What is the primary mechanism that contributes to abnormal esophageal peristalsis in patients with reflux? How can the neural or myogenic abnormalities be stated?
D. Sifrim, J. Tack, J. Janssens (Leuven)
Abnormal esophageal motility results in an increased exposure of the esophageal mucosa to gastric contents. Whereas a defective gastroesophageal barrier accounts for an increased number of gastroesophageal reflux episodes, abnormal esophageal peristalsis results in impaired esophageal acid clearance. Experimental evidence suggests that gastroesophageal reflux disease (GERD) is associated with impaired cholinergic excitatory neural modulation of esophageal motility. Prokinetic drugs that stimulate the cholinergic esophageal neuromuscular function were proposed for treatment of GERD because they could increase the lower esophageal sphincter (LES) pressure and improve esophageal acid clearance. In this article, we reviewed the current understanding of the esophageal motor dysfunction present in GERD, and the mechanisms by which cholinergic stimulation may improve esophageal motility in patients with GERD.
Lower esophageal sphincter function in GERD
As a group, patients with GERD have a lower mean value of basal LES pressure than that in normal subjects, although most patients with reflux disease have basal LES pressure in the normal range and only a small subgroup, usually with severe peptic esophagitis, have pressures less than 10 mmHg . While the traditional view was that reflux occurs because of a chronically weak LES, it has been shown that most reflux episodes in normal subjects and patients with mild reflux esophagitis occur during transient relaxations of LES (TLESRs), i.e. relaxations not triggered by swallowing . In more severe reflux esophagitis, although TLESRs are very important and account for two-thirds of reflux episodes, a greater proportion of reflux occurs during absent basal LES pressure .
Esophageal body motor function in GERD
Effective peristalsis is a critical determinant for esophageal clearance of refluxed gastric contents . Evaluation of the normal esophageal peristaltic function using concurrent videofluoroscopy and manometry showed that a single normal peristaltic wave completely clears the entire barium bolus from the esophagus. If a peristaltic wave fails, i.e. does not occur after deglutition, does not traverse the entire length of the esophagus or becomes simultaneous (either within a common cavity phenomenon or real simultaneous contractions) there is little or no volume clearance. The minimum effective contraction strength for clearance in the distal esophagus is approximately 30 mmHg . Above a threshold pressure of 30 mmHg, liquid transport was not affected by amplitude (33 to
500 mmHg) or duration (3 to 15 seconds) of esophageal contractions .
The relationship between esophageal peristalsis and gastroesophageal reflux (GER) has been extensively studied in patients with GERD using both stationary esophageal manometry and more recently, ambulatory prolonged esophageal manometry.
There is a trend toward a greater percentage of failed primary peristalsis with increasing severity of reflux disease [4-6]. In normal volunteers, the failure rate is of 9% whereas in patients with mild and severe GERD it is 25% and 36% respectively . The amplitude of peristaltic contractions in the distal esophagus is significantly lower in the esophagitis patients group than in controls [4-7]. The amplitude of peristaltic contractions is inversely related to the severity of esophagitis [4, 8]. The duration of contractions was described either shorter  or longer  but the propagation velocity is unequivocally slower in patients with esophagitis than in controls [4, 5, 9].
Prolonged esophageal manometry
During prolonged overnight stationary manometry, Dodds et al. found a significantly high rate of incomplete primary peristaltic sequences in a group of patients with GERD . In patients with low grade of GERD, Timmer et al. found relative small changes in esophageal motility as compared to controls. However, there was an increased number of non-transmitted contractions. When contractions were normally transmitted they had normal amplitude but shorter duration and slower propagation velocity . In patients with esophagitis grade III and IV, the amplitude of contractions observed during 24-hour ambulatory recording was not significantly reduced but like in patients with less severe esophagitis, contractions had shorter duration and slower propagation velocity .
Patients with abnormal GER but no esophagitis and patients with mild esophagitis (grade I and II) had normal amplitude of contractions but an increased prevalence of simultaneous contractions [13, 14].
Patients with stricture or Barrett's esophagus had a low median amplitude of contractions, an increased frequency of contractions with an amplitude below 30 mmHg and an increased prevalence of failed peristalsis .
In summary, primary esophageal peristalsis is not significantly impaired in patients with abnormal esophageal acid exposure without esophagitis or patients with esophagitis grade I-II. These patients may have a slightly increased number of failed peristalsis. Patients with severe esophagitis, however, can have an increased rate of failed primary peristalsis; reduced amplitude of contractions in the distal esophagus and slow propagation velocities.
Propulsive force and secondary peristalsis
Williams et al. measured the traction force (clearance force) generated by primary peristalsis using a miniature intraluminal force transducer in normal subjects and patients with GERD . The majority of patients with GERD (with and without esophagitis) had both reduced amplitude of esophageal contractions and reduced traction force induced by wet swallows. Some patients, however, had normal peristaltic contractions yet impaired traction forces. This finding suggests that other factors than contraction's amplitude not detected by manometry are also determining the traction force generated by a propagated esophageal contraction, i.e. the magnitude of the pressure differential across the bolus, distal resistance forces and longitudinal muscle contraction. The authors suggested that esophagitis can be more directly related to impaired esophageal clearance forces than contraction amplitudes.
Responses to an intraesophageal balloon distention are also abnormal in patients with esophagitis. These patients showed a higher threshold for induction of contractile activity and weaker traction forces provoked by graded intraluminal distention [16, 17].
Prolonged esophageal manometric studies using an adequate pharyngeal swallowing marker have demonstrated that primary peristalsis is more prevalent than secondary peristalsis as the initial esophageal clearance event both in healthy subjects [18, 19] and in patients with GERD [20, 21]. In healthy subjects, however, the majority of reflux episodes with supine are followed by secondary peristalsis . Secondary peristalsis is likely to be important during sleep when the rate of primary peristalsis is reduced.
Secondary peristalsis in response to esophageal distention with air or water is impaired in patients with GERD with and without esophagitis . Patients may have normal primary peristalsis but abnormal secondary peristalsis. In patients, the response rate to air or water injection was significantly low.
In summary, in patients with GERD with or without esophagitis there is an impaired response to esophageal distention. The traction force generated either by primary or secondary peristalsis (balloon distention) is reduced and the distention threshold needed to trigger secondary peristalsis is higher than in normal subjects.
Esophageal motor response to reflux events
Response to endogenous intraluminal acidification
In patients with GERD without esophagitis, intraesophageal acidification caused an increase in deglutition frequency, amplitude and duration of primary peristaltic contractions (mainly in the proximal esophagus) but a decrease in propagation velocities. This effect is independent from volume distention of the esophagus suggesting a reaction of acid sensitive receptors in the esophageal mucosa .
Peristaltic response to gastroesophageal reflux
Two recent studies assessed the esophageal peristaltic response immediately after a reflux episode in patients with GERD and esophagitis. Bumm et al.  found an impaired or even absent peristalsis during a "response period" (duration of GER plus additional 4 min) in many patients. Timmer et al., however, did not find impairment in the peristaltic response to reflux during the 2 min period after the onset of each reflux episode .
Esophageal neural and myogenic abnormalities in experimental esophagitis
The pathogenic correlation between the esophageal mucosal inflammation and motility disturbances was studied in cats and opossums after repeated intraesophageal acid perfusion. Most of the studies focussed on the LES and little information is available from the esophageal body.
Repeated intraesophageal acid perfusion provokes a decrease in amplitude of esophageal body circular contractions [25, 26]. In the opossum there was in addition an increased rate of failed primary peristalsis; the appearance of repetitive spontaneous contractions and esophageal shortening [26, 27].
The acid perfusion-induced motility abnormalities can be due to changes in contractile function of the muscle, in the neural modulation of contractions or in both. Another possibility is that release of inflammatory mediators, i.e. mast cell degranulation during acid-induced mucosal injury, may affect both smooth muscle and neural function [27, 28].
In vitro experiments using muscle strips from acid perfusion induced-esophagitis were performed to elucidate this problem.
Myogenic integrity was studied, either with direct pharmacologic stimulation of muscle receptors or with electrical field stimulation using parameters for muscle stimulation.
In cats, stimulation of esophageal body muscle strips with bethanechol showed a reduced but not abolished response of circular, longitudinal and muscularis mucosae smooth muscle . However, the LES muscle strips responsiveness to bethanechol was not reduced by esophagitis [29,30].
In opossums, the response to electrical fields stimulation (EFS) using myotropic parameters was reduced in amplitude but prolonged (recovery phase) and followed by spontaneous activity (increased muscle membrane excitability) .
The LES smooth muscle tone depends on high intracellular basal levels of 1, 4, 5, inositol triphosphate (IP3) and release of calcium from intracellular stores. In cats, acute and chronic esophagitis provokes a reduction of IP3 and intracellular calcium stores and an alteration of signal transduction pathways [31, 32].
The integrity of neural control of esophageal motility was studied with pharmacologic stimulation or inhibition of the cholinergic system or with EFS using parameters known to stimulate intrinsic neurons.
In cats with esophagitis, the response of esophageal body circular smooth muscle strips to EFS using parameters known to stimulate intrinsic neurons was completely abolished . In the opossum, the amplitude of contractions was also significantly reduced .
The neural excitatory and inhibitory pathways that control the LES function were studied in cats with acid-perfusion induced acute esophagitis . In these experiments, the excitatory response to bethanechol (myogenic stimulation) was maintained but there was a reduction in the excitatory response to Mc Neil A343 and CCK at high doses, suggesting an impairment somewhere in the LES cholinergic excitatory pathway and a resulting decrease in acetylcholine release. The inhibitory responses to CCK, Mc Neil A343 and esophageal balloon distention were maintained suggesting that esophagitis decreases cholinergic excitation but neural inhibition to the LES remains intact.
Cholinergic stimulation of esophageal motility in man
Experimental evidence suggests that esophagitis is associated with impaired cholinergic excitatory neural modulation of esophageal motility.
In humans, anticholinergic agents weaken esophageal smooth muscle contractions impairing primary and secondary peristalsis and affecting esophageal clearance [33-35]. It is widely believed that anticholinergic agents increase GER and that they are contraindicated in patients prone to GERD. Several studies evaluated the effect of anticholinergic drugs on LES pressure in humans [33, 36, 37] and found them to reduce basal LES pressure. Phaosawasdi et al., using combined esophageal manometry and gastroesophageal scintigraphy, showed that atropine decreased LES pressure and significantly increased reflux as shown by scintigraphy in patients with heartburn . In a recent study, however, Mittal et al. found that atropine reduced the frequency of reflux in healthy subjects by decreasing the rate of spontaneous TLESRs .
Therapy to improve the esophageal neuromuscular function in patients with esophagitis has been directed to replace defective cholinergic excitation and to stimulate muscle function.
Esophageal cholinergic stimulation has been attempted using either cholinomimetic agents with direct action on smooth muscle muscarinic receptors like bethanechol or other agents that indirectly activate the release of acetylcholine at the level of the myenteric plexus by stimulating different receptors like metoclopramide, cisapride or erythromycin.
To be effective as a treatment of the esophageal motility disorders observed in patients with GERD, cholinergic stimulation must:
- increase the rate of successful primary peristalsis in patients with elevated percentage of failed peristalsis;
- increase the amplitude of contractions in those patients with hypotensive peristalsis (amplitude < 30 mmHg);
- increase the propulsive force generated by primary or secondary peristalsis;
- increase the rate of successful secondary peristalsis mainly during night;
- increase fasting and postprandial LES pressure in patients with very low LES pressure
(< 5 mmHg) without affecting swallow induced LES relaxations;
- decrease the rate of TLESRs;
- accelerate gastric emptying in patients with proven delayed gastric emptying.
Bethanechol is a cholinergic agonist that activates muscarinic M2 receptors in the smooth muscle.
The effect of bethanechol on esophageal propulsive force has not been tested so far. Bethanechol increases the amplitude of secondary peristalsis induced by rapid instillation of water in the proximal esophagus both in healthy subjects and in patients with GERD .
The effect of bethanechol on the frequency of TLESRs has not been tested so far. Bethanechol does not accelerate gastric emptying in GERD patients with proven delayed emptying .
As a result of its cholinergic effects, bethanechol stimulates the secretion of gastric acid and can produce abdominal cramping, blurred vision, fatigue and increased urinary frequency.
Metoclopramide is a dopamine antagonist but also increases the release of acetylcholine from myenteric neurons and sensitives muscarinic receptors in the gastrointestinal tract.
In patients with GERD, metoclopramide increases basal LES pressure from values below 10 mmHg [45-50]. The effect is dose-dependent and high doses are needed in patients with very low LES pressure .
In one study performed on 6 patients with GERD, in whom TLESRs were not the main mechanism of GER, metoclopramide failed to reduce the frequency of postprandial TLESRs .
Metoclopramide accelerates gastric emptying in patients with GERD and delayed gastric emptying .
Metoclopramide can provoke central and peripheral antidopaminergic side effects like drowsiness, lassitude, anxiety, Parkinson's symptoms or enhanced released of prolactine with gynaecomastia, galactorrea and menstrual disorders.
Cisapride increases acetylcholine release from myenteric neurons. It has no antidopaminergic effects and unlike cholinomimetic drugs does not affect gastrointestinal secretions.
In patients with GERD, cisapride increases the amplitude of primary peristaltic contractions after EV administration or oral administration in high doses (20 mg) combined with ranitidine [51-53]. Low oral doses (5-10 mg) do not increase the amplitude of primary peristaltic contractions [54-55].
Cisapride does not reduce the rate of failed primary peristalsis in patients with GERD .
Esophageal propulsive force increases after cisapride .The effect of cisapride on secondary peristalsis has not been tested.
Cisapride accelerates esophageal transit of solids in patients with diabetes and sclerodermia . A study in patients with GERD, however, showed no changes of the esophageal transit time for liquids after cisapride .
Cisapride increases low fasting basal LES pressure to normal values in patients with GERD [51, 53, 54]. In the postprandial period, however, oral administration of cisapride (10 mg) does not increase LES pressure [55, 59].
In patients with GERD, cisapride failed to reduce the frequency of postprandial TLESRs associated with reflux .
Cisapride improves esophageal acid clearance and reduces the number of reflux episodes of more than 5 min . This can be due to a reduction in the volume of refluxate with each reflux episode following an acceleration of gastric emptying . The most common side-effects of cisapride are abdominal cramping, borborygmi and diarrhoea.
Erythromycin activates motilin receptors on the gastro-intestinal smooth muscle  and also on myenteric cholinergic neurons . The effects of erythromycin on the esophagus are blocked by atropine .
Erythromycin does not affect the amplitude of primary peristaltic contractions neither in healthy subjects [63-65] nor in patients with GERD [66, 67]. A recent 24-hour manometric and pH study in patients with GERD, however, found that erythromycin tended to decrease esophageal contraction velocities and increase the rate of successful primary peristalsis in supine position .
Esophageal propulsive force and secondary peristalsis have not been evaluated after erythromycin.
Erythromycin improves esophageal transit time in diabetic esophagoparesis  but the effect of erythromycin on esophageal and acid clearance has not been tested.
In healthy subjects erythromycin increases fasting LES pressure [63-65] and also prevents the normal postprandial decrease in LES pressure . In patients with GERD, intravenous administration of erythromycin increases the fasting low LES pressure to normal values . The effect of oral erythromycin on postprandial LES pressure has not been evaluated in patients with GERD.
The effect of erythromycin on the frequency of TLESRs has not been evaluated. Erythromycin improves gastric emptying in patients with severe idiopathic and diabetic gastroparesis .
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