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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/R1283    most recent 00366.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Bailey, D. M. Articles by Möller, K. PubMed PubMed Citation Articles by Bailey, D. M. Articles by Möller, K.

Articles

Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?

¹Neurovascular Research Laboratory, Faculty of Health, Science and Sport, University of Glamorgan, Mid-Glamorgan, United Kingdom; ²Centre of Inflammation and Metabolism, Department of Infectious Diseases and ³Copenhagen Muscle Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; and ⁴Centre for Public Health, Queen's University Belfast, Belfast, N. Ireland; ⁵Wales Heart Research Institute, School of Medicine, Cardiff University, Cardiff; and ⁶Department of Medical Biochemistry, Royal Glamorgan Hospital, Mid-Glamorgan, United Kingdom; ⁷Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado-Denver, Denver, Colorado; and ⁸Department of Cardiothoracic Anesthesia and Intensive Care Unit 4131, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Submitted June 29, 2009 ; accepted in final form August 26, 2009

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% O₂). 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), S100β, 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 S100β 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.

blood-brain barrier; nitric oxide; vasogenic edema; electron paramagnetic resonance spectroscopy; spin trapping