Two pathways of nitric oxide production through glutamate receptors in the rat cerebellum in vivo.
The effects of N-methyl-D-aspartate (NMDA), (+)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and trans-(+/-)-1-amino-(1S,3R)-cyclopentanedicarboxylic acid (ACPD) on nitric oxide (NO) production in the cerebellum of conscious rats were investigated by measuring the levels of total NO metabolites (nitrite plus nitrate, NOx-) in dialysates obtained by in vivo microdialysis. All glutamate receptor agonists dose-dependently increased NOx- levels. Pharmacological characterization with various glutamate receptor antagonists indicated that the effects of NMDA, AMPA and ACPD are mediated by NMDA, non-NMDA, and L(+)-2-amino-3-phosphonopropionic acid (L(+)-AP-3)-sensitive metabotropic glutamate receptors, respectively. The NO synthase (NOS) inhibitors, including NG-nitro-L-arginine methyl ester (L-NAME), NG-nitro-L-arginine (L-NA), 7-nitroindazole (7-NI), and NG-monomethyl-L-arginine, inhibited NMDA-induced, but not AMPA- or ACPD-induced, increase in NOx- levels. L-Arginine enhanced NMDA-induced, but not AMPA- or ACPD-induced, increase in NOx- levels. Cytochrome P-450 inhibitors, SKF525A and erythromycin, inhibited the effect of NMDA, but not AMPA or ACPD. These results suggest that AMPA and ACPD may induce NO production through a NOS-independent pathway although NMDA receptor-mediated NO production is dependent on NOS activity in the rat cerebellum in vivo.
Yamada
K
K
Department of Neuropsychopharmacology, Nagoya University School of Medicine, Japan.
Nabeshima
T
T
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000502:physiology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009566:Nitrates; D009573:Nitrites; D017470:Receptors, Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D009569:Nitric Oxide; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D001120:Arginine; D019001:Nitric Oxide Synthase; D002118:Calcium