PT  - JOURNAL ARTICLE
AU  - Alan S. Braverman
AU  - Anil K. Vegesna
AU  - Larry S. Miller
AU  - Mary F. Barbe
AU  - Mansoor Tiwana
AU  - Kashif Hussain
AU  - Michael R. Ruggieri, Sr
TI  - Pharmacologic Specificity of Nicotinic Receptor-Mediated Relaxation of Muscarinic Receptor Precontracted Human Gastric Clasp and Sling Muscle Fibers within the Gastroesophageal Junction
AID  - 10.1124/jpet.110.177097
DP  - 2011 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 37--46
VI  - 338
IP  - 1
4099  - http://jpet.aspetjournals.org/content/338/1/37.short
4100  - http://jpet.aspetjournals.org/content/338/1/37.full
SO  - J Pharmacol Exp Ther2011 Jul 01; 338
AB  - 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 β-adrenoceptor antagonist propranolol, the glycine receptor antagonist strychnine or ginkgolide B, and the GABAA 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 GABAA 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 β-adrenergic agonist isoproterenol (clasp fibers only) but not by the glycine receptor agonist taurine or glycine or the GABAA agonist muscimol. These data indicate that nicotinic receptor activation mediates relaxation via release of nitric oxide in clasp and sling fibers, norepinephrine acting on β-adrenoceptors in clasp fibers, and GABA acting on GABAA receptors in sling fibers. Agents that selectively prevent these relaxations may be useful in the treatment of GERD.