Mechanism of stretch-activated excitatory and inhibitory responses in the lower esophageal sphincter

Abstract

We recently found that an orally directed stretch of the esophagus activates a neurally mediated relaxation of the lower esophageal sphincter (LES). Goals of our study were to characterize the neural mechanisms responsible for axial and transverse stretch-activated responses in the LES. LES pressure was monitored in anesthetized and artificially ventilated mice. Sutures were placed in the esophagus to exert graded stretch in the longitudinal and transverse directions. Effects of bilateral vagotomy and pharmacological agents on the stretch-activated LES responses were investigated. The relationship between vagally stimulated axial stretch and LES relaxation was also studied. Stretch in the longitudinal and transverse directions caused a dose-dependent LES relaxation and contraction, respectively, that were not affected by bilateral vagotomy and sympathectomy but were blocked by tetrodotoxin. In bilateral vagotomized animals, hexamethonium, atropine, pyridoxalphosphate-6-azophenyl-2',4' disulfonic acid (PPADS), and ondansetron did not block the stretch-activated LES relaxation and contraction. Axial stretch-activated LES relaxation was blocked by nitric oxide inhibitor and transverse stretch-activated LES contraction was blocked by a combination of atropine and substance P antagonist. Electrical stimulation of the vagus nerve induced LES relaxation and axial stretch on the LES, both of which were blocked by rocuronium. Axial and transverse stretch-activated LES relaxation and contraction were present in the W/W(v) mice that lack interstitial cells of Cajal (ICC). Stretch-activated LES relaxation and contraction are mediated through mechanosensitive neurons located in the myenteric plexus, which involves neither synaptic transmission nor ICC.

Inhibitory motor neurons of the esophageal myenteric plexus are mechanosensitive

“…Furthermore, stretch-activated reflexes exist in the stomach, where there are no IPANs (41). Our earlier in vivo studies (7,22,23) and the present in vitro study clearly prove that the inhibitory motor neurons are indeed mechanosensitive. Our findings are in agreement with the concept of multifunctionality of myenteric neurons proposed by Schemann and colleagues (28,29), who demonstrated that a large number of myenteric neurons possess sensory, integrative, and motor functions in the same cell.…”

“…In whole animal studies, we found that mechanical stretch of the esophagus in the axial and transverse directions induces neurally mediated LES relaxation and LES contraction, respectively (22,23). Pharmacological analysis of in vivo studies suggests that esophageal motor neurons might be mechanosensitive (22); however, this novel notion needs direct evidence. Moreover, although a growing body of literature suggests that enteric neurons respond directly to mechanical stretch in the small intestine and colon (6,28,36,41), whether isolated enteric neurons are mechanosensitive has not been studied.…”

“…The esophageal motor neurons have their cell bodies in the myenteric ganglia, and their axons innervate the longitudinal and circular smooth muscle layers of the esophagus and lower esophageal sphincter (LES) (11,47). In whole animal studies, we found that mechanical stretch of the esophagus in the axial and transverse directions induces neurally mediated LES relaxation and LES contraction, respectively (22,23). Pharmacological analysis of in vivo studies suggests that esophageal motor neurons might be mechanosensitive (22); however, this novel notion needs direct evidence.…”

Pressure morphology of the relaxed lower esophageal sphincter: the formation and collapse of the phrenic ampulla

“…Assuming that the extent of yield amounts to ϳ50% elongation, the size of the stretched and effaced LES closely corresponds to the observed 4-cm length of the ampulla at the time of the CDP. These observations also fit well with the recent demonstration that axial traction on the LES activates neural pathways that elicit LES relaxation, possibly mediated by mechanosensitive enteric neurons in the LES segment (8,9). Concurrent with this axial traction, the distal esophagus is tethered to the CD by the phrenoesophageal ligament.…”

Circular and longitudinal muscles shortening indicates sliding patterns during peristalsis and transient lower esophageal sphincter relaxation

“…Axial stretch of esophagus in the oral direction activates neurologically mediated LES relaxation and possibly descending relaxation of the esophagus (7). Therefore, it is hypothesized that longitudinal muscle contraction related axial stretch is of fundamental importance in the descending relaxation of the peristaltic reflex.…”