The non-adrenergic non-cholinergic innervation of the esophagus and the lower esophageal sphincter.

Electrical stimulation of the vagus nerve causes the relaxation of the lower esophageal sphincter (LES), followed by the sequential contraction of the esophageal body smooth muscle. These responses are similar to those in response to swallowing. The nature of the inhibitory neurotransmitter responsible for the LES relaxation is not exactly known. Following the preliminary criteria, we systematically examined the possibility of different candidate substances as the inhibitory neurotransmitter. We ruled out the role of different neurotransmitter substances including the cholinergic and adrenergic ones. Finally, we examined the possibility of VIP as the inhibitory neurotransmitter of non-adrenergic non-cholinergic intramural neurons of the LES, responsible for LES relaxation. VIP caused relaxation of the LES by its action directly at the muscle. VIP antiserum, which antagonized the action of VIP, caused a significant antagonism of LES relaxation caused by vagal stimulation and local stimulation. These results suggest that VIP acts as an inhibitory neurotransmitter for LES relaxation. The exact nature of the neurotransmitter responsible for the esophageal peristalsis is also not known. It is suggested that the contraction of the longitudinal smooth muscle of the esophagus is mediated by acetylcholine and substance P, while the circular smooth muscle contraction is mediated through the release of acetylcholine and an unknown non-adrenergic non-cholinergic neurotransmitter. Whether the latter neurotransmitter is VIP remains to be seen.