This study examined whether
hypoxia causes
free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute
mountain sickness (AMS). Ten men provided internal jugular vein and radial artery blood samples during normoxia and 9-h passive exposure to
hypoxia (12.9% O(2)). Cerebral blood flow was determined by the Kety-Schmidt technique with net exchange calculated by the Fick principle. AMS and
headache were determined with clinically validated questionnaires. Electron paramagnetic resonance spectroscopy and
ozone-based chemiluminescence were employed for direct detection of spin-trapped
free radicals and
nitric oxide metabolites.
Neuron-specific enolase (NSE), S100beta, and
3-nitrotyrosine (3-NT) were determined by ELISA.
Hypoxia increased the arterio-jugular venous concentration difference (a-v(D)) and net cerebral output of
lipid-derived alkoxyl-alkyl
free radicals and
lipid hydroperoxides (P < 0.05 vs. normoxia) that correlated with the increase in AMS/
headache scores (r = -0.50 to -0.90, P < 0.05). This was associated with a reduction in a-v(D) and hence net cerebral uptake of plasma
nitrite and increased cerebral output of 3-NT (P < 0.05 vs. normoxia) that also correlated against AMS/
headache scores (r = 0.74-0.87, P < 0.05). In contrast,
hypoxia did not alter the cerebral exchange of S100beta and both global cerebral oxidative metabolism (cerebral metabolic rate of
oxygen) and neuronal integrity (NSE) were preserved (P > 0.05 vs. normoxia). These findings indicate that
hypoxia stimulates cerebral oxidative-nitrative stress, which has broader implications for other clinical models of human disease characterized by
hypoxemia. This may prove a risk factor for AMS by a mechanism that appears independent of impaired BBB function and cerebral oxidative metabolism.