Nitric oxide participates in excitotoxic mechanisms induced by chemical hypoxia.
Changes in the activity of the NMDA receptor-gated ionic channels induced by potassium cyanide were studied in rat hippocampal slices utilizing a [3H]MK-801 binding technique. A 30-min exposure of slices to potassium cyanide (KCN) increased MK-801 binding by 252%. Co-application of N omega-nitro-L-arginine (NNLA), a competitive antagonist of nitric oxide (NO) synthase, reduced this increase by 72%. This inhibition by NNLA was completely reversed by an excess of L-arginine, a substrate for NO synthase, suggesting that the KCN-induced increase in MK-801 binding is mediated by NO synthase activity. KCN had no effect on MK-801 binding in synaptic membranes. In Ca(2+)-containing medium, KCN increased the release of glutamate, aspartate and glycine by 4- to 5-fold, and this was blocked by application of NNLA. NNLA inhibition was reversed by an excess of L-arginine, indicating that KCN-stimulated release of these amino acids is mediated by NO synthase activity. In Ca(2+)-free medium, a KCN-induced increase in MK-801 binding and in excitatory amino acid release was also observed, however, this increase was not influenced by NO-related agents, suggesting that these changes were not mediated by NO synthase activation. NNLA given after the end of exposure to KCN did not reverse the increase in MK-801 binding. These findings suggest that NO is involved in the initial activation of NMDA receptor-gated ionic channels and in the enhanced amino acid transmitter release induced by KCN, but that KCN can also induce some of these effects by a Ca(2+)- and NO-independent mechanism.
Akira
T
T
Brain Research Institute, UCLA School of Medicine, 90024.
Henry
D
D
Baldwin
R A
RA
Wasterlain
C G
CG
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D003470:Culture Media; D016291:Dizocilpine Maleate / Q000378:metabolism; D000860:Hypoxia / Q000139:chemically induced / Q000378:metabolism*; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D011190:Potassium Cyanide / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D000596:Amino Acids; D003470:Culture Media; D007473:Ion Channels; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D016291:Dizocilpine Maleate; D011190:Potassium Cyanide; D002118:Calcium