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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1860.)
© 2004 American Heart Association, Inc.

Vascular Biology

Exogenous NADPH Increases Cerebral Blood Flow Through NADPH Oxidase–Dependent and –Independent Mechanisms

Laibaik Park; Josef Anrather; Ping Zhou; Kelly Frys; Gang Wang; Costantino Iadecola

From the Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY.

Correspondence to C. Iadecola, MD, Division of Neurobiology, Weill Medical College of Cornell University, 411 E 69th St, KB410, New York, NY 10021. 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— These data suggest that the mechanisms of the CBF increases produced by exogenous NADPH are multifactorial and include NADPH oxidase–dependent and –independent factors.

We investigated the mechanisms of the increase in cerebral blood flow (CBF) produced by NADPH. We found that the CBF response to NADPH is mediated by NADPH oxidase, but that nitric oxide synthase also plays a role. Therefore, the cerebrovascular effects of NADPH include both NADPH oxidase-dependent and -independent mechanisms.

Key Words: hydroethidine • gp91phox • cerebral blood flow • laser-Doppler flowmetry • reactive oxygen species

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