Pharmacologic Specificity of Nicotinic Receptor-Mediated Relaxation of Muscarinic Receptor Precontracted Human Gastric Clasp and Sling Muscle Fibers within the Gastroesophageal Junction

Abstract

Relaxation of gastric clasp and sling muscle fibers is involved the transient lower esophageal sphincter relaxations underlying the pathophysiology of gastroesophageal reflux disease (GERD). These fibers do not contribute tone to the high-pressure zone in GERD patients, indicating their role in pathophysiology. This study identifies some mediators of the nicotine-induced relaxation of muscarinic receptor precontracted gastric clasp and sling fibers. Muscle strips from organ donors precontracted with bethanechol were relaxed with nicotine and then rechallenged after washing and adding inhibitors tetrodotoxin (TTX), the nitric-oxide synthase inhibitor L-nitro-arginine methyl ester (L-NAME), the ␤-adrenoceptor antagonist propranolol, the glycine receptor antagonist strychnine or ginkgolide B, and the GABA A receptor antagonist bicuculline or 2-(3-carboxypropyl)-3-amino-6-(4 methoxyphenyl)pyridazinium bromide [(gabazine) SR95531]. TTX only inhibited clasp fiber relaxations. L-NAME and propranolol inhibited, and ginkgolide B was ineffective in both. SR95531 was ineffective in clasp fibers and partially effective in sling fibers. Strychnine and bicuculline prevented relaxations with low potency, indicating actions not on glycine or GABA A receptors but more consistent with nicotinic receptor blockade. Bethanechol-precontracted fibers were relaxed by the nitric oxide donor S-nitroso-N-acetyl-DL-penicillamine and by the ␤-adrenergic agonist isoproterenol (clasp fibers only) but not by the glycine receptor agonist taurine or glycine or the GABA A agonist muscimol. These data indicate that nicotinic receptor activation mediates relaxation via release of nitric oxide in clasp and sling fibers, norepinephrine acting on ␤-adrenoceptors in clasp fibers, and GABA acting on GABA A receptors in sling fibers. Agents that selectively prevent these relaxations may be useful in the treatment of GERD.

Esophagogastric anastomosis in rats: Improved healing by BPC 157 and L-arginine, aggravated by L-NAME

“…Additionally, sphincter failure is proposed as a hallmark of ongoing injury[17,18,20-23] along with an injurious effect of L-NAME itself[1,5,7,17,18,20,45-51] that overrides previous considerations about NO-sphincter relationships[57] while being unrelated to injurious conditions ( i.e ., in dogs, ferrets and muscle strips[58-60]). In rats that underwent esophagogastric anastomosis and L-NAME therapy, the final drop of pressure within the esophagus at the site of anastomosis on day 4 occurs just prior to death.…”

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

“…We previously found that nicotine causes relaxation of bethanechol precontracted clasp, sling and LEC muscle strips and that this effect occurs indirectly, by activation of nicotinic receptors on enteric nerves that induces release of multiple relaxing substances. These relaxing substances include nitric oxide (NO) in clasp, sling, and LEC fibers, norepinephrine acting on β ‐adrenoceptors in clasp fibers, and GABA acting on GABA A receptors in sling fibers . The current study was undertaken to characterize the pharmacology of the enteric nerve nicotinic receptors mediating these relaxations of the UGS using currently available nicotinic receptor subtype selective agents.…”

Nicotinic Regulation of Energy Homeostasis

“…However, some basic insights have been obtained. In most species and experimental preparations, nicotine causes contraction of stomach, jejunal, and ileal muscles, and relaxation of colonic muscles and lower oesophageal sphincter (Braverman et al, 2011;Murakami et al, 2009;Vural, Ozturk Fincan, Bozkurt, Ercan, & Sarioglu, 2009). At a more integrated level, nAChRs are thought to play a crucial role in ascending reflexes but only a minor role in descending reflexes of the myenteric plexus, whereas in the submucosal plexus, most nAChRs are associated with descending projections (Galligan & North, 2004).…”