The resting state of the LES is one of contraction. Cholinergic neurons provide resting tone, whereas inhibitory neurons provide vagal-mediated relaxation34,41,42 Vagal efferents contain both excitatory and inhibitory signals; however, the predominant effect of vagal stimulation is LES relaxation, as mediated by non-adrenergic, non-cholinergic (NANC) nerves.43 In normal patients, stimuli from gastric, esophageal and pharyngeal sensory nerves
are relayed to, and processed by, the dorsal motor nucleus of the vagus, which results in modulation of both excitatory and inhibitory impulses to the LES.44
Two strong candidates for mediation of LES relaxation are vasoactive intestinal polypeptide (VIP) and nitric oxide (NO). After it was realized that VIP was found in high concentrations in gut sphincters, subsequent investigations showed it to be a potent inhibitor of LES contraction in vitro.45,46 Further association of VIP with sphinc-teric relaxation and achalasia is suggested by immunohistochemical studies that have shown decreased or absent VIP-containing neurons in LES specimens from patients with achalasia.47-49 Human manometric studies have shown that the LES in patients with achalasia, as compared to normal controls, is hypersensitive to exogenous VIP, again supporting a role for VIP in LES relax-
NO also figures prominently in gastrointestinal tract smooth muscle and sphincteric mechanisms.50-57 The role of NO appears to be that of sphincter-muscle hyperpolarization, and therefore relaxation, and the loss of NO has been associated with conditions of persistent contraction, such as achalasia.58-62 Preiksaitis et al elegantly demonstrated that blocking NO synthase prevents relaxation of LES muscles by NANC nerves, and that exogenous NO from sodium nitroprusside can overcome this inhibition.57 Inhibitory regulation of gastrointestinal muscles by NANC transmitters was generally believed to be direct, until an intermediary, interstitial cell was proposed by Cajal (a cell that bears his name).63 Recent work in both animal and human models confirms the relationship of interstitial cells of Cajal (ICC) to nitric oxide synthase (NOS)-positive neurons.53,64 It is accepted that NO release results in sphincteric relaxation; however, the exact mechanism has not been fully elucidated. While evaluation of the LES in adults shows that ICC are altered, this may be a result of disruption of the interaction between NOS-positive neurons and ICC, because examination of the pediatric esophagus in achalasia (and therefore a shorter duration of disease) shows morphologically normal ICC, but disrupted contact with NOS-positive neurons.53,54
The precise cause of achalasia remains to be elucidated but the loss of NO- and/or VIP-associated neurons appears to be integral to the disease. By their destruction, these neurons permit unopposed contraction of the LES.
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