The relaxing effect of ketamine on isolated rabbit lower esophageal sphincter

We used ketamine to investigate the effects and intracellular mechanisms of several anesthetics on strips of lower esophageal sphincter (LES) from rabbits. Ketamine induced dose-dependent relaxation of LES preparations. It increased the content of 3',5'-cyclic adenosine monophosphate (cAMP) dose-dependently, but decreased that of 3',5'-cyclic guanosine monophosphate (cGMP). Pretreatment with nicotinic acid, an inhibitor of adenylate cyclase, along with atropine to block neurogenic effects, antagonized ketamine-induced relaxation. Pretreatment with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-89), a selective antagonist for cAMP-dependent protein kinase, similarly antagonized the relaxant effect of ketamine. Cholera toxin and dibutyryl cAMP induced LES relaxation. However, dibutyryl cGMP induced little LES relaxation, and pretreatment with NG-nitro-L-arginine or methylene blue did not alter the relaxant effect. Atropine, propranolol, phentolamine, vasoactive intestinal peptide (VIP) antagonist, and tetrodotoxin did not affect the ketamine-induced relaxation. This response, however, was potentiated in the presence of indomethacin or diphenhydramine. Ketamine-induced relaxation was inhibited in the presence of verapamil. These findings suggest that ketamine induces relaxation of LES, in part, by modulating the activity of adenylate cyclase and in part by inhibiting transmembrane influx of Ca2+.