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

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Abstract
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%, P2O2 scavenger catalase. The response was also attenuated by gp91ds-tat (−64%, PNω-nitro-l-arginine (−44%, PPConclusions— 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.