Which stimulus increases the tone of the esophageal sphincter

The antireflux barriers include two sphincters, namely, the lower esophageal sphincter LES and the diaphragmatic sphincter, and the unique anatomic configuration at the gastroesophageal junction. The two sphincters maintain tonic closure and augmented reflex closure of the sphincter mechanism.

The LES is composed of smooth muscles, and it maintains tonic contraction owing to myogenic as well as neurogenic factors. It relaxes due to vagally mediated inhibition involving nitric oxide as a neurotransmitter.

The diaphragmatic sphincter is composed of striated muscles that also exhibit tone and contracts due to the excitatory nerves. The loss of inhibitory mechanisms leads to esophageal achalasia, and increased frequency of TLESR is associated with gastroesophageal reflux disease. Top of page Introduction The anatomy and functioning of the sphincter at the lower end of the esophagus is fairly complex, and there has been tremendous progress in our understanding of all aspects of it since the original description of a high pressure zone by Code and Schlegel 50 years ago.

Top of page Lower Esophageal Sphincter Anatomic Considerations The smooth muscles of the esophagus are organized into two distinct layers, the circular and the longitudinal, and these layers continue into the LES. Figure 1: Anatomy of the esophagogastric junction. Figure 2: Ultrasonographic images of the esophagus left and lower esophageal sphincter LES , right.

Lower Esophageal Tone and Contraction The difference between LES and esophageal muscle is that the former maintains higher basal tone than the latter, and in the in vivo situation the LES in humans is recognized as a zone of high pressure, 2 to 4 cm in length. Table 1: Effects of some hormones and putative neurotransmitters on the lower esophageal sphincter and the possible sites of action.

Top of page Diaphragmatic Sphincter Anatomic Consideration The mammalian diaphragm is primarily a respiratory muscle. Top of page Diaphragmatic Contraction Measuring the contribution of diaphragmatic sphincter pressure to the EGJ is problematic in humans for three reasons: 1 The LES and diaphragmatic sphincter are anatomically superimposed on each other, and therefore it is difficult to discern whether the intraluminal pressure is related to LES or diaphragmatic sphincter contraction.

Figure 4: Reflex contraction of the esophagogastric junction recorded by a reverse perfused sleeve sensor equipped with electrodes to record crural DEMG activity. Top of page Asymmetry of the Intraluminal Pressure at the Lower End of the Esophagus Originally described by Winan, several investigators have noticed that the LES pressure is circumferentially asymmetric. Top of page Phrenoesophageal Ligament Loose areolar tissue surrounds the esophagus from the level of mediastinum to the upper abdomen.

Top of page Relaxation of the Lower Esophageal Sphincter and the Diaphragmatic Sphincter Lower Esophageal Sphincter Relaxation For the transport of ingested contents into the stomach, relaxation of both the LES and the diaphragmatic sphincter is essential. Top of page Diaphragmatic Sphincter Relaxation Deglutition and esophageal distention, besides causing LES relaxation, also induces selective inhibition of the diaphragmatic sphincter muscle. Top of page Neural Pathways Mediating Transient Lower Esophageal Sphincter Relaxation Transient LES relaxation is a neural reflex with afferent and efferent pathways and a pattern generator located in the swallow center of the brainstem.

Figure 7: Neural pathways to the LES and crural diaphragm. Table 2: Pharmacologic agents known to inhibit transient lower esophageal sphincter relaxations. Top of page Ancillary details.

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For example, as gastric pH declines, esophageal clearance time increases. The duration of esophageal exposure to a refluxate with a pH of less than 4. A recent study 21 that evaluated acid exposure found that the percentage of time that the intragastric pH was less than 4. The ability and rapidity with which injured esophageal mucosa undergo repair are critical to limiting further mucosal damage and for healing completely.

Rapid restitution of the gastroduodenal epithelium initially repairs mucosal injury, often taking less than 1 hour, and this precedes cell replication.

The esophageal epithelium does not undergo a similar rapid repair process. Once injury to the esophageal mucosa occurs, cell replication rather than migration occurs, taking from days to weeks for complete healing. Mucosal exposure to a refluxate with a pH of less than 4. The mucosal repair was completely and irreversibly abolished when the mucosa was exposed to a pH of less than 3.

To prevent mucosal injury and effectively ensure healing of esophagitis, the treatment of patients with GERD depends on the ability to increase and maintain gastric pH above 4. This finding was confirmed in a meta-analysis 19 of clinical trials of patients with GERD and esophagitis and clinical pharmacodynamic studies with the same dose regimens of antisecretory drugs. Drug therapy that raised intragastric pH and intraesophageal pH above 4. Other agents used to treat GERD include the prokinetic agents cisapride and metoclopramide sulfate and the site-protective agent sucralfate, which do not affect pH in any substantial way.

Various antacid preparations neutralize gastric acid within the lumen and raise the pH of refluxed gastric contents, but to varying degrees. Although antacids are used by many to alleviate intermittent, mild GERD-related symptoms, particularly heartburn, they do so for relatively short periods, thereby requiring frequent administrations per day. In addition, antacids do not affect the volume of acid secretion or significantly help heal esophagitis or prevent the complications of GERD.

Given the less-than-ideal effects of antacid preparations, the advent of the H 2 RAs cimetidine, ranitidine, famotidine, and nizatidine provide some improvement for the treatment of GERD. They decrease gastric acid secretion by reversible, competitive inhibition of histamine-stimulated acid secretion and are considered equivalent in acid suppression when given in equipotent doses. Athough effective in reducing basal acid secretion, they are much less effective at inhibiting meal-stimulated acid secretion.

In , Sontag 32 published an exhaustive analysis of controlled trials of H 2 RA treatment in patients with GERD, concluding that only half the patients who received H 2 RAs for 6 to 12 weeks had relief of reflux symptoms when compared with placebo. The introduction of the PPIs omeprazole, lansoprazole, and pantoprazole has provided, for the first time, effective medical treatment for patients with GERD. Also, unlike the H 2 RAs, the PPI agents block the final step of acid secretion and inhibit acid secretion regardless of the stimulus.

Omeprazole reaches maximum plasma concentrations between 1. Numerous placebo-controlled and comparative studies have been performed that evaluate the effect of H 2 RAs and PPIs on intragastric pH.

While different methods of assessing intragastric pH have been used that make direct comparisons difficult, definitive trends are clear.

Patients with reflux disease often require higher double-dose regimens to attain an intragastric pH above the critical threshold of 4. Bell and Hunt 39 analyzed intragastric pH data for various dose regimens of H 2 RAs and for several omeprazole dose regimens. Figure 1 illustrates that H 2 RAs cannot maintain pH greater than 4. More recent data support these findings. The PPIs are significantly more effective at attaining and maintaining an intragastric pH above 4.

More recent comparative studies show similar results 40 - 42 , 48 , 49 and have been confirmed by meta-analysis by Chiba et al. The acid-inhibitory effects of the PPIs omeprazole and lansoprazole are determined by their dose, extent and consistency of their bioavailability, and plasma half-life. Given its increased bioavailability, lansoprazole would be expected to attain maximal acid-inhibitory effects sooner than omeprazole.

One study 53 that evaluated the time to maximum inhibition of gastric acidity following repeated oral administration of lansoprazole, 30 mg, found a rapid onset of action. Lansoprazole, 30 mg, increased the mean hour intragastric pH significantly from baseline on day 1 from a baseline pH of 2. The maximum effect occurred as early as 6 hours following administration of the first dose. In a recently published study, 50 10 healthy male volunteers were treated for 5 consecutive days with a single morning dose of lansoprazole, 15 mg; lansoprazole, 30 mg; omeprazole, 20 mg; omeprazole, 40 mg; and placebo.

The investigators reasoned that the decreased effects observed with omeprazole may be due to its low first-day bioavailability and that the antisecretory effects of lansoprazole, 30 mg, equaled those of omeprazole, 40 mg. Given the results of this study, 30 mg of lansoprazole is likely to display greater gastric acid antisecretory efficacy than 20 mg of omeprazole and, therefore, may prove advantageous in the treatment of acid-related diseases when these doses are used.

Several controlled, double-blind pharmacodynamic studies in healthy volunteers have shown that lansoprazole, 30 mg, sustains the hour intragastric pH above 3. While the effect of lansoprazole, 30 mg, on gastric pH was always greater than that of omeprazole, 20 mg, the difference between the 2 agents reached statistical significance only for the percentage of time lansoprazole sustained pH greater than 3.

In a crossover comparison of the effect that low-dose PPI therapy has on gastric acidity, 12 healthy H pylori— negative males were treated with lansoprazole, 15 mg; omeprazole, 10 mg; and omeprazole, 20 mg, for 5 days. Comparisons between lansoprazole and omeprazole and between both doses of omeprazole revealed no significant difference in median intragastric pH and the time over pH 4. Blum et al 42 recently compared 2-dose regimens of lansoprazole to omeprazole and to ranitidine at the recommended dose for the treatment of erosive esophagitis.

This was a randomized, double-blind, 4-way crossover study in 29 healthy male volunteers comparing the effects on intragastric pH of lansoprazole, 15 mg once daily, lansoprazole, 30 mg once daily, omeprazole, 20 mg once daily, and ranitidine, mg 4 times daily.

Ambulatory hour pH was monitored at baseline and on the last day day 5 of each crossover period, and mean intragastric pH and proportion of time pH was greater than 3. The results obtained in this study are similar to a prior investigation 57 that compared the acid inhibitory acitivity of omeprazole, lansoprazole, and famotidine.

Ten healthy volunteers were treated sequentially with lansoprazole, 30 mg once daily in the morning; famotidine, 20 mg twice daily; and omeprazole, 20 mg once daily in the morning. Although the hour profile of acid suppression with the 2 PPIs was similar, the percentage of time that intragastric pH was above 4.

The relative antisecretory efficacy of pantoprazole, the newest of the PPIs, appears to be comparable to that of omeprazole yet less effective than lansoprazole in 2 studies. Twelve healthy volunteers participated in a 2-way crossover study 59 comparing intragastric pH after lansoprazole, 30 mg; and pantoprazole, 40 mg. Lansoprazole maintained pH above 4. In summary, the results of several meta-analyses 19 , 24 , 35 and several recent direct comparison studies 40 - 42 , 48 , 49 confirm that the PPIs are more effective at achieving and maintaining intragastric pH above 4.

Furthermore, data 54 suggest that lansoprazole, 30 mg, is significantly more effective at raising intragastric pH above 4. Moreover, lansoprazole, 30 mg, appears to be equipotent to omeprazole, 40 mg, in inhibiting meal-stimulated gastric acid secretion. Results of a recent study 56 suggest that lansoprazole, 15 mg, is comparable to omeprazole, 10 mg and 20 mg, for raising intragastric pH, with no difference noted between the 2 doses of omeprazole.

The effective and sustained increase in intragastric pH manifested by the PPIs translates into significantly more rapid relief of symptoms and greater healing compared with the H 2 RAs. Moreover, speed of healing with PPI treatment was calculated to be approximately twice as fast as that observed with the H 2 RAs In the meta-analysis by Chiba and colleagues, Similar to the results observed in comparative trials with lansoprazole and H 2 RAs, pantoprazole is also more effective than the H 2 RAs for healing erosions and relieving symptoms.

Five controlled trials have confirmed that treatment with either omeprazole or lansoprazole in patients refractory to H 2 RA therapy markedly increased esophagitis healing. Similarly, lansoprazole produced significantly higher healing rates at 4 and 8 weeks compared with ranitidine in patients resistant to H 2 RAs.

In addition to healing erosive esophagitis effectively, maintenance therapy with a PPI once daily prevents recurrence of erosive lesions. While all the PPIs are effective for healing esophagitis, a more rapid relief of symptoms is seen with lansoprazole than with omeprazole, thereby enhancing patients' well-being.

In studies 73 - 75 comparing lansoprazole and omeprazole in patients with GERD, lansoprazole provided more effective and rapid symptom relief. Similar findings were reported by Mee and colleagues, 74 who studied patients with GERD treated with lansoprazole, 30 mg once daily, and patients treated with omeprazole, 20 mg once daily.

During all 8 weeks of therapy, patients treated with omeprazole experienced a significantly higher percentage of nights with heartburn compared with those treated with lansoprazole, 30 mg. A recently presented meta-analysis 60 of 37 double-blind, randomized, comparative studies involving 77 treatment arms and patients with erosive esphagitis confirmed the findings of earlier investigators.

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