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Stimulation of nitric oxide synthase in cerebral cortex due to elevated partial pressures of oxygen: an oxidative stress response
Journal article

Stimulation of nitric oxide synthase in cerebral cortex due to elevated partial pressures of oxygen: an oxidative stress response

Stephen R Thom, Veena Bhopale, Donald Fisher, Yefim Manevich, Paul L Huang and Donald G Buerk
Journal of neurobiology, v 51(2), pp 85-100
May 2002
DOI: https://doi.org/10.1002/neu.10044
PMID: 11932951
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

Animals Antioxidants - pharmacology Cerebral Cortex - enzymology Cerebral Cortex - physiology Enzyme Activation - drug effects Enzyme Activation - physiology Hyperbaric Oxygenation - methods Hyperbaric Oxygenation - statistics & numerical data Isoenzymes - deficiency Isoenzymes - metabolism Male Mice Mice, Knockout Nitric Oxide - antagonists & inhibitors Nitric Oxide - physiology Nitric Oxide Synthase - antagonists & inhibitors Nitric Oxide Synthase - deficiency Nitric Oxide Synthase - metabolism Nitric Oxide Synthase Type I Oxidative Stress - physiology Oxygen - metabolism Partial Pressure Precipitin Tests Rats Rats, Wistar
The purpose of this investigation was to determine the impact of elevated partial pressures of O(2) on the steady state concentration of nitric oxide ((*)NO) in the cerebral cortex. Rodents with implanted O(2)- and (*)NO-specific microelectrodes were exposed to O(2) at partial pressures from 0.2 to 2.8 atmospheres absolute (ATA) for up to 45 min. Elevations in (*)NO concentration occurred with all partial pressures above that of ambient air. In rats exposed to 2.8 ATA O(2) the increase was 692 +/- 73 nM (S.E., n = 5) over control. Changes were not associated with alterations in concentrations of nitric oxide synthase (NOS) enzymes. Based on studies with knock-out mice lacking genes for neuronal NOS (nNOS) or endothelial NOS (eNOS), nNOS activity contributed over 90% to total (*)NO elevation due to hyperoxia. Immunoprecipitation studies indicated that hyperoxia doubles the amount of nNOS associated with the molecular chaperone, heat shock protein 90 (Hsp90). Both (*)NO elevations and the association between nNOS and Hsp90 were inhibited in rats infused with superoxide dismutase. Elevations of (*)NO were also inhibited by treatment with the relatively specific nNOS inhibitor, 7 nitroindazole, by the ansamycin antibiotics herbimycin and geldanamycin, by the antioxidant N-acetylcysteine, by the calcium channel blocker nimodipine, and by the N-methyl-D-aspartate inhibitor, MK 801. Hyperoxia did not alter eNOS association with Hsp90, nor did it modify nNOS or eNOS associations with calmodulin, the magnitude of eNOS tyrosine phosphorylation, or nNOS phosphorylation via calmodulin kinase. Cerebral cortex blood flow, measured by laser Doppler flow probe, increased during hyperoxia and may be causally related to elevations of steady state (*)NO concentration. We conclude that hyperoxia causes an increase in (*)NO synthesis as part of a response to oxidative stress. Mechanisms for nNOS activation include augmentation in the association with Hsp90 and intracellular entry of calcium.

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Collaboration types
Domestic collaboration
Web of Science research areas
Neurosciences
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