Ann Oto184: 1975

PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE LOWER ESOPHAGEAL SPHINCTER CAPT. DONALD

O.

CASTELL, MC

USN

BETHESDA,~ARYLAND

SU~~ARY - The physiologic factors controlling lower esophageal sphincter (LES) function are interrelated in a complex fashion and include the autonomic nerve supply, gastrointestinal hormones, and specific characteristics of the circular smooth muscle at the esophagogastric junction. It might be expected that a defect in any of these three controlling mechanisms would result in a clinically recognizable symptom complex. Abnormalities with either high or low LES pressure have been shown to relate to these specific aspects. Studies of the effects of various foods and other agents which decrease or increase LES pressure are of therapeutic interest in relating to patients with reflux symptoms. Decreases in LES pressure occurring after fat ingestion may explain a mechanism for many cases of fatty food intolerance. Pressure decreases after chocolate ingestion, after smoking, and after alcohol all have strong therapeutic implications in patients with chronic heartburn. Gastric alkalinization will increase pressure for up to one hour in patients with basal sphincter hypotension and reflux symptoms. Recent studies with drugs that work through the cholinergic mechanism have important therapeutic considerations. Anticholinergic agents produce definite decreases in LES l?ressure and are to be avoided in treatment of patients with reflux symptoms. On the other hand cholinergic drugs such as bethanechol have been shown to increase LES pressure in normal subjects and in patients with chronic sphincter incompetence. Recently, a double-blind therapeutic trial with bethanechol in patients with chronic heartburn has indicated that this drug, when given on a regular basis, is an effective adjunct to therapy in these patients.

Although a specific muscular structure defining the sphincteric mechanism at the esophagogastric junction has never been identified anatomically in man, there is no question that such a sphincter exists functionally. This lower esophageal sphincter (LES) is readily identified both manometrically and radiographically. The past few years have seen a remarkable information explosion relative to physiology and pathophysiology of this smooth muscle structure. This new information has resulted in major changes in our understanding of esophageal disease and its therapy. It is now clear that the LES performs two major functions in digestive physiology: 1) relaxation from its usually tonic state during swallowing to allow free passage of ingested material from

esophagus to stomach, and 2) maintenance of an effective high pressure zone preventing the reflux of acid gastric material from the stomach to the esophagus. It might be anticipated that a defect in either one of these normal functions of the LES would be manifest in a clinically recognizable disorder. PHYSIOLOGIC CONTROLS OF LFS FUNCJ:ION

Through refinements in manometric techniques and the use of animal models, the factors of importance in normal control of the function of the LES have been clarified. Three major components have been identified to be crucial in regulation of sphincter function: the nervous supply to the sphincter muscle; gastrointestinal hormones, particularly gastrin; and the intrinsic

From the Clinical Investigation Center and Gastroenterology Division, Internal Medicine Service, U.S. Naval Hospital, Philadelphia, Pennsylvania 19145. This work was supported by Bureau of Medicine and Surgery Clinical Investigation Program # 5-05-530R. Presented at the meeting of the American Broncho-Esophagological Association, Atlanta, Georgia, April 7-8, 1975. 569

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DONALD O. CASTELL

sphincteric smooth muscle itself. Studies using either in vitro smooth muscle preparations or in vivo animal experiments in the cat or opossum have revealed that the circular smooth muscle at the esophagogastric junction is indeed unique in its ability to respond to pharmacologic and hormonal stimulation.l-" Thus, although a definite anatomic sphincter has not been identified at the distal end of the esophagus, chemical identification of a unique muscle segment has been shown. The full details of the neural control of LES function remain to be elucidated. One clear observation from numerous studies is that vagotomy, whether intraabdominal or cervical does not result in a change in resting LES pressure.i'-" This observation at least suggests that the parasympathetic nervous system has little effect in maintenance of the resting tone of the LES. However, pharmacologic doses of cholinergic or anticholinergic compounds markedly raise or lower LES pressure respectively.P-" Further studies with cervical vagotomy in the opossum have revealed that stimulation of the distal end of the transected vagus produces LES relaxation.' This observation indicates that LES inhibitory tracts are contained within the vagus nerve. Additional studies in man and cats have revealed supersensitivity to both a cholinomimetic agent and to pentagastrin after truncal vagotomy at the esophagogastric junction, possibly due to release from these inhibitory pathways." Studies in the opossum have revealed that the sympathetic nervous system may account for a portion of the resting tone of the LES, and that the alphaadrenergic portion of this system exerts a major effect," Finally, recent observations in animal models suggest that nonadrenergic inhibitory fibers (the so-called purinergic nervous systern) may be responsible for the normal relaxation of the LES during swallowing.?

In 1970 the effect of pentagastrin on this sphincteric mechanism was first shown.!" Following the injection of

Fig. 1. Schematic representation of the interaction of gastrin and secretin on the lower esophageal sphincter (LES) and gastric acid (H +) production.

pentagastrin, marked increases in lower esophageal sphincter pressure occurred in normal subjects. Other studies indicated that not only did exogenous pentagastrin affect this sphincter, but the stimulation of the release of endogenous gastrin from the gastric antrum, would also increase pressure in this area.'! Numerous studies have been performed on the effect of gastrointestinal hormones on the LES. It is now clear that pharmacologic doses of gastrin will increase LES pressure, but to date this is the only hormone that has been shown to result in increases in sphincter pressure. Subsequent studies have demonstrated that besides gastrin other gastrointestinal hormones, particularly secretin, may affect this sphincter.P These interrelationships are shown schematically in Figure 1. The effect of secretin in blocking the gastrin stimulatory effect on the sphincter is illustrated. This is not surprising, since secretin is a known inhibitor of gastric acid stimulation by gastrin. The hormones cholecystokinin and glucagon have also been studied, and both result in decreases in sphincter pressure, with the mechanism apparently due to competitive inhibition of gastrin stimulation.Pi'"

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LOWER ESOPHAGEAL SPHINCTER

TABLE I CLINICAL DISORDERS OF LES FUKCTION

Disorder

LES Pressure (mmHg)

Normal Achalasia

40-60

Proposed Defect

15-20

Scleroderma Zollinger-Ellison Syndrome