Oxygen seizure latency and peroxynitrite formation in mice lacking neuronal or endothelial nitric oxide synthases.
Nitric oxide (NO) from endothelial or neuronal NO synthases (eNOS or nNOS) may contribute both to the cerebrovascular responses to oxygen and potentially to the peroxynitrite-mediated toxic effects of hyperbaric oxygen (HBO(2)) on the central nervous system (CNS O(2) toxicity). In mice lacking eNOS or nNOS (-/-), regional cerebral blood flow (rCBF) and 3-nitrotyrosine (3-NT), a biochemical marker for peroxynitrite (ONOO(-)) formation, were measured in the brain during HBO(2) exposure. These variables were then correlated with EEG spiking activity related to CNS O(2) toxicity. In wild-type (WT) mice, HBO(2) exposure transiently reduced rCBF, but by 60 min rCBF was restored to baseline levels and above, followed by EEG spikes. Mice lacking nNOS also showed initial depression of rCBF followed by hyperemia but the delay in the onset of EEG discharges was greater. In contrast, in eNOS-deficient mice rCBF did not decrease and hyperemia was less pronounced during HBO(2). EEG spike latency was longer in eNOS(-/-) compared to WT or nNOS(-/-) mice. 3-NT gradually increased in all strains during HBO(2) but accumulation was slower in nNOS(-/-) mice, consistent with less ONOO(-) production. These results indicate that NOS-deficient mice have different cerebrovascular responses and tolerance to HBO(2) depending on which enzyme isoform is affected. The data suggest a key role for eNOS-dependent NO production in cerebral vasoconstriction and in the development of hyperoxic hyperemia preceding O(2) seizures, whereas neuronal NO may mediate toxic effects of HBO(2) mainly by its reaction with superoxide to generate the stronger oxidant, peroxynitrite.
Demchenko
Ivan T
IT
Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St Petersburg, 194223, Russia.
Atochin
Dmitriy N
DN
Boso
Albert E
AE
Astern
Joshua
J
Huang
Paul L
PL
Piantadosi
Claude A
CA
D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology; D004569:Electroencephalography / Q000187:drug effects; D006931:Hyperbaric Oxygenation / Q000009:adverse effects*; D006940:Hyperemia; D007527:Isoenzymes; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism*; D010100:Oxygen / Q000633:toxicity*; D030421:Peroxynitrous Acid / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced*; D013687:Telencephalon / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*
D007527:Isoenzymes; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010100:Oxygen