Regulation of the brain's vascular responses to oxygen.
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*.
Demchenko
Ivan T
IT
Duke University Medical Center, Durham NC 27710, USA.
Oury
Tim D
TD
Crapo
James D
JD
Piantadosi
Claude A
CA
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000098:blood supply* / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006931:Hyperbaric Oxygenation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017551:Microdialysis; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010100:Oxygen / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism; D014666:Vasomotor System / Q000187:drug effects* / Q000502:physiology
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; C000606290:SOD1 protein, human; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; C441642:SOD3 protein, human; C000606291:Sod1 protein, mouse; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D010100:Oxygen