Human Lower Esophageal Sphincter Pressure Research Articles

Mechanism of bombesin-induced tonic contraction of the porcine lower esophageal sphincter.

Gastroesophageal reflux disease (GERD) is a disorder that is related to an incompetent lower esophageal sphincter (LES). Previous studies showed that bombesin could increase LES pressure in humans and opossums. The aim of the present study was to characterize the effects of bombesin on porcine LES contraction. We used the selective agonists, neuromedin B (NMB), gastrin-releasing peptide (GRP), and [D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6-14) (DTACPN-BN), as well as receptor antagonists of bombesin receptor subtype 2 (BB2), and 3 (BB3) for ex vivo contraction studies. Atropine, nifedipine, tetrodotoxin, and ω-conotoxin GVIA were used to explore the agonist-induced LES contraction mechanism. Reverse transcription polymerase chain reaction and immunohistochemistry were applied to detect bombesin receptor expression. Our results indicate that GRP and DTACPN-BN, but not NMB, induced tonic contractions of the porcine LES in a dose-dependent manner, and the contractions were inhibited with selective BB2 and BB3 antagonists. The GRP-induced contraction is mainly caused by L-type Ca2+ channel-mediated Ca2+ influx. However, DTACPN-BN-induced contractions are associated with neuronal conduction. RT-PCR and immunohistochemistry revealed that BB2 and BB3 were expressed in the porcine LES. Bombesin-induced tonic contraction of the LES is mediated through BB2 and BB3. Bombesin, BB2, and BB3 agonists might have the potential to treat GERD.

Human lower esophageal sphincter pressure response to increased intra-abdominal pressure

We studied the effects of increased intra-abdominal pressure on the lower esophageal sphincter (LES) pressure in 15 healthy subjects. The role of the diaphragm in the genesis of LES pressure during increased intra-abdominal pressure was determined by measuring diaphragm electromyogram (EMG). The latter was recorded using bipolar intraesophageal platinum electrodes that were placed on the nonpressure sensing surface of the sleeve device. We also measured the LES pressure response to increased intra-abdominal pressure during inhibition of the smooth muscles of the LES by intravenous atropine (12 micrograms/kg). Straight-leg raising and abdominal compression were used to increase intra-abdominal pressure. Our results show that the increase in LES pressure during straight-leg raising is greater than the increase in gastric pressure. During abdominal compression, the rate of LES pressure increase is faster than that of the gastric pressure, suggesting an active contraction at the esophagogastric junction. The increase in LES pressure during periods of increased intra-abdominal pressure is associated with a tonic contraction of the crural diaphragm as demonstrated by EMG recording. Atropine inhibited the resting LES pressure by 50-70% in each subject but had no effect either on the peak LES pressure attained during increased intra-abdominal pressure or tonic crural diaphragm EMG. We conclude that 1) there is an active contraction at the esophagogastric junction during periods of increased intra-abdominal pressure and 2) tonic contraction of the crural diaphragm is a mechanism for this LES pressure response.

Effects of cimetidine and ranitidine on interdigestive and postprandial lower esophageal sphincter pressures and plasma gastrin levels in normal subjects

The purpose of this study was to investigate the effects of cimetidine and ranitidine on human lower esophageal sphincter pressure (LESP) and plasma levels of gastrin in all phases of the interdigestive motor complex and after a test meal. In a random, double-blind manner, placebo, cimetidine (1.0 mg/kg · h), and ranitidine (0.16 mg/kg · h) were administered by intravenous infusion to nine healthy volunteers. By using a sleeve catheter assembly, LESP was constantly monitored, as were esophageal, fundic, antral, and duodenal pressures. Considerable minute-to-minute and interdigestive motor phase-related LESP variations were observed. Cimetidine and ranitidine decreased the interdigestive LESP, but did not abolish the gradual increase in LESP from phase I to phase III. During the first 2 h after the meal, cimetidine and ranitidine had no significant effect on LESP. Plasma gastrin levels were increased by cimetidine and ranitidine, both in the interdigestive and in the postprandial state. The results indicate that the effect of H2-blockers on LESP is not gastrin-mediated. The results further indicate that, in studies on the effects of drugs on LESP, prolonged recording of LESP in all motor states is a prerequisite.

Effect of Thyrotropin-Releasing Hormone on the Human Lower Esophageal Sphincter Pressure

The effect of thyrotropin-releasing hormone (TRH) on the human lower esophageal sphincter pressure (LESP) was studied in eight healthy volunteers. After injection of 200 μg TRH intravenously LESP fell from 10.6 (SD, 1.6) to 6.4 (SD, 2.3) mm Hg after 5 min, to 7.5 (SD, 3.0) mm Hg after 10 min, and to 8.0 (SD, 2.7) mm Hg after 15 min. These data were compared with change in LESP after injection of 0.9% NaCl (no. = 8), and we found significant difference (p < 0.05) in LESP after 5, 10, and 15 min. Whether this response was a direct myogenic effect on the LES or an indirect action via the dopaminergic nerve system requires further investigation.

Human lower esophageal sphincter responses to synthetic human gastrins 34 (G-34) and 17 (G-17)

Gastrin is a potent stimulant of human lower esophageal sphincter pressure (LESP), but previous studies have indicated that G-17 is not likely to be the major physiologic regulator of LESP in humans. The effects of big gastrin (G-34) on human LESP have not been reported previously. This study was conducted to determine the pharmacologic and possible physiologic effects of G-34 on LESP in normal human subjects. Equimolar rapid injections of synthetic human G-17 and G-34 in doses ranging from 6.25 to 100 pmol/kg resulted in similar dose-related increases in LESP that commenced within 2 min after injection of either peptide. After rapid intravenous injection, the threshold change in serum gastrin for stimulation of LESP was more than 100 fmol/ml for both peptides. The LESP returned to baseline within 15 min after G-17, but remained elevated for more than 45 min after G-34. The magnitude of LES responses to equal increments of G-34 was less at 30 min than at 10 min, indicating a loss of sensitivity to this peptide over time. Continuous intravenous infusion of G-34, 100 pmol · kg−1 · hr−1, and of G-17, 200 pmol · kg−1 · hr−1, significantly increased LESP above control values and produced similar peak responses. During G-17 and G-34 infusions, the threshold change in serum gastrin estimated to produce any increase in LESP was 30–50 fmol/ml, half maximal responses were obtained at approximately 140 fmol/ ml, and maximal responses were achieved with increases of 210–290 fmol/ml above baseline values. Intragastric instillation of 10% peptone resulted in a mean peak increase in total gastrin of 58 fmol/ml, well below the change in serum gastrin necessary for half maximal LESP responses. Neither the peptone meal nor the control saline meal produced a significant increase in LESP in these subjects. It is concluded that: (a) circulating G-17 and G-34 have similar potency for stimulation of human LESP, (b) the total change in serum G-17 and G-34 after a peptone meal approached the threshold stimulation of LESP for these forms of gastrin but was accompanied by no significant increase in LESP, and (c) G-17 and G-34 are not likely to be physiologic regulators of the human LES.

The Effect of Oral and Intravenous Metoclopramide on Human Lower Esophageal Sphincter Pressure

Lower esophageal sphincter (LES) pressure was evaluated in response to oral or intravenous metoclopramide in normal subjects and in patients with symptomatic gastroesophageal reflux. Both the oral and intravenous administration of metoclopramide gave a dose-related increase in LES pressure. Complete dose-response curves to the oral compound showed greater absolute responsiveness in normals as compared to patients with LES incompetence. The generally accepted oral dose of 10.0 mg of metoclopramide gave a slight increase in LES pressure which was not consistent in all symptomatic patients. These studies suggest that higher doses of metoclopramide may be required for treating symptomatic gastroesophageal reflux secondary to LES incompetence.