The effect of superoxide anion on autoregulation of cerebral blood flow

Background and Purpose - Recent studies have suggested that autoregulation of cerebral blood flow (CBF) is impaired after traumatic and ischemic brain injury. Given that the levels of superoxide anion (O₂^.-) are increased in these conditions, we postulate that O₂^.- contributes to the impairment of CBF autoregulation. Methods - CBF was monitored with laser Doppler flowmetry during increases in blood pressure. Results - During the control period, CBF was well autoregulated after the increase in mean arterial pressure (MAP) from 98±3 to 140±6 mm Hg. The autoregulation index (AI; ΔCBF/ΔMAP) averaged 0.25±0.02 (n=6). O₂^.- in the brain was then increased by subdural perfusion of xanthine/xanthine oxidase (different concentrations) and catalase. Low concentrations of O₂^.- decreased basal CBF by 10±1.6% but had no effect on autoregulation (AI, 0.19±0.02; n=6). Higher concentrations of O₂^.- (0.2 mmol/L xanthine and either 3 or 20 mU xanthine oxidase) increased basal CBF by 30±2% and 42±4%, respectively, and impaired autoregulation of CBF (AI, 0.55±0.03 and 0.76±0.02; n=6). Inclusion of superoxide dismutase in the O₂^.--generating system restored autoregulation (AI, 0.28±0.05; n=6). Neither inhibition of NO synthase nor the addition of deferioxamine had any effect on the ability of higher concentrations of O ₂^.- to impair autoregulation of CBF (AI, 0.65±0.07 and 0.72±0.05 respectively; n=6). O₂^.- also increased the activity of K_Ca channels in cerebral vascular smooth muscle cells (VSMCs; n=8). Conclusion - These results suggest that O ₂^.- increases basal CBF and impairs autoregulation of CBF, likely through the activation of K_Ca channels in cerebral VSMCs.