The Esophagus. Группа авторов

Figure 5.15 Lower esophageal sphincter (LES) radial muscle thickness and 3D manometric pressure image. Radial thickness shown in millimeters is on the left, and the 3D pressure image in mmHg is plotted on the right around an axis representing atmospheric pressure. The thickest portion of the LES and highest pressure are seen on the left lateral side. GC, greater curve; LC, lesser curve; PW, posterior wall; AW, anterior wall.

      Source: Stein et al. [312] with permissions of Elsevier.

      The sling contraction and the normal position of the stomach, with its fundus projecting upward under the left diaphragm, act to form an acute angle where the left lateral wall of the esophagus meets the medial aspect of the dome of the stomach, the angle of His. The LES portion of the distal esophagus tends to angle obliquely and to the left to meet the stomach wall. Viewed from the gastric lumen, this region can be seen as a fold or ridge that has been considered as a flap valve if compressed against the LES opening [302]. As one contributing factor, if the angle of His is less acute, such as with a hiatus hernia or after distal gastrectomy, gastroesophageal reflux is more likely to occur [303–306]. A longitudinal smooth muscle layer covers the sphincter region.

      As in the esophageal body, LES circular muscle is formed into bundles separated by connective tissue. The LES cells are somewhat larger and the connective tissue lamina more numerous than in the esophageal body [307]. ICCs are present in both circular and longitudinal muscle layers [158, 159, 308, 309]. Their role as either mechanical receptors and/or transducers of neural input to the smooth muscle cells remains uncertain [308, 310, 311].

The LES receives preganglionic vagal fibers from the DMNV in the brainstem SPG. These fibers enter the esophagus up to 9 cm or more proximal to the LES [313, 314] and synapse on excitatory and inhibitory neurons [30, 32]. Central SPG preganglionic fibers to the LES are also linked to sensory information from the fundus [30]. As in the esophageal body, the neurons have a number of peptides and potential neurotransmitters [315]. However, normal muscle excitation is primarily cholinergic, and inhibition is nitrergic, although the neurons also contain VIP. A VIP or other peptide‐mediated component of inhibition may be present under certain circumstances [248, 308, 310,316–319]. Nitrergic innervation and its effect are greatest in the circular clasp muscle [320, 321]. The inhibitory neurons receive input from the vagus, esophageal body, and gastric fundus, and the clasp and sling are separately innervated [30, 322]. Sympathetic innervation to the LES arrives from the stellate ganglion and from the sympathetic chain via the splanchnic nerve after passing through the celiac ganglion. This innervation excites the muscle directly and through stimulation of acetylcholine release from cholinergic postganglionic nerves while inhibiting the inhibitory innervation, all by alpha‐receptor activation [152, 323, 324]. There is some beta‐receptor–mediated inhibition of the muscle, with its effect species‐dependent and of uncertain importance [151, 323, 325].

      Activation of the excitatory and inhibitory neurons in the myenteric plexus is primarily through cholinergic nicotinic receptors, and the inhibitory neuron to a lesser extent by a muscarinic M₁ receptor. Both may be activated directly or indirectly by other neurotransmitters, and these activations can have clinical implications. The inhibitory neuron can be activated directly by serotonin [326], but the importance of this is uncertain and by cholecystokinin (CCK) [327–329]. CCK excitation of the excitatory neuron can occur by stimulation of preganglionic nerve structures [329].

      There appear to be two vagal pathways to the LES. The first pathway is tonically active and likely excitatory to help maintain resting tone; this discontinues with a swallow. The other pathway is quiescent at rest and activates with a swallow, presumably to stimulate inhibitory neurons for LES relaxation [330, 331]. The inhibitory pathway within the esophageal body to the LES is paucisynaptic and can extend over long sections of the esophageal body [175].

      Functional motor activity

      The LES is tonically closed at rest and maintains a basal resting pressure. The sphincter must relax and open to allow the esophageal bolus to pass into the stomach and to permit retrograde passage with belching and vomiting. LES relaxation occurs with virtually all swallows, even when peristalsis fails to occur. Similarly, distention in the esophagus and secondary peristalsis are associated with LES relaxation. The interactive central and peripheral mechanisms producing the relaxation are related to the mechanisms involved with the production of primary and secondary peristalsis [332, 333].

      Resting or basal pressure

      The resting pressure varies with the measurement method and the respiratory cycle and maintains an average pressure of about 20 mmHg relative to gastric pressure [90]. With a swallow, the LES relaxes and pressure decreases within 1–2.5 s and remains low until the arrival of the esophageal peristaltic contraction, when a sequential LES contraction then occurs and pressure again increases. The decrease in pressure lasts for the duration of the peristaltic esophageal wave in the smooth muscle esophagus that may take 5 s or more. However, esophageal opening depends on a combination of factors. These factors include intrabolus pressure due to peristaltic force and gravity, the abdominothoracic pressure gradient, and the residual LES pressure due to its smooth muscle, the diaphragm, and intra‐abdominal pressure surrounding the sphincter. Pressures are higher at the level of the diaphragm and increase with inspiration [284, 334]. Intrinsic sphincter pressure reflected at end inspiration is greater than 5 mmHg. Both radial and axial asymmetry can be demonstrated by high‐definition manometric reconstructions including 3‐D HRM. (Figure 5.15) [284, 312].

The circular/clasp and sling muscles are functionally different in many ways that impact on resting tone and responses to neural input and potentially to drugs. The circular muscle has significant spontaneous tone, whereas the sling muscle has little tone and compared to the circular muscle is much more responsive to cholinergic stimulation. The higher pressure in the left lateral position of the sling is reduced by atropine, compatible with the sling contributing to this higher pressure along with the diaphragm. The pressure in the remainder of the LES circumference is unchanged or little changed by cholinergic blockade. These two muscles demonstrate differences in resting membrane potential and voltage‐gated K+ channel densities [335] and in the L‐type Ca2+ channel and calcium handling [264, 336, 337]. For example, although influx of extracellular calcium is central to the maintenance of myogenic tone and acetylcholine‐induced contractility in both LES muscles, this influx occurs through an L‐type Ca2+ channel in LES circular muscle and a nifedipine‐insensitive, non–L‐type Ca2+ channel in sling muscle. Therefore, an L‐type Ca2+ channel blocker such as nifedipine would affect only the circular muscle. The cellular pathways and mechanisms determining contraction in the circular muscle of the esophageal body and LES have been well established and vary depending on the calcium source [266, 338, 339]. These mechanisms are altered by esophagitis, and these changes carry potential therapeutic implications [340–342].

Regional differences in the LES dictate that the mechanisms maintaining resting LES tone will be different for the LES smooth muscle, cholinergic excitation for the sling, and intrinsic myogenic tone for the circular clasp muscle and set the basal conditions for the mechanisms necessary for LES relaxation. Both muscles