The lower Esophageal Sphincter: LES

The LES provides a pressure barrier between the esophagus and stomach. Although an anatomically distinct LES has been difficult to identify, microdissection studies show that, in humans, the sphincterlike function is related to the architecture of the muscle fibers at the junction of the esophageal tube with the gastric pouch. The sphincter actively remains closed to prevent reflux of gastric contents into the esophagus and opens by a relaxation that coincides with a pharyngeal swallow . The LES pressure returns to its resting level after the peristaltic wave has passed through the esophagus. Consequently, reflux of gastric juice that may occur through the open valve during a swallow is cleared back into the stomach.
If the pharyngeal swallow does not initiate a peristaltic contraction, then the coincident relaxation of the LES is unguarded and reflux of gastric juice can occur. This may be an explanation for the observation of spontaneous LES relaxation, thought by some to be a causative factor in gastroesophageal reflux disease (GERD). The power of the esophageal body is insufficient to force open a valve that does not relax. The relaxation of the LES that occurs with pharyngeal swallowing or distention of the esophagus is mediated by parasympathetic activity. Consequently, vagal function appears to be important in coordinating the relaxation of the LES with esophageal contraction.
The LES has intrinsic myogenic tone, which is modulated by neural and hormonal mechanisms. Alpha-adrenergic neurotransmitters or beta-blockers stimulate the LES, and alpha blockers and beta stimulants decrease its pressure. It is not clear to what extent cholinergic nerve activity controls LES pressure. The vagus nerve carries both excitatory and inhibitory fibers to the esophagus and sphincter. The hormones gastrin and motilin have been shown to increase LES pressure; and cholecystokinin, estrogen, glucagon, progesterone, somatostatin, and secretin decrease LES pressure. The peptides bombesin, B-enkephalin, and substance P increase LES pressure; and calcitonin gene-related peptide, gastric inhibitory peptide, neuropeptide Y, and vasoactive intestinal polypeptide decrease LES pressure. Some pharmacologic agents such as antacids, cholinergics, domperidone, metoclopramide, and prostaglandin F2 are known to increase LES pressure; and anticholinergics, barbiturates, calcium channel blockers, caffeine, diazepam, dopamine, meperidine, prostaglandin E1 and E2, and theophylline decrease LES pressure. Peppermint, chocolate, coffee, ethanol, and fat are all associated with decreased LES pressure and may be responsible for esophageal symptoms after a sumptuous meal.
During 24-hour esophageal pH monitoring, healthy individuals have occasional episodes of GE reflux. This physiologic reflux is more common when a person is awake and in the upright position than during sleep in the supine position. When reflux of gastric juice occurs, normal subjects rapidly clear the acid gastric juice from the esophagus regardless of their position.

Adrenergic drugs and acid reflux

The lower esophageal sphincter is a physiological sphincter acting like a valve. It is a ring of smooth muscle fibers at the junction of the esophagus and stomach.
As the stomach generates strong acids and enzymes to aid in food digestion; it is protected at the same time by virtue of its inner lining which has several mechanisms to resist the effect of gastric juice on itself. On the other hand the mucosa of the esophagus does not have these protective mechanisms. Fortunately the esophagus is normally protected from these acids by this one-way valve mechanism at its junction with the stomach i.e. lower esophageal sphincter (LES), which prevents gastric juice from flowing back into the esophagus.
During peristalsis, the LES allows the food bolus to pass into the stomach. It prevents chyme (a mixture of bolus, stomach acid, and digestive enzymes) from returning up the esophagus. The LES is aided in the task of keeping the flow of materials in one direction by external supportive muscle fibers derived from the diaphragm.
Contraction of smooth muscle fibers of the lower esophageal sphincter is controlled by many factors, of which the adrenergic receptors are of utmost importance.
A receptor is a molecule on the surface of the smooth muscle cell that recognizes and binds with specific molecules, producing some effect in the cell. The cell is called the effector as it performs the action dictated by a signal released following stimulation of the specified receptor.
The term adrenergic means having physiological effects similar to those of epinephrine, a hormone and neurotransmitter released at the nerve endings in contact with smooth muscle fibers.
Receptors are named after the action of epinephrine, the alternative name for adrenaline. Alpha receptors, which are stimulated by norepinephrine and blocked by agents such as phenoxybenzamine, produce contraction of the smooth muscles of the sphincter. Beta receptors, which are stimulated by epinephrine and blocked by agents such as propranolol, produce smooth muscle relaxation.
The term adrenergic is also used for drugs, which have effects similar to, or the same as, epinephrine (adrenaline). Adrenergic drugs that stimulate a response are called (agonists) and those that inhibit a response called (antagonists).
Accordingly, Alpha Adrenergic Agonists produce contraction of the lower esophageal sphincter and Beta Adrenergic Agonists are associated with relaxation of the sphincter and trigger reflux.
On the contrary, Alpha Adrenergic Antagonists produce sphincter relaxation and Beta Adrenergic Antagonists increase lower esophageal sphincter pressure.
Alpha blockers and beta-agonists are directly related to relaxation of the LES and acid reflux.
Alpha blockers ( alpha-adrenergic blocking agents) constitute a variety of drugs which block alpha-adrenergic receptors in arteries and smooth muscles.
These drugs may be used to treat:
benign prostatic hyperplasia (BPH)
high blood pressure (hypertension).
symptoms of non inflammatory chronic pelvic pain syndrome.
Examples include:
Doxazosin (Cardura)
Prazosin (Minipress)
Phenoxybenzamine
Phentolamine (Regitine)
Tamsulosin (Flomaxtra/Flomax)
Alfuzosin (Uroxatral)
Terazosin (Hytrin)
Beta adrenergic receptor agonists are a class of drugs used to treat asthma and other pulmonary disease states.
They act on the beta-adrenergic receptor, thereby causing smooth muscle relaxation resulting in dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle and release of insulin. All beta agonists are available in inhaler form (either metered-dose inhalers, which aerosolize the drug, or dry powder which can be breathed in).
In addition, several of these medications are available in intravenous forms including both salbutamol and terbutaline. It can be used in this form in severe cases of asthma, but more commonly it is used to suppress premature labor because it also relaxes uterine muscle, thereby inhibiting contractions.
Examples include:
salbutamol (albuterol)
levalbuterol
terbutaline
pirbuterol
procaterol
metaproterenol
fenoterol
bitolterol mesylate
In patients with acid reflux disease, drug history should be reviewed to detect any of these drugs associated with sphincter relaxation. The physician, would evaluate the medical background and reconsider all medications given.