on August 12, 2004
Published online before print August 12, 2004, doi: 10.1161/01.ATV.0000142446.75898.44
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Submitted on April 23, 2004
Accepted on August 4, 2004
Exogenous NADPH Increases Cerebral Blood Flow Through NADPH Oxidase-Dependent and -Independent Mechanisms
Laibaik Park ;
From the Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY.
* To whom correspondence should be addressed. E-mail: coi2001{at}med.cornell.edu.
Objective--NADPH, a substrate for the superoxide-producing enzyme NADPH oxidase, produces vasodilation in the cerebral circulation. However, the mechanisms of the effect have not been fully elucidated. We used a peptide inhibitor of NADPH oxidase (gp91ds-tat) and null mice lacking the gp91phox subunit of NADPH oxidase to examine the mechanisms of the cerebrovascular effects of exogenous NADPH.
Methods and Results--Cerebral blood flow (CBF) was assessed by laser-Doppler flowmetry in anesthetized mice equipped with a cranial window. Superfusion with NADPH increased CBF (27% at 100 µmol/L) without affecting the EEG. The CBF increase was attenuated by the free-radical scavenger MnTBAP (-54%, P<0.05) but not by the H2O2 scavenger catalase. The response was also attenuated by gp91ds-tat (-64%, P<0.05) and by the nitric oxide synthase inhibitor N
-nitro-L-arginine (-44%, P<0.05). The increase in CBF produced by NADPH was attenuated in gp91-null mice (-41%, P<0.05). NADPH increased production of reactive oxygen species, assessed by hydroethidine microfluorography, an effect blocked by MnTBAP or gp91ds-tat and not observed in gp91-null mice.
Conclusions--The data suggest that the mechanisms of the CBF increases produced by exogenous NADPH are multifactorial and include NADPH oxidase-dependent and -independent factors.
Key words: hydroethidine • gp91phox • cerebral blood flow • laser-Doppler flowmetry • reactive oxygen species
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