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].
Transient lower esophageal sphincter relaxations
Independent of swallowing, the LES relaxes spontaneously (TLESR) and with retching and vomiting. In both patients and normal subjects, the TLESR in the face of a normal LES pressure is the most common mechanism of gastroesophageal reflux [373, 374]. Transient LES relaxation occurs largely during daytime post‐prandial periods [375] attributed to a vagal reflex initiated by gastric distention [376, 377]. Belching occurs with a TLESR in response to gastric distention [378]. TLESRs are accompanied by crural diaphragm inhibition except when initiated by laryngeal or pharyngeal stimulation [379–381] and last longer than 10 s (average 21 s), which is longer than swallow‐related relaxations [375, 377, 382]. TLESRs are mediated centrally in the brainstem SPG in response to afferent input from the stomach, esophagus, pharynx or larynx, and crural diaphragm. The efferent signal is then carried in the vagus to produce relaxation of the LES and via the phrenic nerve to the crural diaphragm [290]. The reflex pathways, neurotransmitters, and chemical mediators involved are shown in Figure 5.16. NO may also be released at the diaphragm as a mediator of inhibition. Knowledge of these pathways had led to the potential for therapies directed at reducing TLESRs in GERD [383] by inhibiting cholinergic (M1 receptor), and CCK‐A receptor effects and enhancing GABA‐B receptor effects [384–386]. Longitudinal muscle contraction participates in LES relaxation and crural diaphragm inhibition that occur concurrent with TLESRs [387], resulting in proximal migration of the EGJ. The rapid return of the EGJ to its resting location following TLESRs is thought to be partly due to elastic recoil of the phrenoesophageal ligament, which is stretched during TLESRs [388].
Figure 5.16 Reflex arc underlying transient lower esophageal sphincter relaxations (TLESRs), and potential sites of actions of different agents. CCK, cholecystokinin; ACh, acetylcholine; GABA, gamma butyric acid; NO, nitric oxide; CD, crural diaphragm; ENS, enteric nervous system; GN, nodose ganglion. NO may also act at the level of the crural diaphragm.
Source: Hirsch [383] with permissions of John Wiley & Sons.
Diaphragm
The diaphragm contributes to LES pressure and especially to antireflux barrier function [281, 389]. The crural diaphragm coordinates with LES relaxation during swallowing and with TLESRs [383, 390]. A hiatus hernia separates the contribution of the diaphragm to the antireflux barrier function, the hernia acting as one contributing factor to gastroesophageal reflux. Using HRM, morphology of the EGJ has been categorized into three subtypes based on the relationship between the crural diaphragm and the intrinsic LES: type 1, where diaphragm and LES are superimposed; type 2, where separation is 2 cm or less; and type 3, where separation is 3 cm or higher [391]. These EGJ morphology phenotypes demonstrate an increasing gradient of esophageal acid exposure as separation increases between the intrinsic LES and the crural diaphragm [392, 393].
References
1 1 Ertekin C, Kiylioglu N, Tarlaci S, et al. Voluntary and reflex influences on the initiation of swallowing reflex in man. Dysphagia 2001; 16:40–7.
2 2 Bautista TG, Sun QJ, Pilowsky PM. The generation of pharyngeal phase of swallow and its coordination with breathing: interaction between the swallow and respiratory central pattern generators. Prog Brain Res 2014; 212:253–75.
3 3 Lear CS, Flanagan JB, Jr., Moorrees CF. The frequency of deglutition in man. Arch Oral Biol 1965; 10:83–100.
4 4 Bianchi AL, Gestreau C. The brainstem respiratory network: an overview of a half century of research. Respir Physiol Neurobiol 2009; 168:4–12.
5 5 Lang IM. Brain stem control of the phases of swallowing. Dysphagia 2009; 24:333–48.
6 6 Lang IM, Dean C, Medda BK, et al. Differential activation of medullary vagal nuclei during different phases of swallowing in the cat. Brain Res 2004; 1014:145–63.
7 7 Jean A. Electrophysiologic characterization of the swallowing pattern generator in the brainstem. Part 1: Oral cavity, pharynx and esophagus. GI Motility online. 2006.
8 8 Doty R. Neural organization of deglutition. In: Code CF, ed. Handbook of physiology sect. 6, vol. 4, Washington, D.C.: American Physiological Society; 1968. p 1861–1902.
9 9 Yoshida Y, Tanaka Y, Hirano M, et al. Sensory innervation of the pharynx and larynx. Am J Med 2000; 108 Suppl 4a:51S–61S.
10 10 Beyak MJ, Collman PI, Valdez DT, et al. Superior laryngeal nerve stimulation in the cat: effect on oropharyngeal swallowing, oesophageal motility and lower oesophageal sphincter activity. Neurogastroenterol Motil 1997; 9:117–27.
11 11 Ciampini G, Jean A. Role of glossopharyngeal and trigeminal afferents in the initiation and propagation of swallowing. II – Trigeminal afferents (author's transl). J Physiol (Paris) 1980; 76:61–6.
12 12 Ciampini G, Jean A. Role of glossopharyngeal and trigeminal afferents in the initiation and propagation of swallowing. I – Glossopharyngeal afferents (author's transl). J Physiol (Paris) 1980; 76:49–60.
13 13 Shaker R, Ren J, Zamir Z, et al. Effect of aging, position, and temperature on the threshold volume triggering pharyngeal swallows. Gastroenterology 1994; 107:396–402.
14 14 Lang IM, Medda BK, Ren J, et al. Characterization and mechanisms of the pharyngoesophageal inhibitory reflex. Am J Physiol 1998; 275:G1127–36.
15 15 Mansson I, Sandberg N. Oro‐pharyngeal sensitivity and elicitation of swallowing in man. Acta Otolaryngol 1975; 79:140–5.
16 16 Randich A, Gebhart GF. Vagal afferent modulation of nociception. Brain Res Brain Res Rev 1992; 17:77–99.
17 17 Shaker R. Reflex interaction of pharynx, esophagus, and airways. Part 1: Oral cavity, pharynx and esophagus. GI Motility Online. 2006.
18 18 Broussard DL, Altschuler SM. Brainstem viscerotopic organization of afferents and efferents involved in the control of swallowing. Am J Med 2000; 108 Suppl 4a:79S–86S.
19 19 Chiang CY, Hu JW, Dostrovsky JO, et al. Changes in mechanoreceptive field properties of trigeminal somatosensory brainstem neurons induced by stimulation of nucleus raphe magnus in cats. Brain Res 1989; 485:371–81.
20 20 Sengupta JN,