Regulation of basal tone, relaxation and contraction of the lower oesophageal sphincter. Relevance to drug discovery for oesophageal disorders

Abstract

The lower oesophageal sphincter (LOS) is a specialized region of the oesophageal circular smooth muscle that allows the passage of a swallowed bolus to the stomach and prevents the reflux of gastric contents into the oesophagus. The anatomical arrangement of the LOS includes semicircular clasp fibres adjacent to the lesser gastric curvature and sling fibres following the greater gastric curvature. Such anatomical arrangement together with an asymmetric intrinsic innervation and distinct proportion of neurotransmitters in both regions produces an asymmetric pressure profile. The LOS tone is myogenic in origin and depends on smooth muscle properties that lead to opening of L-type Ca(2+) channels; however it can be modulated by enteric motor neurons, the parasympathetic and sympathetic extrinsic nervous system and several neurohumoral substances. Nitric oxide synthesized by neuronal NOS is the main inhibitory neurotransmitter involved in LOS relaxation. Different putative neurotransmitters have been proposed to play a role together with NO. So far, only ATP or related purines have shown to be co-transmitters with NO. Acetylcholine and tachykinins are involved in the LOS contraction acting through acetylcholine M(3) and tachykinin NK(2) receptors. Nitric oxide can also be involved in the regulation of LOS contraction. The understanding of the mechanisms that originate and modulate LOS tone, relaxation and contraction and the characterization of neurotransmitters and receptors involved in LOS function are important to develop new pharmacological tools to treat primary oesophageal motor disorders and gastro-oesophageal reflux disease.

Figures

Figure 1

Schematic representation of the neurotransmitters and K+ channels involved in LOS smooth muscle relaxation. Nitric oxide (NO) released by nerve varicosities activates guanylate cyclase, which increases cGMP levels followed by activation of membrane Cl(Ca) and/or K(Ca) channels, hyperpolarizing the cell and inducing LOS relaxation. Purines (ATP/ADP) can relax LOS by activation of P2Y1 receptor, which is associated with activation of a K(Ca,slow) channel. PACAP may also provoke relaxation by activation of K(Ca,slow) channel acting through an unknown VIP/PACAP receptor. LOS, lower oesophageal sphincter; PACAP, pituitary adenylate cyclase-activating peptide; VIP, vasoactive intestinal polypeptide.

Figure 2

Schematic representation of the neurotransmitters involved in LOS smooth muscle contraction. ACh and tachykinins (substance P, neurokinin A and B) released by nerve varicosities induce LOS contraction by activation of M3 and NK2 receptors respectively. Nitric oxide (NO) can also participate in the LOS contraction by a cGMP pathway. LOS, lower oesophageal sphincter.