Neuronal activation leads to an increase in regional cerebral blood flow (rCBF) and blood oxygenation (rCBO). The underlying mechanisms of neurovascular coupling are poorly understood. Recently a new model of activity induced vascular regulation was proposed by Stamler et al. (1997) based on the fact that nitric oxide (NO), a potent vasodilator, binds to hemoglobin in the oxygenated state (oxy-Hb) but is released upon deoxygenation of hemoglobin (deoxy-Hb). It was suggested that during cellular activity oxygen consumption locally increases which causes deoxygenation of hemoglobin and release of NO. Indeed it has recently been shown that red blood cell-bound NO mediates hypoxic vasodilation in vitro, and transpulmonary gradients of hemoglobin-bound NO are evident in patients with congestive heart failure (Datta et al., 2004). According to this elegant model of combined oxygen and NO release, blood flow will be directly matched to tissue oxygen demands. To test this model as a physiological mechanism of neurovascular coupling in the brain, we measured rCBF and rCBO responses to functional activation under hyperbaric oxygenation (3 ATA, FiO2 1.0) in the anesthetized rat. During hyperbaric oxygenation oxygen supply to tissue is entirely provided through physically dissolved oxygen. During activation no deoxygenation of hemoglobin and thus no allosteric release of NO occurs. Laser Doppler flowmetry combined with microfiber Hb-spectroscopy was performed through the thinned skull in rats to measure relative changes in rCBF and rCBO and cortical hemoglobin saturation. Averaged rCBF and rCBO responses to electrical forepaw stimulation (3 Hz, 10 s stimulation period) were recorded under normobaric normoxia and compared with responses during hyperbaric hyperoxygenation. Hyperbaric hyperoxygenation increased hemoglobin saturation within the microcirculation from 44 ± 2 to 103 ± 3%. The deoxy-Hb decrease normally occurring during functional activation disappeared. The oxy-Hb increase was unchanged, and the rCBF response to functional activation was increased but not decreased under hyperbaric hyperoxygenation compared with control responses. In most animals the observed increase in the rCBF response was paralleled by an increase in the amplitude of somatosensory evoked potentials. Our results suggest that in contrast to the in-vitro situation and to pathophysiological conditions of severe hypoxia rCBF regulation during physiological neuronal activation involves other mechanisms than oxygen-dependent delivery and release of NO from hemoglobin.
