Can nitric oxide be considered as the mediator of lower esophageal sphincter relaxation?
A. Keshavarzian (Chicago)
Nitric oxide (NO) is one of the most important inhibitory neurotransmitter in the enteric nervous system and is typically co-localized with other inhibitory neurotransmitters such as vaso-intestinal peptide (VIP). It is present in the myenteric plexus throughout the esophagus including myenteric plexus in the striated muscle portion of the proximal esophagus where it innervates motor end plates. NO is essential for normal peristalsis in gastrointestinal (GI) tract including esophagus since it participates in 1) tonic inhibition of myogenic contractions; 2) relaxation of muscle below the stimulus (bolus) by activation of cholinergic interneurons as part of peristaltic reflex; and 3) generations of graded increase in duration of "on-response" inhibition of muscle contraction across the esophageal body - a prerequisite for normal esophageal peristalsis. NO is also essential for normal sphincter function since it is pivotal for sphincter relaxation in response to stimuli such as lower esophageal sphincter (LES) relaxation after swallowing.
It is, therefore, not surprising that nitric oxide has been postulated in the pathogenesis of several GI motility disorders . For example, achalasia is believed to be due to a selective loss or dysfunction of inhibitory neurons containing NO and VIP in the myenteric plexus of the esophagus and LES. It is also suggested that esophageal spasm could be due to lack of NO containing neurons in the esophagus that results in loss of initial "on-response" inhibition thereby causing simultaneous contractions throughout the esophagus.
Low levels of NO synthase activity and/or loss of NO containing neurons have also been reported in several syndromic dysmotility conditions such as infantile hypertrophic pyloric stenosis and familial achalasia.
Furthermore, deleterious side effects of compounds/medication on GI motility can be mediated through NO. For example, inhibitory effect of acute ethanol ingestion on esophageal muscle contractions appears to be mediated through NO . NO inhibitor prevented the inhibitory effects of ethanol on esophageal muscle strip contraction. NO inhibitor also prevented the ethanol induced potentiation of "on-response" relaxation of LES muscle strip.