Skip to main content
NCBI home page
Gut logoLink to Gut
. 2000 Jun;46(6):756–761. doi: 10.1136/gut.46.6.756

Neuromuscular function of the human lower oesophageal sphincter in reflux disease and Barrett's oesophagus

S Smid 1, L Blackshaw 1
PMCID: PMC1756439  PMID: 10807884

Abstract

BACKGROUND—Columnar lined (Barrett's) oesophagus is often considered a sequel to chronic severe reflux disease. Aberrant lower oesophageal sphincter (LOS) motility associated with Barrett's oesophagus includes reduced basal LOS pressures. The aim of this study was to characterise neuromuscular function of the LOS in normal (squamous cell carcinoma (SCC) with uninvolved LOS) and reflux affected (Barrett's) oesophagus in vitro.
METHODS—Strips of LOS muscle were prepared at biopsy following oesophagectomy from 16 patients with SCC and seven patients with oesophageal adenocarcinoma and Barrett's oesophagus associated with a history of reflux disease. LOS smooth muscle responses were recorded in response to electrical field stimulation (EFS), potassium chloride (KCl), DMPP, isoprenaline, capsaicin, bethanechol, and tachykinins.
RESULTS—Basal LOS tone and LOS relaxations in response to isoprenaline, EFS, and DMPP were not significantly altered in the Barrett's group. After tetrodotoxin pretreatment, responses to KCl and DMPP were significantly reduced in the SCC but not in Barrett's LOS. Maximal contraction in response to bethanechol was significantly decreased in Barrett's LOS while substance P and NK-2 receptor mediated contraction was unaltered. Capsaicin, NK-1, and NK-3 receptor agonists exerted negligible effects on LOS tone.
CONCLUSIONS—LOS muscle strips from patients with reflux associated Barrett's oesophagus exhibit a reduction in cholinergic muscle contraction while retaining similar features of basal tone, responses to tachykinins, and inhibitory muscle and neural function. Enteric inhibitory neurones in LOS muscle strips from patients with reflux associated Barrett's oesophagus display resistance to axonal sodium channel blockade. No evidence for functional NK-1 or NK-3 receptors or capsaicin sensitive axon collateral reflexes was observed in the human LOS.


Keywords: Barrett's oesophagus; lower oesophageal sphincter; tachykinins; inhibitory motorneurones; tetrodotoxin; smooth muscle

Full Text

The Full Text of this article is available as a PDF (160.7 KB).

Figure 1  .

Figure 1  

Open in a new tab

Concentration-response curve representing contraction in response to bethanechol in squamous cell carcinoma (SCC) and Barrett's lower oesophageal sphincter (LOS) muscle strips, expressed in terms of absolute contraction (B) or relative to maximal contraction in response to the NK-2 receptor agonist [β-Ala8]-neurokinin A 4-10 (A). Contraction was suppressed based on both indices and significantly decreased in the Barrett's group (significant difference in maximal responsiveness: EMAX 264.1 (24)% SCC v 145 (50)% Barrett's,*p<0.05).

Figure 2  .

Figure 2  

Open in a new tab

Concentration-response curve representing absolute contraction in response to the NK-2 receptor agonist [β-Ala8]-neurokinin A 4-10 in squamous cell carcinoma (SCC) and Barrett's lower oesophageal sphincter (LOS) muscle strips. While increased, maximal responsiveness was not significantly altered in Barrett's group.

Figure 3  .

Figure 3  

Open in a new tab

Concentration-response curves showing the response to the non-specific neurokinin receptor agonist substance P in squamous cell carcinoma (SCC) and Barrett's lower oesophageal sphincter (LOS) muscle strips. Substance P elicited modest contraction in LOS muscle strips of approximately 30% of the maximal contraction to the NK-2 receptor agonist [β-Ala8]-neurokinin A 4-10. There was no difference in tension development in the Barrett's or SCC group in response to substance P. 

Figure 4  .

Figure 4  

Open in a new tab

Frequency-response curve representing relaxation in response to electrical field stimulation in squamous cell carcinoma (SCC) and Barrett's lower oesophageal sphincter (LOS) muscle strips. While attenuated at most frequencies, relaxation was not significantly altered in the Barrett's group. Relaxation expressed relative to relaxation induced by a supramaximal concentration of isoprenaline (ISO; 10 µM).

Figure 5  .

Figure 5  

Open in a new tab

Histogram representing lower oesophageal sphincter (LOS) muscle strip relaxation to KCl 20 mM (A) and DMPP 10 µM (B) in the control and Barrett's group, before and after axonal sodium channel blockade with tetrodotoxin (TTX 1 µM). Relaxation expressed relative to relaxation induced by a supramaximal concentration of isoprenaline (10 µM). Muscle strips from Barrett's LOS showed similar degrees of relaxation to either DMPP or KCl compared with controls. Tetrodotoxin significantly inhibited relaxation to DMPP in both groups (**p<0.001 controls, *p<0.05 Barrett's) and inhibited relaxation to KCl in the control (*p<0.05) but not in the Barrett's group.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akopian A. N., Sivilotti L., Wood J. N. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature. 1996 Jan 18;379(6562):257–262. doi: 10.1038/379257a0. [DOI] [PubMed] [Google Scholar]
  2. Allescher H. D., Berezin I., Jury J., Daniel E. E. Characteristics of canine lower esophageal sphincter: a new electrophysiological tool. Am J Physiol. 1988 Oct;255(4 Pt 1):G441–G453. doi: 10.1152/ajpgi.1988.255.4.G441. [DOI] [PubMed] [Google Scholar]
  3. Beveridge A. A., Taylor G. S. Evidence for a lower oesophageal sphincter in the guinea-pig. Comp Biochem Physiol C. 1989;93(2):293–301. doi: 10.1016/0742-8413(89)90236-3. [DOI] [PubMed] [Google Scholar]
  4. Biancani P., Billett G., Hillemeier C., Nissensohn M., Rhim B. Y., Szewczak S., Behar J. Acute experimental esophagitis impairs signal transduction in cat lower esophageal sphincter circular muscle. Gastroenterology. 1992 Oct;103(4):1199–1206. doi: 10.1016/0016-5085(92)91504-w. [DOI] [PubMed] [Google Scholar]
  5. Biancani P., Harnett K. M., Sohn U. D., Rhim B. Y., Behar J., Hillemeier C., Bitar K. N. Differential signal transduction pathways in cat lower esophageal sphincter tone and response to ACh. Am J Physiol. 1994 May;266(5 Pt 1):G767–G774. doi: 10.1152/ajpgi.1994.266.5.G767. [DOI] [PubMed] [Google Scholar]
  6. Dodds W. J., Dent J., Hogan W. J., Arndorfer R. C. Effect of atropine on esophageal motor function in humans. Am J Physiol. 1981 Apr;240(4):G290–G296. doi: 10.1152/ajpgi.1981.240.4.G290. [DOI] [PubMed] [Google Scholar]
  7. Goldstein S. R., Yang G. Y., Curtis S. K., Reuhl K. R., Liu B. C., Mirvish S. S., Newmark H. L., Yang C. S. Development of esophageal metaplasia and adenocarcinoma in a rat surgical model without the use of a carcinogen. Carcinogenesis. 1997 Nov;18(11):2265–2270. doi: 10.1093/carcin/18.11.2265. [DOI] [PubMed] [Google Scholar]
  8. Huber O., Bertrand C., Bunnett N. W., Pellegrini C. A., Nadel J. A., Nakazato P., Debas H. T., Geppetti P. Tachykinins mediate contraction of the human lower esophageal sphincter in vitro via activation of NK2 receptors. Eur J Pharmacol. 1993 Aug 3;239(1-3):103–109. doi: 10.1016/0014-2999(93)90982-n. [DOI] [PubMed] [Google Scholar]
  9. Kortezova N., Velkova V., Mizhorkova Z., Bredy-Dobreva G., Vizi E. S., Papasova M. Participation of nitric oxide in the nicotine-induced relaxation of the cat lower esophageal sphincter. J Auton Nerv Syst. 1994 Dec 1;50(1):73–78. doi: 10.1016/0165-1838(94)90124-4. [DOI] [PubMed] [Google Scholar]
  10. Li H., Walsh T. N., O'Dowd G., Gillen P., Byrne P. J., Hennessy T. P. Mechanisms of columnar metaplasia and squamous regeneration in experimental Barrett's esophagus. Surgery. 1994 Feb;115(2):176–181. [PubMed] [Google Scholar]
  11. Lidums I., Checklin H., Mittal R. K., Holloway R. H. Effect of atropine on gastro-oesophageal reflux and transient lower oesophageal sphincter relaxations in patients with gastro-oesophageal reflux disease. Gut. 1998 Jul;43(1):12–16. doi: 10.1136/gut.43.1.12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lidums I., Holloway R. Motility abnormalities in the columnar-lined esophagus. Gastroenterol Clin North Am. 1997 Sep;26(3):519–531. doi: 10.1016/s0889-8553(05)70311-3. [DOI] [PubMed] [Google Scholar]
  13. Liebermann-Meffert D., Allgöwer M., Schmid P., Blum A. L. Muscular equivalent of the lower esophageal sphincter. Gastroenterology. 1979 Jan;76(1):31–38. [PubMed] [Google Scholar]
  14. Niemantsverdriet E. C., Timmer R., Breumelhof R., Smout A. J. The roles of excessive gastro-oesophageal reflux, disordered oesophageal motility and decreased mucosal sensitivity in the pathogenesis of Barrett's oesophagus. Eur J Gastroenterol Hepatol. 1997 May;9(5):515–519. doi: 10.1097/00042737-199705000-00019. [DOI] [PubMed] [Google Scholar]
  15. Preiksaitis H. G., Diamant N. E. Regional differences in cholinergic activity of muscle fibers from the human gastroesophageal junction. Am J Physiol. 1997 Jun;272(6 Pt 1):G1321–G1327. doi: 10.1152/ajpgi.1997.272.6.G1321. [DOI] [PubMed] [Google Scholar]
  16. Preiksaitis H. G., Tremblay L., Diamant N. E. Cholinergic responses in the cat lower esophageal sphincter show regional variation. Gastroenterology. 1994 Feb;106(2):381–388. doi: 10.1016/0016-5085(94)90596-7. [DOI] [PubMed] [Google Scholar]
  17. Rakic S., Stein H. J., DeMeester T. R., Hinder R. N. Role of esophageal body function in gastroesophageal reflux disease: implications for surgical management. J Am Coll Surg. 1997 Oct;185(4):380–387. [PubMed] [Google Scholar]
  18. Richardson B. J., Welch R. W. Differential effect of atropine on rightward and leftward lower esophageal sphincter pressure. Gastroenterology. 1981 Jul;81(1):85–89. [PubMed] [Google Scholar]
  19. Riddell R. H. Early detection of neoplasia of the esophagus and gastroesophageal junction. Am J Gastroenterol. 1996 May;91(5):853–863. [PubMed] [Google Scholar]
  20. Smid S. D., Lynn P. A., Templeman R., Blackshaw L. A. Activation of non-adrenergic non-cholinergic inhibitory pathways by endogenous and exogenous tachykinins in the ferret lower oesophageal sphincter. Neurogastroenterol Motil. 1998 Apr;10(2):149–156. doi: 10.1046/j.1365-2982.1998.00092.x. [DOI] [PubMed] [Google Scholar]
  21. Smid S. D., Page A. J., O'Donnell T., Langman J., Rowland R., Blackshaw L. A. Oesophagitis-induced changes in capsaicin-sensitive tachykininergic pathways in the ferret lower oesophageal sphincter. Neurogastroenterol Motil. 1998 Oct;10(5):403–411. doi: 10.1046/j.1365-2982.1998.00118.x. [DOI] [PubMed] [Google Scholar]
  22. Sohn U. D., Harnett K. M., Cao W., Rich H., Kim N., Behar J., Biancani P. Acute experimental esophagitis activates a second signal transduction pathway in cat smooth muscle from the lower esophageal sphincter. J Pharmacol Exp Ther. 1997 Dec;283(3):1293–1304. [PubMed] [Google Scholar]
  23. Stein H. J., Hoeft S., DeMeester T. R. Functional foregut abnormalities in Barrett's esophagus. J Thorac Cardiovasc Surg. 1993 Jan;105(1):107–111. [PubMed] [Google Scholar]
  24. Stein H. J., Liebermann-Meffert D., DeMeester T. R., Siewert J. R. Three-dimensional pressure image and muscular structure of the human lower esophageal sphincter. Surgery. 1995 Jun;117(6):692–698. doi: 10.1016/s0039-6060(95)80014-x. [DOI] [PubMed] [Google Scholar]
  25. Tanaka M., Cummins T. R., Ishikawa K., Dib-Hajj S. D., Black J. A., Waxman S. G. SNS Na+ channel expression increases in dorsal root ganglion neurons in the carrageenan inflammatory pain model. Neuroreport. 1998 Apr 20;9(6):967–972. doi: 10.1097/00001756-199804200-00003. [DOI] [PubMed] [Google Scholar]
  26. Triadafilopoulos G., Kaczynska M., Iwane M. Esophageal mucosal eicosanoids in gastroesophageal reflux disease and Barrett's esophagus. Am J Gastroenterol. 1996 Jan;91(1):65–74. [PubMed] [Google Scholar]
  27. Trimble K. C., Pryde A., Heading R. C. Lowered oesophageal sensory thresholds in patients with symptomatic but not excess gastro-oesophageal reflux: evidence for a spectrum of visceral sensitivity in GORD. Gut. 1995 Jul;37(1):7–12. doi: 10.1136/gut.37.1.7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tøttrup A., Forman A., Madsen G., Andersson K. E. The actions of some beta-receptor agonists and xanthines on isolated muscle strips from the human oesophago-gastric junction. Pharmacol Toxicol. 1990 Oct;67(4):340–343. doi: 10.1111/j.1600-0773.1990.tb00841.x. [DOI] [PubMed] [Google Scholar]
  29. Tøttrup A., Forman A., Uldbjerg N., Funch-Jensen P., Andersson K. E. Mechanical properties of isolated human esophageal smooth muscle. Am J Physiol. 1990 Mar;258(3 Pt 1):G338–G343. doi: 10.1152/ajpgi.1990.258.3.G338. [DOI] [PubMed] [Google Scholar]
  30. Tøttrup A., Ny L., Alm P., Larsson B., Forman A., Andersson K. E. The role of the L-arginine/nitric oxide pathway for relaxation of the human lower oesophageal sphincter. Acta Physiol Scand. 1993 Dec;149(4):451–459. doi: 10.1111/j.1748-1716.1993.tb09642.x. [DOI] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES