Nicotinic receptor subtypes mediating relaxation of the normal human clasp and sling fibers of the upper gastric sphincter

Abstract

Background Proper function of the gastroesophageal high pressure zone is essential for the integrity of the antireflux barrier. Mechanisms include tonic contractions as well as the decreased tone during transient lower esophageal sphincter relaxations. Methods We characterized the pharmacology of nicotinic receptors mediating relaxations of the human upper gastric sphincter (clasp and sling fibers) using currently available subtype selective nicotinic antagonists in tissue from organ transplant donors. Donors with either a history of gastroesophageal reflux disease or histologic evidence of Barrett’s esophagus were excluded. Clasp and sling muscle fiber strips were used for one of three paradigms. For paradigm 1, each strip was exposed to carbachol, washed, exposed to nicotinic antagonists then re-exposed to carbachol. In paradigm 2, strips were exposed to a near maximally effective bethanechol concentration then nicotine was added. Strips then were washed, exposed to nicotinic antagonists then re-exposed to bethanechol followed by nicotine. In paradigm 3, strips were exposed to bethanechol then choline or cytisine. Key Results 100 µM methyllycaconitine has no inhibitory effects on relaxations, eliminating homomeric α7 subtypes. Subtypes composed of α4β2 subunits are also eliminated because choline acts as an agonist and dihydro-beta-erythroidine is ineffective. Conclusions & Inferences Because mecamylamine blocks the relaxations and both choline and cytisine act as agonists in both clasp and sling fibers, the nicotinic receptor subtypes responsible for these relaxations could be composed of α3β4β2, α2β4 or α4β4 subunits.

Nerve transfer for restoration of lower motor neuron-lesioned bladder, urethral, and anal sphincter function in a dog model. Part 3. nicotinic receptor characterization

“…Thus, the amount of muscle involved in generating the force is very similar for all strips regardless of strip size. Use of this methodology also matches previously reported methods from our laboratory ( 19 , 33 , 34 ).…”

Involvement of interstitial cells of Cajal in nicotinic acetylcholine receptor-induced relaxation of the porcine lower esophageal sphincter

“…The action of swallowing has been shown to stimulate the afferent and efferent vagal nerves (Hornby and Abrahams, 2000). Indeed, stimulation of the nicotinic acetylcholine receptor is responsible for relaxation of the LES (Kadakia et al, 1996;Ruggieri et al, 2014). Accumulated evidence has shown that the relaxant responses to vagal stimulation are reduced by interfering with neurotransmitters, including nitric oxide (NO) (Kawahara et al, 1997;Paterson et al, 1992) and vasoactive intestinal polypeptide (VIP) (Rattan, 1986), in the gastrointestinal tract.…”