Exogenous NADPH increases cerebral blood flow through NADPH oxidase-dependent and -independent mechanisms

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 mumol/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-omega-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.