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

Background: Nonadrenergic noncholinergic (NANC) nerves have important roles in the regulation of the lower esophageal sphincter (LES) motility and fun ction, The effects of thiopental, ketamine, and midazolam on NANC LES relax ation were investigated. Methods: The isometric tension of circular muscle strips from Japanese Whit e rabbits was examined. The NANC relaxation was Induced by KCl (30 mM) in t he 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(-6) M)-induced relaxation by the anesthetics were examined. The content of 3 ' ,5 ' -cycl ic guanosine monophosphate (cGMP) was measured by radioimmunoassay. Results: The KCl-induced relaxation was abolished by pretreating with tetro dotoxin (10(-6) M). The NANC relaxation was inhibited in the presence of NG -nitro-L-arginine (L-NNA; 3 x 10(-5) M), methylene blue (10(-6) M), apamin (10(-7) M), and gilbenclamide (10(-5) M). The SNP-induced relaxation was in hibited by methylene blue but was not affected by tetrodotoxin, L-MYA, apam in, 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. Conclusion: The NANC relaxation was mediated by nitric oxide and by low-con ductance calcium- and adenosine triphosphate-sensitive potassium channels o f smooth muscle. The modulation of the nitric oxide-GMP pathway was related at least in part, to the inhibitory actions of ketamine and midazolam on t he NANC LES relaxation.