Published online before print October 24, 2002, doi: 10.1161/01.RES.0000043500.03647.81
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Submitted on April 17, 2002
Revised on October 15, 2002
Accepted on October 15, 2002
Regulation of the Brain's Vascular Responses to Oxygen
Ivan T. Demchenko ;
From Duke University Medical Center (I.T.D., C.A.P.), Durham NC; the University of Pittsburgh Medical Center (T.D.O.), Pittsburgh, Pa; and the National Jewish Medical Center (J.D.C.), Denver, Colo.
* To whom correspondence should be addressed. E-mail: piant001{at}mc.duke.edu.
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·.
Key words: cerebral blood flow • hyperoxia • superoxide dismutase • nitric oxide • peroxynitrite
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