Mechanisms Involving in the Inhibition of Nitric Oxide-Mediated Lower Esophageal Sphincter Relaxation Induced by Volatile Anesthetics in Rabbits.

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Nonadrenergic noncholinergic (NANC) nerves, which regulate peristaltic waves and/or relaxing mechanisms of the gastrointestinal tract, are known to be nitrergic and to initiate NO-cGMP signaling pathway. We investigated the effect of sevoflurane on NANC relaxation of the lower esophageal sphincter (LES), and the relevance of peripheral N-methyl-D-aspartate (NMDA) receptors in the myenteric plexus mediating NANC relaxation. Sevoflurane inhibited NANC relaxation in a concentration-dependent manner. MK801 concentration-dependently inhibited NANC relaxation, accompanied by a decrease in cGMP production. NMDA induced a concentration-dependent relaxation, which is antagonized by MK801. NMDA stimulated cGMP production, which was inhibited by N^G-nitro-L-arginine. Superoxide dismutase (SOD) shifted the concentration-response relationship of MK801 mediating inhibition of NANC relaxation to the right, but catalase did not. Treatment with diethyldithiocarbamic acid to inactivate Cu/Zn SOD shifted the concentration-response relationships of pyrogallol, ketamine, and MK801 mediating the inhibition of NANC relaxation to the left. These findings suggest that the peripheral NMDA receptors mediates NANC smooth muscle relaxation, and modulates it in part through extracellular production of superoxide anion thus eliminating the relaxant effect of endogenous NO, and that volatile anesthetics may modify LES function by modulating NANC relaxation through antagonism of peripheral NMDA receptors. The functional linkage of peripheral NMDA receptors in the myenteric plexus and NO-cGMP pathway leading to smooth muscle relaxation could provide a key on elucidating the roles of peripheral excitatory amino acids and endogenous NO regulating gastrointestinal motility in the near future.