Is the hormonal regulation of the lower esophageal sphincter function known ?

M. Mignon, G. Cadiot, E. Malikova (Paris)

The answer to this question must be no : indeed, although many peptides have demonstrated a pharmacological effect on the lower esophageal sphincter (LES), none of them has been found to exert a definite physiological control on the sphincteric function [1]. It must be remembered, however, that to be classified as physiological, any hormonal action must satisfy the following requirements :

a) a significant correlation must exist between any modification of LES pressure and any variation in serum hormone concentration during physiological stimulation (e.g. meal).

b) continuous perfusion of the putative hormone to a level equivalent to physiological concentration in the serum must reproduce the physiological action of the hormone on LES function.

However, these perequisites do not take into account, either the possible paracrine

or neurocrine interaction of peptides, or the role, yet unexplored, of the intermediate products of peptides metabolism. The study of the effects of the administration of specific antibodies directed against hormones may in the future bring new insight in the hormonal aspect of LES function regulation.

It seems currently accepted that the resting tone of LES is secondary to both myogenous and neurogenous mechanisms. It is also accepted that LES relaxation, whether it is spontaneous or evoked by swallowing or esophageal distension, is mediated essentially by neurogenous phenomena. According to this theoretical schematisation, peptides can only exert a modulating effect, acting either at the muscular level itself or at the neurotransmission mechanism (interfering for instance with the non-adrenergic non-cholinergic inhibitory neurons). The effects of various peptides and neuro-transmitters on LES function are summarized in Table 1.

Table 1. Effects of various peptides and neurotransmitters on LES pressure in man

	Increase in pressure	Decrease in pressure
	Gastrin	Cholecystokinin
	Motilin	Secretin
	Substance P	Glucagon
	Bombesin	VIP, PHI
	Galanin	Gastric Inhibitory Peptide
	Pancreatic polypeptide	Somatostatin
		Calcitonin-gene related peptide
		TRH
		Opioids

In the human, the lower esophagus contains numerous nervous fibers containing VIP, substance P, enkephalins and the neuropeptide PYY. These peptides are potential neuro-transmitters [2, 3]. Several arguments support strongly a physiological role for VIP [4] and substance P [5, 6] in LES pressure regulation.

In addition, motilin could as well be responsible for LES contractions noted during interdigestive phases II and III of the migrating motor complex [7].

References

1. Christensen J (1987) Motor functions of the pharynx and esophagus. Physiology of the gastrointestinal tract. LR Johnson Ed. Raven Press. New York : 595-612.

2. Aggestrup S, Uddman R, Jensen SL, Sundler F, Schaffalitzky de Muckadell O, Hoist JJ, Hakanson R, Ekman R, Sorensen HR (1985) Regulatory peptides in the lower esophageal sphincter of man. Regulatory peptides 10: 167-178.

3. Wattchow DA, Furness JB, Costa M, O'Brien PE, Peacock M (1987) Distributions of neuropeptides in the human esophagus. Gastroenterology 93 : 1363-1371.

4. Goyal RK, Rattan S (1980) VIP as a possible neurotransmitter of non-cholinergic non adrenergic inhibitory neurones. Nature 228 : 378-380.

5. Reynolds JC, Ouyang A, Cohen S (1984) A lower esophageal sphincter reflex involving substance P. Am J Physiol 246 : G346-G354.

6. Sandier A, Maher J, Weinstock J, Schlegel J, Williams T (1989) Substance P in the canine distal esophagus. Gastroenterology 96 : A439.

7. Holloway RH, Blank E, Takahashi I, Dodds WJ, Layman RD (1985) Motilin: a mechanism incorporating motor complex. Gastroenterology 89 : 507-515.