Intravenous anesthetics inhibit nonadrenergic noncholinergic lower esophageal sphincter relaxation via nitric oxide-cyclic guanosine monophosphate pathway modulation in rabbits.

Abstract

Nonadrenergic noncholinergic (NANC) nerves have important roles in the regulation of the lower esophageal sphincter (LES) motility and function. The effects of thiopental, ketamine, and midazolam on NANC LES relaxation were investigated. The isometric tension of circular muscle strips from Japanese White rabbits was examined. The NANC relaxation was induced by KCl (30 mM) in the presence of atropine (3 x 10(-6) M) and guanethidine (3 x 10(-6) M). The modifications of the NANC and sodium nitroprusside (SNP; 10(-5) M)-induced relaxation by the anesthetics were examined. The content of 3',5'-cyclic guanosine monophosphate (cGMP) was measured by radioimmunoassay. The KCl-induced relaxation was abolished by pretreating with tetrodotoxin (10(-6) M). The NANC relaxation was inhibited in the presence of N(G)-nitro-L-arginine (L-NNA; 3 x 10(-5) M), methylene blue (10(-6) M), apamin (10(-7) M), and glibenclamide (10(-5) M). The SNP-induced relaxation was inhibited by methylene blue but was not affected by tetrodotoxin, L-NNA, apamin, or glibenclamide. Ketamine (EC50 = 8.8 x 10(-5) M) and midazolam (EC50 = 4.8 x 10(-6) M) suppressed the NANC response in a concentration-dependent manner, leaving SNP-induced response unchanged. Thiopental altered neither of the relaxations. cGMP content was decreased in the presence of ketamine and midazolam. The NANC relaxation was mediated by nitric oxide and by low-conductance calcium- and adenosine triphosphate-sensitive potassium channels of smooth muscle. The modulation of the nitric oxide-cGMP pathway was related, at least in part, to the inhibitory actions of ketamine and midazolam on the NANC LES relaxation.