gastroesophageal reflux disease (GERD) was thought to be a relatively trivial problem, and pharmaceutical companies initially had remarkably little interest in clinical trials for GERD. Over the last ten years, GERD therapy has become the subject of intense interest, since reflux disease is now recognized as a major market for antisecretory and prokinetic drugs. Even low-technology antacids are now known to effectively neutralize esophageal acid prevent acid reflux for up to 90 minutes. Esophageal pH profiling is known to be an excellent surrogate for clinical efficacy of GERD drugs, particularly in erosive esophagitis. Years ago, famotidine normalized esophageal mucosal exposure to pH < 4.0 only when administered in doses of 40 mg twice a day. Subsequent studies confirmed that multiple daily dosing of histamine-2 receptor antagonists (H2RAs) was mandatory for GERD treatment, with clear dose-response relationships for each agent. Proton pump inhibitors (PPIs) have each been carefully assessed in terms esophageal and gastric pH profiles. Omeprazole has a particularly flat dose response curve, making it difficult to differentiate pH or clinical effects of 20 vs. 40 mg doses. Improved rapidity of onset and/or enhanced potency is demonstrable in pH data obtained with lansoprazole, rabeprazole and pantoprazole. Such differences will translate to improved clinical efficacy, based on the meta-analyses of Richard Hunt and his group in Canada that correlate pH effects and symptom relief/healing. PPI's have dependably surpassed H2RAs and prokinetic drugs in management of the more severe grades of esophagitis. Helicobacter pylori has a peculiar relationship to GERD. There has been some concern that PPIs given to patients with H. pylori might accelerate development of severe atrophic gastritis. It is also now known that eradication of H. pylori may increase symptomatic GERD (possibly as a result of increased gastric acid secretion once the bacteria have been eliminated). New data confirm nocturnal breakthrough of acid secretion and esophageal acid exposure in three-fourths of patients on omeprazole 20 mg twice daily. This nocturnal acidity can be controlled more effectively with a nighttime dose of an H2RA than with a third dose of omeprazole. Control of acid secretion and improved gastric and esophageal pH profiles are goals of modern GERD therapy, and the product that most cost effectively normalizes esophageal acid exposure will have a substantial advantage in the ever-growing GERD marketplace.     

Proinflammatory cytokines alter/reduce esophageal circular muscle contraction in experimental cat esophagitis

Cholinergic mechanisms are largely responsible for esophageal contraction in response to swallowing or to in vitro electrical field stimulation (EFS). After induction of experimental esophagitis by repeated acid perfusion, the responses to swallowing and to EFS were significantly reduced but contraction in response to ACh was not affected, suggesting that cholinergic mechanisms are damaged by acid perfusion but that myogenic mechanisms are not. Measurements of ACh release in response to EFS confirmed that release of ACh was reduced in esophagitis compared with normal controls. To examine factors contributing to this neuropathy, normal esophageal strips were incubated for 1-2 h with the proinflammatory cytokines IL-1beta (100 U/ml), IL-6 (1 ng/ml), or TNF-alpha (1 ng/ml). IL-1beta and IL-6 levels, measured by Western blot analysis, increased in esophagitis compared with normal circular muscle. IL-1beta and IL-6 reduced contraction in response to EFS (2-10 Hz, 0.2 ms) but did not affect ACh-induced contraction, suggesting that these cytokines inhibit ACh release without affecting myogenic contractile mechanisms. EFS-induced ACh release was significantly reduced in normal esophageal strips by incubation in IL-1beta or IL-6, suggesting that they may contribute to the contractility changes. TNF-alpha at 1 ng/ml, however, did not affect the response to ACh or to electrical stimulation but inhibited both at higher concentrations. TNF-alpha levels were low in normal muscle and did not increase with esophagitis. The data suggest that the proinflammatory cytokines IL-1beta and IL-6 contribute to reduced esophageal contraction by inhibiting release of ACh from myenteric neurons.     

Vagal esophageal receptors in anesthetized dogs: mechanical and chemical responsiveness.

This study was performed to evaluate the characteristics of esophageal receptors in anesthetized and artificially ventilated dogs. The electrical activity of the esophageal afferents was recorded from the peripheral cut end of the cervical vagus nerve. A cuffed catheter was inserted into the esophagus at the level of the third tracheal ring and was used to establish the esophageal location of the endings. Most of the receptors were localized in the intrathoracic portion of the esophagus. The majority of the receptors studied (36 of 43) showed a slow adaptation to a maintained stretch of the esophageal wall. Vagal cooling blocked receptor activity at temperatures ranging from 3.5 to 25 degrees C. Twenty-eight of 43 receptors, including 4 rapidly adapting endings (RAR), were challenged with saline, HCl + pepsin (HCl-P; pH 1) and distilled water (8 ml, 37 degrees C). HCl-P solutions specifically stimulated only three receptors; saline or water did not. Five slowly adapting receptors and two RARs were also challenged with topically applied capsaicin; only one RAR was stimulated. To ascertain a possible effect of smooth muscle contraction, 17 receptors were tested with intravenous injections of ACh and/or asphyxia; only 4 were stimulated. These characteristics do not support an important reflexogenic role of the esophagus in response to chemical stimuli.     

Pharmacologic modulation of motility

Etiologically, gastroesophageal reflux disease (GERD) can be regarded as motility disorder: Although blocking acid is effective in the treatment of GERD, it does not overcome the underlying pathologic factors that allow acid, pepsin, and bile to reflux into the esophagus. Prokinetic agents address the upper gastrointestinal motility disturbances contributing to GERD and, thus, have an important role in the short- and long-term medical management of reflux esophagitis. This paper discusses the rationale for the effectiveness of pharmacologic modulation by reviewing current concepts and postulated theories about the mechanisms underlying the neuromuscular abnormalities. The multifactorial aspects of GERD are addressed and the potential for tailoring medical therapy also emphasized.     

Gastroesophageal reflux: clinical presentations,diagnosis and management.

Symptomatic gastroesophageal reflux occurs daily in an estimated 7% of adults and weekly or monthly in 29%. Untreated it can lead to esophageal erosions, ulceration and stricture formation. The pathogenesis is often multifactorial: defects in the function of the lower esophageal sphincter, esophageal clearance mechanisms and gastric emptying combine to produce frequent lengthy periods during which the lower esophagus is bathed in regurgitated acid. In most patients reflux disease is easily recognized as recurrent heartburn, regurgitation or dysphagia, or a combination. When acute chest pain or respiratory illness is the primary presenting complaint the patient needs particularly careful investigation to determine whether the symptoms are due to a primary cardiac or respiratory condition, are secondary to gastroesophageal reflux alone or represent a combination of disorders. Endoscopy with biopsy and long-term pH monitoring are the most reliable ways of determining whether reflux disease is present. Additional investigations, such as exercise testing, cardiac catheterization or inhalation challenge, may be needed in patients with cardiac or respiratory symptoms. Treatment should follow a stepped-care approach and in most patients should begin with changes in lifestyle, including dietary manipulation, reducing alcohol and cigarette consumption, and raising the head of the bed, together with appropriate use of antacids or alginate-antacid combinations. H2-receptor antagonists and agents to improve both gastric emptying and the tone of the lower esophageal sphincter may be added in sequence. Most patients will respond well to this regimen. Surgery should be considered only for those with intractable symptoms or with complications (e.g., stricture formation, bleeding, development of dysplastic epithelium in those with Barrett''s esophagus, or secondary pulmonary disease that does not respond to medical management). It is successful in 85% of well-selected patients and has few complications.