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 pre-contracted gastric clasp and sling fibers. Muscle strips from organ donors pre-contracted with bethanechol were relaxed with nicotine then rechallenged after washing and adding inhibitors: tetrodotoxin (TTX), the nitric oxide synthase inhibitor L-NAME , the β adrenoceptor antagonist propranolol, the glycine receptor antagonists strychnine or ginkgolide B and the GABAA receptor antagonists bicuculline or 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 pre-contracted fibers were relaxed by the nitric oxide donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) and by the β adrenergic agonist isoproterenol (clasp fibers only) but not by the glycine receptor agonists 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.
- Received November 8, 2010.
- Revision received March 31, 2011.
- Accepted March 31, 2011.
- The American Society for Pharmacology and Experimental Therapeutics