l-Dopa inhibits metoclopramide stimulation of the lower esophageal sphincter in man

Opossum lower esophageal sphincter smooth muscle contains inhibitory dopaminergic receptors. Since metoclopramide is a dopaminergic antagonist in many experimental situations, the present study was designed to investigate whether this mechanism could explain the lower esophageal sphincter (LES) stimulating action of metoclopramide in man. The interactions of (1) orall-dopa, a dopamine precursor, and metoclopramide; and (2)l-dopa and the cholinergic agent, bethanechol, on lower esophageal sphincter pressure (LESP) in normal subjects were examined. Orall-dopa significantly inhibited LESP response to either oral metoclopramide 20 mg (P<0.05), or intravenous metoclopramide 20 mg (P<0.05). In contrast,l-dopa did not inhibit the LESP response to subcutaneous bethanechol (0.07 mg/kg). Mean basal LESP measured 50 min after ingestion of 1000 mgl-dopa, 19.3±3.1 mm Hg, was significantly less than basal LESP afterl-dopa placebo, 29.3±4 mm Hg (P<0.01). It is concluded that (1)l-dopa inhibited the metoclopramide-induced rise in LESP but not peak stimulation of LESP by bethanechol; (2) there is evidence for the possibility of LES dopaminergic inhibitory receptors in man; and (3) these data are consistent with the hypothesis that metoclopramide acts on the LES by blocking a dopaminergic pressure-lowering mechanism.     

Inhibition of the lower oesophageal sphincter by fat— a mechanism for fatty food intolerance

The effect of fat and protein meals on the lower oesophageal sphincter pressure was tested in normal subjects using an infused open-tipped manometric system. After ingestion of a minced beef meal, the mean peak pressure at the lower oesophageal sphincter increased 5·8 ± 1·5 mm Hg (± 1 SE). By contrast, ingestion of a corn oil meal resulted in a mean peak decrease of 7·8 ± 1·9 mm Hg. Following the combined minced beef/corn oil meal, mean peak pressure decreased 3·0 ± 2·1 mm Hg. Pentagastrin (3 μg/kg, subcutaneously) resulted in a mean peak increase of 20·6 ± 7·0 mm Hg when given to the subjects in the fasting state, and produced an increase of only 8·4 ± 1·7 mm Hg when given following the fat meal. Finally, after a mean peak decrease in pressure at the lower oesophageal sphincter of 6·8 ± 1·0 mm Hg 15 minutes after the corn oil meal, gastric alkalinization with 30 ml of antacid resulted in a subsequent increase in sphincter pressure of 5·2 ± 1·6 mm Hg. These data indicate: (1) Fat attenuates the effect of endogenous gastrin as well as exogenous pentagastrin stimulation of the lower oesophageal sphincter. (2) Fat-induced incompetency of the lower oesophageal sphincter can be effectively combated by gastric alkalinization in the form of antacids.     

Effect of gastric distension and duodenal fat infusion on biliary sphincter of oddi motility in healthy volunteers

Although sphincter of Oddi (SO) dysfunction has been implicated in the pathogenesis of postcholecystectomy syndrome and pancreatitis, little is known about normal physiologic stimuli, such as intraduodenal fat on human SO motility. Furthermore, gastric distension that frequently accompanies endoscopic manometry has been shown in animal studies to affect SO motility. We evaluated the effects of intraduodenal fat and gastric distension on SO basal pressure. Asymptomatic volunteers had SO manometry performed while sequentially performing gastric distension and intraduodenal fat perfusion. Five subjects (ages 29.8±4.8 years, range 22–35 years) had a mean basal sphincter of Oddi pressure of 23.4±5 mm Hg (range 17–31 mm Hg). Injection of air into the stomach caused no appreciable change in either intragastric pressure or SO pressure. Intraduodenal fat infusion resulted in a decrease in mean SO basal pressure from 23.4±5.0 to 4.4±4.4 mm Hg (P=0.004). These results demonstrate that gastric distension does not affect SO basal pressure and that intraduodenal fat infusion reduces SO basal pressure.This work was presented in part at the Digestive Disease Week in Boston, Massachusetts, in May 1993.This work was supported in part by a research award from the American Society of Gastrointestinal Endoscopy.     

Achalasia in the elderly

Clinical and manometric data from 13 elderly subjects with idiopathic achalasia (mean age 79±2 years) were compared with findings from younger subjects with the same disease (n=79) to see if aging altered the presentation and outcome of this motor disorder. Fewer elderly subjects complained of chest pain (27% vs 53%), and the pain was significantly less severe (P<0.01). Other presenting features (including sex, duration of symptoms, and presence and severity of dysphagia) did not differ between the groups. Across all patients, age weakly and inversely correlated with residual postdeglutitive lower esophageal sphincter (LES) pressure (R=–0.34), and residual pressure was significantly lower in the older subjects (8.0±1.3 mm Hg vs 11.9±0.8 mm Hg;P=0.02). No differences in basal LES pressure or esophageal-body contraction amplitudes were present between the groups. Initial success with pneumatic dilation was similar in the two subject groups, but the number of older subjects available for analysis was too small to draw strong conclusions. These results indicate that aging decreases the elevation of LES residual pressure that occurs with achalasia. As elderly achalasia patients also present with less chest pain, the findings may be interrelated.Supported in part by grant AMO7130 from the United States Public Health Service. Dr. Todorczuk is supported by an educational grant from Smith, Kline, and French.     

Response of canine ileocolonic sphincter to intraluminal acetic acid and colonic distension

The aim was to determine the effect of intraluminal acetic acid and proximal colonic distension on canine ileocolonic sphincter pressure, ileal motility, and coloileal reflux. In six conscious dogs with an isolated ileocolonic loop, basal pressure of the ileocolonic sphincter was similar during ileal perfusion with 100 mM acetic acid at 1 ml/min (mean±sem=18±0.4 mm Hg) and with saline (18±0.5 mm Hg;P=0.81). Discrete clustered ileal contractions were more frequent with acetic acid, however, and when they propagated across the sphincter, sphincter pressure increased from 18±0.4 mm Hg to 36±1.3 mm Hg (P=0.002). Sphincter pressure was also greater during colonic perfusion with acetic acid (32±0.7 mm Hg) than during ileal perfusion with acetic acid or saline (P<0.017). Moreover, sphincter pressure gradually increased as the colon was distended with saline (slope=0.8 mm Hg/cm H₂O,P<0.017) or acetic acid (slope=0.5 mm Hg/cm H₂O,P<0.017), but the increase did not prevent coloileal reflux. In conclusion, ileal clustered contractions, colonic perfusion of acetic acid, and colonic distension all increased canine ileocolonic sphincter pressure.     

Lower esophageal sphincter pressure as an index of gastroesophageal acid reflux

The purpose of this study was to determine the relationship of lower esophageal sphincter (LES) pressure and the volume of acid placed into the stomach required to induce gastroesophageal reflux in man. LES pressure was recorded continuously and by station pull-through by three radially oriented catheters in both symptomatic and asymptomatic subjects during the graded infusions of 0.1 N HCl acid into the stomach. Sumptomatic subjects had a mean LES pressure of 7.5±0.7 mm Hg and refluxed at a volume of 140.0±21.0 ml. Fifty-five percent of asymptomatic subjects refluxed at a mean volume of 380.0±24.7 ml, and had a mean LES pressure of 13.8±0.4 mm Hg. Asymptomatic nonrefluxers at a volume of 500 ml of 0.1 HCL acid had a mean LES pressure of 18.9±1.1 mm Hg. The mean LES pressure and acid volumes showed statistical significance between the three groups (P<0.01). There was an excellent overall correlation between LES pressure and acid volume required to produce reflux in all subjects (r=0.91,P<0.001). Following reflux, asymptomatic but not symptomatic subjects showed a significant increase in LES pressure. These studies suggest that: (1) LES pressure does provide an accurate index of the gastroesophageal antireflux mechanism, provided that acid volume is considered; and (2) asymptomatic subjects showing acid reflux have higher LES pressures, reflux at higher volumes, and develop an LES contractile response after the reflux episode.This work was supported by a grant from the Smith Kline & French Laboratories, Philadelphia, Pennsylvania.     

Effect of an oral beta2-adrenergic agonist on lower esophageal sphincter pressure in normals and in patients with achalasia

The effect of the beta₂-adrenergic agonist, carbuterol, was studied on the lower esophageal sphincter (LES) pressure in normals and in patients with achalasia. In normals, the mean LES pressure decreased from 23.1±6.2 mm Hg (mean±sem) to 16.0±5.0 mm Hg at a 4.0-mg dose of carbuterol (P<0.05). In patients with achalasia, the mean LES pressure decreased from 50.1±5.1 mm Hg to 22.7±2.4 mm Hg after a 4.0-mg dose of carbuterol (P<0.01). The duration of action following oral administration exceeded 90 min. These studies indicate that the LES in man has beta₂-adrenergic receptors that mediate a reduction in pressure. The magnitude of LES pressure reduction in patients with achalasia suggests that this drug may be of therapeutic benefit.     

Lower esophageal sphincter pressure in Chagas' disease

It is known that lower esophageal sphincter (LES) pressure in patients with idiopathic achalasia is higher than in normal subjects, but in patients with Chagas' disease, who have esophageal disease with similar clinical, manometric, and radiologic results, studies of LES pressure show contradictory findings. We measured the LES pressure in 118 patients with chronic Chagas' disease, 14 patients with idiopathic achalasia, and 50 control subjects using a perfused catheter and the stationary pull-through (SPT) technique. The patients with Chagas' disease had normal esophageal radiologic examination (group A, N=50), delay in esophageal clearance without dilatation (group B, N=41), or delay in esophageal clearance with dilatation (group C, N=27). The LES pressure of Chagas' disease patients of group A (18.6 ±9.1 mm Hg, mean ±SD), group B (17.8 ±9.7mm Hg), and group C (21.6 ±10.1 mm Hg) was lower (P<0.001) than the LES pressure of the controls (24.9 ±10.2 mm Hg). In patients with idiopathic achalasia, the LES pressure (40.7 ±17.8 mm Hg) was higher than in control subjects (P<0.01) and Chagas' disease patients (P<0.001). We conclude that the LES pressure of patients with Chagas' disease tended to be lower than that of control subjects and achalasia patients.Presented in part at the 8th World Congress of Gastroenterology, September 1986, São Paulo, Brazil, and published in abstract form inDig Dis Sci 31:273, 1986.     

Effects of intraduodenal air insufflation on sphincter of oddi motility in conscious dogs

To investigate effects of intraduodenal air insufflation on sphincter of Oddi motility, manometric recordings were obtained during fasting from the sphincter and duodenum in four conscious dogs with duodenal cannula. At 40% of the mean cycle length of the migrating motor complex predetermined from baseline recording, 160 ml of air was injected into the duodenum. In both the sphincter and duodenum, air insufflation produced premature phase III-like activity in seven of 20 experiments (35%) or nonspecific excitatory reaction in eight (40%). In the remaining five experiments (25%), the sphincter exhibited a transient inhibitory response, while the duodenum showed the nonspecific excitatory reaction. Basal pressure of the sphincter increased immediately after air insufflation in 90% of the 20 experiments. The mean basal pressure increased from 12.3±1.6 mm Hg to 22.4±2.1 mm Hg (P<0.0001) and minimum basal pressure from 2.9±0.9 mm Hg to 4.7±0.8 mm Hg (P<0.001). These results indicate that intraduodenal air insufflation does affect motility of the sphincter of Oddi and duodenum in conscious dogs.This work was presented at the 96th Congress of the Japanese Surgical Society on April 10–12, 1996, in Chiba, Japan.     

Lower esophageal sphincter function in cirrhosis

Lower esophageal sphincter (LES) function in cirrhosis was evaluated using an infused manometric system. LES pressure (LESP) in 10 subjects with cirrhosis (22+1 mm Hg) (mean±se) was not significantly (P>0.05) different from that of 10 control subjects (21±1 mm Hg) but was significantly (P<0.01) greater than the LESP recorded in 5 subjects with cirrhosis and ascites (16±2 mm Hg). There was no significant difference in LES response to intravenous pentagastrin, intravenous edrophonium, or straight-leg raising in the three groups. After loss of ascitic fluid, LESP significantly (P<0.01) increased (P9±3 mm Hg) and gastric pressure (GP) significantly (P<0.01) decreased (P8±2 mm Hg). The changes in LESP and GP revealed a significant (R=0.83,P<0.001) linear correlation. These data indicate (1) cirrhosis is associated with normal LES function, and (2) the mechanism of lowered LESP with ascites may be the inability of the LES to maintain a sustained response to chronic increases in GP.Supported by Bureau of Medicine and Surgery Clinical Invesgation Program Project No. 4-16-259.The opinions or assertions expressed herein are those of the author and are not to be construed as official or as reflecting the views of the Navy Department or the naval service at large.     

Does lower esophageal sphincter incompetency contribute to esophageal bleeding?

The purpose of this study is to determine whether lower esophageal sphincter (LES) incompetency is a common occurrence in patients with liver cirrhosis and contributes to the development of variceal bleeding. Resting LES pressure (17.8 +/- 1.1 mm Hg) in 35 patients with cirrhosis was similar to that of our control population (17.3 +/- 2.0 mm Hg). No differences were found among patients with ascites, variceal hemorrhage, or with different degrees of hepatic decompensation. In both patients and control subjects the LES responded with a significant pressure increase to gastric alkalinization. Symptoms and radiological evidence of gastroesophageal reflux were extremely uncommon in patients with liver cirrhosis. Based on these data it is unlikely that acid-pepsin regurgitation is a significant factor in the development of variceal hemorrhage.     

Studies on the Mechanism of the Lower Esophageal Sphincter Pressure Response to Alkali Ingestion in Humans

To clarify the lower esophageal sphincter (LES) pressure response to alkali ingestion, normal subjects and postantrectomy patients with either a gastroduodenostomy or gastrojejunostomy were studied in a double-blind controlled fashion. LES pressure and serum gastrin concentrations were measured after ingestion of a 100 ml bolus of either 0.4 M NaHCO3 or 0.4 M NaCl. In addition, the effect of a therapeutic dose (30 ml) of a commercial antacid preparation was studied in a double-blind fashion in 14 patients with gastroesophageal reflux disease. Peak increases in LES pressure above basal were significantly higher (p less than 0.05) after NaHCO3 than after NaCl in normal subjects and in patients with vagotomy and Billroth I antrectomy, but not in patients with vagotomy and Billroth II antrectomy. Serum gastrin concentrations were unaffected by alkali. Thirty milliliters of liquid antacid containing aluminum and magnesium hydroxide resulted in a small sustained rise in LES pressure over the first 50 min after ingestion, but this was not statistically different than the placebo response. It is suggested that: 1) neither the antrum nor intact vagi nor gastrin were required for NaHCO3 ingestion to increase LES pressure; 2) the increase in LES pressure with NaHCO3 ingestion appears to rely upon an intact duodenum and may relate to volume and osmolarity of the alkali load; and 3) therapeutic doses of a liquid commercial antacid does not significantly increase LES pressure in the presence of an intact stomach.     

Pathological esophageal acidification and pneumatic dilatation in achalasic patients too much or not enough?

Endoscopy, esophageal manometry and pH monitoring, gastric emptying test, and heartburn quantification on a visual analog scale were performed in 22 achalasic patients in order to clarify which events are associated with pathological esophageal acidification after successful LES dilatation. Five patients presented pathological acidification. Dilatation reduced LES tone from 38.3 ± 4.2 to 14.6 ± 1.1 mm Hg (mean ±sem); there was, however, no difference between nonrefluxers and refluxers (14.8 ± 1.2 vs 13.8 ± 2.5 mm Hg). The emptying time in achalasic patients was delayed compared to controls (315.9 ± 20.9 min vs 209 ± 10.4) due to prolonged lag-phase and reduced slope of the antral section-time curve, but, again, there was no difference between refluxers and nonrefluxers. The acid clearance was delayed in refluxers compared to nonrefluxers (15.9 ± 4.5 vs 2.5 ± 1.8 min,P<0.05). Two refluxers presented grade 1 esophagitis; one of them developed an esophageal ulcer. The heartburn score was the same in refluxers and nonrefluxers. Pathological acidification after pneumatic dilatation is associated with persistent problems in esophageal emptying rather than with excessive sphincter divulsion.     

Effect of propofol on human sphincter of Oddi

The effect of propofol was studied in 11 patients who had common bile duct sphincter of Oddi manometry for suspected dysfunction. Patients were initially sedated with midazolam and then further or resedated with propofol for the second set of pressure measurements. Recordings were made about 10 min after giving each drug. No patient had elevated basal pressure initially. Average basal pressure was unchanged (16.7±16.4 mm Hg), phasic contraction frequency was unchanged (3.4±3.8/min), and phasic contraction amplitude fell but did not achieve statistical significance (91.8±77.3 mm Hg,P=0.1). There was no difference in lowest blood pressure, pulse, or oxygen saturation recorded during midazolam or propofol sedation. Subjectively, the patients were more sedated during propofol administration. It is concluded that propofol is a safe and effective agent for conscious sedation. It does not alter the sphincter of Oddi pressure profile in patients with normal basal sphincter pressures and thus could be used as an alternative and perhaps better form of sedation for ERCP with sphincter of Oddi manometry.Supported by a grant from Poudre Valley Hospital Foundation.     

Effects of exogenous secretin on pancreatic and biliary ductal and sphincteric pressures in man demonstrated by endoscopic manometry and correlation with plasma secretin levels

An endoscopic manometric technique was used to investigate the effects of exogenous secretin on pancreatic duct, common bile duct, pancreatic duct sphincter, and bile duct sphincter pressures in 20 healthy volunteers. Synthetic secretin was infused intravenously at rates of 8.05, 16.1, 32.2, 64.4, 129, 258, and 516 ng/kg/hr, and plasma secretin concentrations were measured by a radioimmunoassay. Secretin produced a significant fall in peak and trough pancreatic duct sphincter pressures from basal values of 48.2±7.9 mm Hg (mean±sd) and 16.9±7.7 mm Hg, respectively, to 34.4±6.8 mm Hg and 11.2 ±5.8 mm Hg (P<0.005), respectively, at a mean plasma secretin concentration of 16 pg/ml (during an infusion rate of 32.2 ng/kg/hr). Higher infusion rates had no additional effect. Pancreatic duct pressure became significantly elevated above basal (11.5±4.0 mm Hg) at the two highest secretin rates. Secretin had no effect on common bile duct or bile duct sphincter pressures. Plasma secretin concentrations were within the postprandial range during the lowest four secretin infusion rates. We conclude that secretin produces selective physiological relaxation of the pancreatic duct sphincter.This work was supported by grants from the Katherine Gavriluk and Sara Jordan Funds, New England Baptist Hospital, Boston, Massachusetts; NIH Research Grant AM 25962. Dr. Carr-Locke is also in receipt of grants from the Wellcome Research Travel Fund, London, England, the Leicester Area Health Authority, Leicester, England, and the P&C Hickinbotham Trust, Leicester, England.     

Stimulation of the incompetent lower esophageal sphincter

The primary function of the lower esophageal sphincter (LES) is to prevent the reflux of gastric contents into the esophagus. We have studied the effect of hormonal and pharmacologic stimuli on LES pressure in patients with symptomatic gastroesophageal reflux due to LES incompetence. Gastric alkalinization, subcutaneous pentagastrin, intravenous edrophonium, and subcutaneous bethanecol each resulted in marked increases in LES pressure. In all studies, pressure rose to a level occurring in normal subjects. Subsequently, the patients were given 25 mg bethanecol orally and pressure monitored for 2 hours. The LES pressure increased from a mean basal pressure of 5.6±0.8 mmHg to a peak of 16.9±2.8 mmHg at 50 minutes. Pressure remained elevated for the full 2-hour study period. Both subcutaneous and oral bethanecol successfully increased LES pressure in all patients with symptomatic reflux to the level of resting pressure seen in normal subjects. These studies suggest a potential role for cholinergic agents in the therapy of symptomatic gastroesophageal reflux.The opinions expressed herein are those of the authors and cannot be construed as reflecting the views of the Navy Department or of the Naval Service at large.Presented at the 53 rd Annual Session of the American College of Physicians, April 19, 1972, Atlantic City, New Jersey.     

Lower esophageal sphincter reacts against intraabdominal pressure in children with symptoms of gastroesophageal reflux

Studies of the effect of increased intraabdominal pressure on the lower esophageal sphincter (LES) are controversial. This study aimed to verify the LES competence against extrinsic abdominal compression in children with and without symptoms of gastroesophageal reflux (GER). Eighteen children ages 6–20 months were evaluated, 11 of them with symptoms of GER (group I) and 7 without symptoms of GER (group II). Manometry of the esophagus, LES, and stomach was performed in all children who underwent extrinsic abdominal compressions of 20, 40, 60, and 80 mm Hg. The pressure gradients in the esophagus, LES, and stomach were measured. The pressure gradient showed a significant difference only in the esophagus after extrinsic abdominal compressions of 60 mm Hg [group I median (range): 7.6mm Hg (2.7–20.0) vs group II: 2.8 mm Hg (1.4–9.6), P < 0.05], and 80 mm Hg [group I median (range): 7.7 mm Hg (3.7–28.9) vs group II: 3.8 mm Hg (1.2–21.1), P < 0.05]. It was concluded that the competence of LES to contain increased intraabdominal pressure might be an important factor in the pathophysiology of GER in children.     

The hypertensive lower esophageal sphincter

Controversy exists as to whether the hypertensive lower esophageal sphincter (HLES) represents a clinical motility disorder of the esophagus or is merely the right-sided expression of a normal distribution curve. In the present study we describe 16 patients with HLES, defined as a lower esophageal sphincter (LES) pressure of 40 mm Hg (mean +3sd of controls) with normal peristalsis. All of the patients suffered from chest pain and nine from dysphagia. Delayed bolus transit at the gastroesophageal junction was demonstrated in four patients by radiography. Manometric studies showed that during swallowing the LES residual pressures were significantly greater (9.2±5.0 mm Hg) than observed in normal controls (1.8±2.2 mmHg) (mean±1sd). However, the percent LES relaxation in patients did not differ significantly from controls. Clinical improvement was associated with pharmacological or mechanical reduction of resting LES pressure with an accompanying fall in the nadir pressure. These observations suggest that HLES may have clinical and pathophysiological significance and that evidence for the entity should be sought during manometric studies in the clinical laboratory.     

Lower esophageal sphincter pressure and serum motilin levels

The gastrointestinal hormone motilin has recently been proposed as having a physiological role in the determination of lower esophageal sphincter (LES) strength. The present study was performed to evaluate the effect of gastric alkalinization on LES pressure and serum motilin levels. Instillation of 0.1N NaHCO₃ into the stomach resulted in a significant increase in LES pressure (P<0.01) without affecting serum motilin levels. No correlation was found between fasting serum motilin levels and resting LES pressure (r=?0.31). These observations do not support the theory that LES pressure increases during gastric alkalinization are mediated through motilin release.     

Chocolate and Heartburn: Evidence of Increased Esophageal Acid Exposure after Chocolate Ingestion

Chocolate has been shown to decrease mean basal lower esophageal sphincter (LES) pressure, providing a rationale for the pathogenesis of chocolate-induced reflux symptoms. We assessed the relationship between chocolate ingestion and increased esophageal acid exposure using intraesophageal pH monitoring. Compared with ingestion of a dextrose control solution of similar volume, osmolality, and calories, postprandial ingestion of chocolate resulted in a significant increase in acid exposure in the first postprandial hour in patients with esophagitis. We conclude that this finding supports recommendations that patients with reflux esophagitis abstain from chocolate.