Peripheral N-methyl-D-aspartate receptors modulate nonadrenergic noncholinergic lower esophageal sphincter relaxation in rabbits.
We investigated the role of peripheral N-methyl-D-aspartate (NMDA) receptors in the myenteric plexus in mediating nonadrenergic noncholinergic (NANC) nitrergic relaxation of the lower esophageal sphincter (LES). Isometric contraction of LES strips from Japanese White rabbits was measured. NANC relaxation was induced by KCl (30 mM) in the presence of atropine and guanethidine. The concentration of 3',5'-cyclic guanosine monophosphate (cGMP) was measured using a radioimmunoassay. The muscle strips were exposed to diethyldithiocarbamic acid (DETCA; 3 mM) to inactivate Cu/Zn superoxide dismutase. MK801 (5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imine) inhibited NANC relaxation in a concentration-dependent manner (EC50 = 1.5 x 10(-5) M), accompanied by a decrease in cGMP production. NMDA induced a concentration-dependent relaxation, which was antagonized by MK801. NMDA stimulated cGMP production, which was inhibited by N(G)-nitro-L-arginine. Superoxide dismutase (100 U/mL) shifted the concentration-response relationship of MK801-mediated inhibition of NANC relaxation to the right (EC50 = 3.4 x 10(-5) M), whereas catalase did not. Treatment with DETCA shifted the concentration-response relationships of pyrogallol-, ketamine- and MK801-mediated inhibition of NANC relaxation to the left. These findings suggest that the peripheral NMDA receptors mediate NANC smooth muscle relaxation, and modulate it, in part, through extracellular production of superoxide anions, thus eliminating the relaxant effect of endogenous nitric oxide.
Kohjitani
Atsushi
A
Departments of Dental Anesthesiology and Anesthesiology and Resuscitology, Okayama University Hospital of Medicine and Dentistry, and Departments of Dental Anesthesiology and Oral Physiology, Okayama University Graduate School of Medicine and Dentistry.
Funahashi
Makoto
M
Miyawaki
Takuya
T
Hanazaki
Motohiko
M
Matsuo
Ryuji
R
Shimada
Masahiko
M
D000818:Animals; D006152:Cyclic GMP / Q000096:biosynthesis; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D049630:Esophageal Sphincter, Lower / Q000294:innervation / Q000502:physiology*; D008274:Magnesium / Q000502:physiology; D008297:Male; D009126:Muscle Relaxation; D016202:N-Methylaspartate / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013482:Superoxide Dismutase / Q000494:pharmacology
D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D016202:N-Methylaspartate; D011189:Potassium Chloride; D016291:Dizocilpine Maleate; D013482:Superoxide Dismutase; D006152:Cyclic GMP; D008274:Magnesium