Central control of lower esophageal sphincter relaxation

doi:10.1016/S0002-9343(99)00345-9

The American Journal of Medicine

Volume 108, Issue 4, Supplement 1, 6 March 2000, Pages 90-98

https://doi.org/10.1016/S0002-9343(99)00345-9 Get rights and content

Abstract

The lower esophageal sphincter is innervated by both parasympathetic (vagus) and sympathetic (primarily splanchnic) nerves; however, the vagal pathways are the ones that are essential for reflex relaxation of the lower esophageal sphincter (LES), such as that which occurs during transient LES relaxations. Vagal afferent sensory endings from the distal esophagus and LES terminate in the hindbrain nucleus tractus solitarius. The preganglionic motor innervation of the LES arises from the dorsal motor nucleus of the vagus. Together these nuclei comprise the dorsal vagal complex within which there is a neural network coordinating reflex control of the sphincter. Vagal efferent preganglionic neurons to the gastrointestinal tract are organized viscerotopically in the dorsal motor nucleus of the vagus. Stimulation of the dorsal motor nucleus of the vagus caudal to the opening of the fourth ventricle results in relaxations, whereas stimulation in the rostral portion of the nucleus evokes contractions of the LES. Few details are known about the neural circuitry that links sensory information from the stomach and esophagus within the nucleus tractus solitarius to these separate populations of neurons within the dorsal motor nucleus of the vagus. The motor vagal preganglionic output is primarily cholinergic, which ultimately stimulates excitatory or inhibitory motor neurons that control the smooth muscle tone. Excitatory neurons evoke muscarinic receptor–mediated muscle contraction. Inhibitory neurons evoke nitric oxide or vasoactive intestinal polypeptide–mediated relaxation of the lower esophageal sphincter. However, other neurotransmitters are found in vagal preganglionic neurons, including norepinephrine/dopamine and nitric oxide. A subpopulation of nitric oxide synthase–containing vagal preganglionic neurons innervate the upper gastrointestinal tract and mediate relaxation. The neurotransmitters and circuitry controlling lower esophageal sphincter pressure are important to characterize, because part of the dorsal vagal complex is outside of the blood–brain barrier and is a potential target for pharmacologic intervention in the treatment of such disorders as gastroesophageal reflux disease.

Section snippets

Central sensory–motor interfaces that control the LES and swallowing

Recently, interest has focused on the central nervous system for the study of extrinsic control of gastrointestinal function. The center of the integration of vagal control of the LES is the dorsal vagal complex, which is located in the dorsomedial hindbrain medulla. The term “dorsal vagal complex” comprises the nucleus tractus solitarius and the dorsal motor nucleus of the vagus, which contains preganglionic motor neurons. The dorsal vagal complex is actually a complex of many subnuclei

The sensory–motor interface as a target for therapeutic intervention

How does knowledge of the neural circuitry controlling LES in the hindbrain translate into insights into treatment of disorders? The gastrointestinal-related neurocircuitry in the brain appears to have evolved in such a way as to listen to neural and circulating messages derived from the gut. For example, it now is evident that many gastrointestinal peptides released in response to food intake can act directly in the dorsal vagal complex to modulate gastrointestinal function.65, 66, 67

Summary

We still do not know the details of the integration within the dorsal vagal complex that controls LES relaxation. It is likely that information from the stomach, buccopharynx, and esophagus is integrated at the level of the hindbrain in order to modulate normal LES control, but how all these different pathways interconnect within subnuclei is unknown. What we have discussed in this review is that feedback from gastric, esophageal, and pharyngeal stimulation reaches the nucleus tractus

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Citation Excerpt :
In a similar manner to the gastrointestinal tract, coordinated esophageal motility is considered to be regulated by a close network among enteric neurons, interstitial cells of Cajal (ICCs) and smooth muscle cells, with the smooth muscle part responsible for the actual output of contractile and relaxant responses (Ward and Sanders, 2001). The action of swallowing has been shown to stimulate the afferent and efferent vagal nerves (Hornby and Abrahams, 2000). Indeed, stimulation of the nicotinic acetylcholine receptor is responsible for relaxation of the LES (Kadakia et al., 1996; Ruggieri et al., 2014).
The interstitial cells of Cajal (ICCs) play an important role in coordinated gastrointestinal motility. The present study aimed to elucidate whether or how ICCs are involved in the lower esophageal sphincter (LES) relaxation induced by stimulation of the nicotinic acetylcholine receptor. The application of 1,1-dimethyl-4-phenyl-piperazinium (DMPP; a nicotinic acetylcholine receptor agonist) induced a transient relaxation in the circular smooth muscle of the porcine LES. DMPP-induced relaxation was abolished by not only 1 μM tetrodotoxin but also the inhibition of ICC activity by pretreatment with 100 μM carbenoxolone (a gap junction inhibitor), pretreatment with 100 μM CaCCinh-A01 (an anoctamin-1 blocker acting as a calcium-activated chloride channel inhibitor), and pretreatment with Cl⁻-free solution. However, pretreatment with 100 μM N^ω-nitro-L-arginine methyl ester had little effect on DMPP-induced relaxation. Furthermore, DMPP-induced relaxation was inhibited by pretreatment with 1 mM suramin, a purinergic P2 receptor antagonist, but not by 1 μM VIP (6–28), a vasoactive intestinal peptide (VIP) receptor antagonist. Stimulation of the purinergic P2 receptor with adenosine triphosphate (ATP) induced relaxation, which was abolished by the inhibition of ICC activity by pretreatment with CaCCinh-A01. In conclusion, membrane hyperpolarization of the ICCs via the activation of anoctamin-1 plays a central role in DMPP-induced relaxation. ATP may be a neurotransmitter for inhibitory enteric neurons, which stimulate the ICCs. The ICCs act as the interface of neurotransmission of nicotinic acetylcholine receptor in order to induce LES relaxation.
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^☆: Supported by PHS Grant DK42714 (PJH) from the National Institutes of Health (Washington, DC, USA) and, in part, by an Astra Zeneca (Mölndal, Sweden) collaborative joint venture grant (PJH and TPA).

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Sensory Physiology of the EsophagusCentral control of lower esophageal sphincter relaxation☆

Abstract

Section snippets

Central sensory–motor interfaces that control the LES and swallowing

The sensory–motor interface as a target for therapeutic intervention

Summary

Gastroenterology

Gastroenterology

Gastroenterol Clin North Am

Gastroenterology

J Auton Nerv Syst

Gastroenterology

J Auton Nerv Syst

Brain Res

J Auton Nerv Syst

Gastroenterology

Arch Pediatr

J Auton Nerv Syst

Gastroenterology

Brain Res

Gastroenterology

Neuropharmacology

Brain Res Bull

Neuropharmacology

Brain Res Mol Brain Res

Neuropharmacology

Neuropharmacology

Gastroenterology

Brain Res

Gastroenterology

Gastroenterology

Gastroenterology

J Auton Nerv Syst

J Auton Nerv Syst

Brain Res Bull

Exp Neurol

Influence of breathing pattern on the esophagogastric junction pressure and esophageal transit

Am J Physiol

Characterization of neuropeptide Y (NPY) receptors in human cerebral arteries with selective agonists and the new Y1 antagonist BIBP 3226

Br J Pharmacol

Limited excitatory local effector function of gastric vagal afferent intraganglionic terminals in rats

Am J Physiol

Experimental induction of isolated lower esophageal sphincter relaxation in anesthetized opposums

J Clin Invest

Sensory Physiology of the Esophagus
Central control of lower esophageal sphincter relaxation☆