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 | √ |
|