Abstract
The mechanism of oxygen-induced cerebral vasoconstriction has been sought for more than a century. Using genetically altered mice to enhance or disrupt extracellular superoxide dismutase (EC-SOD, SOD3), we tested the hypothesis that this enzyme plays a critical role in the physiological response to oxygen in the brain by regulating nitric oxide (NO*) availability. Cerebral blood flow responses in these genetically altered mice to changes in PO2 demonstrate that SOD3 regulates equilibrium between superoxide (*O2-) and NO*, thereby controlling vascular tone and reactivity in the brain. That SOD3 opposes inactivation of NO* is shown by absence of vasoconstriction in response to PO2 in the hyperbaric range in SOD3+/+ mice, whereas NO-dependent relaxation is attenuated in SOD3-/- mutants. Thus, EC-SOD promotes NO* vasodilation by scavenging *O2- while hyperoxia opposes NO* and promotes constriction by enhancing endogenous *O2- generation and decreasing basal vasodilator effects of NO*.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blood Flow Velocity / drug effects
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Blood Pressure / drug effects
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Blood Pressure / physiology
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Brain / blood supply*
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Brain / metabolism*
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Cerebrovascular Circulation / drug effects*
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Dose-Response Relationship, Drug
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Enzyme Inhibitors / pharmacology
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Humans
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Hyperbaric Oxygenation
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microdialysis
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Nitric Oxide / metabolism
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Nitric Oxide Donors / pharmacology
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Nitric Oxide Synthase / antagonists & inhibitors
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Oxygen / pharmacology*
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Peroxynitrous Acid / metabolism
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Superoxide Dismutase / pharmacology
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Superoxide Dismutase-1
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Superoxides / metabolism
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Tyrosine / analogs & derivatives*
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Tyrosine / metabolism
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Vasomotor System / drug effects*
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Vasomotor System / physiology
Substances
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Enzyme Inhibitors
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Nitric Oxide Donors
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SOD1 protein, human
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Superoxides
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Peroxynitrous Acid
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Nitric Oxide
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3-nitrotyrosine
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Tyrosine
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Nitric Oxide Synthase
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SOD3 protein, human
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Sod1 protein, mouse
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Sod3 protein, mouse
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Superoxide Dismutase
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Superoxide Dismutase-1
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Oxygen