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Proper function of the gastro-esophageal high pressure zone is essential for the integrity of the antireflux barrier. Mechanisms include tonic contractions and the decreased tone during transient lower esophageal sphincter relaxations.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 gastro-esophageal 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.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.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.The nicotinic receptors responsible for relaxation of the gastric clasp and sling fibers that compose the upper gastric sphincter were investigated in 14 whole human stomach and esophagus specimens obtained from organ transplant donors using currently available nicotinic receptor subtype selective agonists and antagonists. 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 either α3β4β2 subunits (producing Type III currents) or α2β4/α4β4 subunits (producing Type IV currents). If these nicotinic receptors in clasp and sling fibers are different than the ganglionic nicotinic receptors found elsewhere that mediate major functions such as blood pressure, then selective inhibition of the unique nicotinic receptors in the UGS may be an effective treatment for GERD.