Читать книгу The Esophagus - Группа авторов - Страница 146

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 have the capacity for repetitive contractile activity [343]. The circular muscle develops membrane electrical slow waves and/or spiking activity, with the intensity of the spiking related to tone development and to changes in pressure with the migrating motor complex (MMC) [344–348]. Potassium‐ and calcium‐activated chloride channels have important opposing roles in the control of the spiking activity and the genesis of LES tone [348]. The circular clasp muscle with its high resting intrinsic tone is relaxed predominantly by release of NO. There is little effect of NO on the sling muscle [320], and relaxation of the sling muscle is likely due predominantly to turning off its cholinergic excitation. That is, the dominant innervation of the circular clasp muscle is nitrergic and inhibitory, whereas that of the sling is cholinergic and excitatory. Therefore, a balance between excitatory and inhibitory innervation to the two muscles sets the level of resting tone at any time. The ability to pharmacologically manipulate this balance has clinical and therapeutic implications. Increasing LES pressure could be advantageous for patients with gastroesophageal reflux. The sling would lend itself to extracholinergic excitation and support the use of cholinergic agonists to raise pressure in these patients [349]. Decreasing tone in disorders where the sphincter is hypertensive or fails to relax, e.g. achalasia, could be directed at the circular muscle with L‐type calcium blockers [350] or phosphodiesterase inhibitors such as sildenafil that prevent the degradation of NO [351, 352]. Botulinum toxin injection to lower pressure by decreasing acetylcholine release would involve primarily the sling muscle [353]. The same reasoning can be applied to surgical interventions. Perhaps cutting the circular muscle in patients with achalasia is all that is necessary, while leaving the cholinergic sling activity intact to protect against reflux [354].

Table 5.1 Effects of hormones and putative neurotransmitters on the lower esophageal sphincter.

Agent	Effect	Site of action	Comments
Circular smooth muscle	Inhibitory neurons	Excitatory neurons
Bombesin	Contraction	√	—	√	Releases norepinephrine from adrenergic neurons
Calcitonin gene‐related peptide	Relaxation	√	√	—
Cholecystokinin	Biphasic	√	√	—	Inhibition overrides excitation, causes paradoxical excitation in achalasia patients
Dopamine	Relaxation (D2)	√	—	—
	Contraction (D1)	√	—	—
Galanin	Contraction	√	—	—
Gastric inhibitory polypeptide	Relaxation	?	?	?
Gastrin	Contraction	√	—	—
Glucagon	Relaxation	√	—	—	Releases catecholamines from adrenal medulla
Histamine	Contraction	√ (H1)	—	—
Motilin	Contraction	√	—	√
Neurotensin	Contraction	√	—	—
Nitric oxide	Relaxation	√	—	—
Pancreatic polypeptide	Contraction	√	—	√
PGF2α	Contraction	√	—	—
PGF1,2	Relaxation	√	—	—
Progesterone	Relaxation	√	—	—
Secretin	Relaxation	√	—	—
Serotonin	Contraction	√	—	—
Somatostatin	Contraction	?	?	?
Substance P	Contraction	√	—	√
VIP	Relaxation	√	—	—

PGE, prostaglandin E; PGF, prostaglandin F; VIP, vasoactive intestinal peptide.

A number of influences affect the resting tone and pressure. There is an increase in LES pressure with a rise in intra‐abdominal pressure that is mediated by the vagus in the cat [355], but whether the rise is a passive response or a vagally mediated response in the human is controversial [353,356–359]. The LES pressure increases in the recumbent position [360, 361]. Fasting pressures are higher during phase III of the MMC and lowest during phase I. Feeding is often associated with a drop in LES pressure, resulting in large part from the secretion of hormones such as secretin and CCK with fat intake [362, 363] or from the nature of the food itself or its contents, such as with chocolate [364], alcohol [365], and caffeine [366]. Even colonic fermentation can lower LES pressure, the mechanism being unclear [367]. Smoking decreases LES pressure [368], as does pregnancy, the latter due in part to the hormone progesterone [369]. Sleep has little or no effect on LES pressure [370, 371]. Psychologic stress can lower the pressure. Many other hormones, neurotransmitters, and ingested medications can alter LES pressure (Table 5.1), such as anticholinergic drugs, nitrates, calcium‐channel blockers, and certain prostaglandins, and can potentially predispose to gastroesophageal reflux. Other substances and drugs have therapeutic potential because of their effects [372].