title: Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?
abstract: 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.
authors.affiliation: Neurovascular Research Laboratory, Faculty of Health, Science and Sport, University of Glamorgan, Mid-Glamorgan, United Kingdom. dbailey1@glam.ac.uk
authors.forename: Damian M
authors.initials: DM
authors.lastname: Bailey
authors.forename: Sarah
authors.initials: S
authors.lastname: Taudorf
authors.forename: Ronan M G
authors.initials: RM
authors.lastname: Berg
authors.forename: Carsten
authors.initials: C
authors.lastname: Lundby
authors.forename: Jane
authors.initials: J
authors.lastname: McEneny
authors.forename: Ian S
authors.initials: IS
authors.lastname: Young
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Evans
authors.forename: Philip E
authors.initials: PE
authors.lastname: James
authors.forename: Angharad
authors.initials: A
authors.lastname: Shore
authors.forename: David A
authors.initials: DA
authors.lastname: Hullin
authors.forename: Joe M
authors.initials: JM
authors.lastname: McCord
authors.forename: Bente K
authors.initials: BK
authors.lastname: Pedersen
authors.forename: Kirsten
authors.initials: K
authors.lastname: Möller
mesh_terms: D000208:Acute Disease; D000328:Adult; D000532:Altitude Sickness / Q000453:epidemiology / Q000378:metabolism* / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism*; D006261:Headache / Q000378:metabolism / Q000503:physiopathology; D006306:Health Surveys; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010100:Oxygen / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D012189:Retrospective Studies; D012307:Risk Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005609:Free Radicals; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C002744:3-nitrotyrosine; D014443:Tyrosine; D010751:Phosphopyruvate Hydratase; D010100:Oxygen