T1220 Pharmacologic Specificity of Nicotinic Receptors Mediating Relaxation of Muscarinic Receptor Pre-Contracted Human and Pig Gastric Clasp Fibers

Abstract

The circular muscle fibers at the end of the esophagus are traditionally considered the lower esophageal sphincter. However, the first barrier to gastric reflux is actually the clasp/sling fiber complex of the stomach. Relaxation mediates transient lower esophageal sphincter relaxation underlying the pathophysiology of gastroesophageal reflux disease (GERD). This study determined the pharmacologic specificity of the nicotinic receptor mediated relaxation of pre-contracted strips of human and porcine clasp muscle fibers. Human specimens were obtained from organ transplant donors. Clasp fiber muscle strips were exposed to increasing carbachol concentrations (human) or acetylcholine with physostigmine to block cholinesterase (pig). At concentrations higher than 30 uM, abrupt relaxations were produced. After 60 minutes of repeated washing, strips were exposed to various ganglionic and neuromuscular nicotinic receptor antagonists for 30 minutes then rechallenged with cholinergic agonists. Results, as a percentage of relaxation in time control strips are shown in the figure below. The neuromuscular blockers d-tubocurarine, decamethonium (human) and pancuronium (pig) inhibited relaxation whereas the ganglionic blocker hexamethonium (human) and the alpha7 selective antagonist methyllycaconitine did not. Other ganglionic blockers such as MG624, NDNI and TMPH blocked these relaxations whereas mecamylamine was only partially effective in human tissue. These results indicate that the pharmacology of the nicotinic receptor mediating relaxation of the gastric clasp fibers may be unique and a potential target for development of selective agents for treatment of GERD.