Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA164

Poster Communications

Hypoxia compounds exercise-induced free radical formation in humans; partitioning contributions from the cerebral and femoral circulation

D. M. Bailey1, P. Rasmussen2, K. Evans1, A. Bohm2, M. Zaar2, H. Niel2, P. Brassard3, N. Nordsborg2, P. Homann4, P. Raven5, J. McEneny6, I. Young6, J. McCord7, N. H. Secher2

1. Faculty of Faculty of Life Sciences and Education, University of South Wales, South Wales, United Kingdom. 2. University of Copenhagen, Copenhagen, Denmark. 3. Université Laval, Laval, Quebec, Canada. 4. The Danish Health Authority, Islands Brygge 67, Denmark. 5. University of North Texas Health Science Center, Texas, United Kingdom. 6. Queen's University Belfast, Belfast, Ireland. 7. University of Colorado at Denver, Denver, Colorado, United States.

Historically considered as toxic, mutagenic "accidents" of in-vivo chemistry constrained to cellular oxidative damage and pathophysiology, it has become increasingly clear that at physiological, albeit undefined concentrations, free radicals and associated reactive oxygen species formation during hypoxia and exercise can equally serve as important signal transductants that collectively serve to defend cellular oxygen (O2) homeostasis (Bailey et al, 2017). We designed the first human study to simultaneously measure free radical exchange across the cerebral and femoral circulation to evaluate the dynamic interplay taking place as a function of altered O2 demand at rest and during exercise-induced responses to hypoxia. This was considered an ideal model system characterized by physiological extremes of O2 flux (low in brain, high in muscle) facilitating experimental manipulation of local O2 tension (PO2) independently of flux ( O2). Healthy participants (5♂, 5♀) were randomly assigned single-blinded to normoxic (21% O2) and hypoxic (10% O2) trials with measurements taken at rest and 30 min after cycling at 70% of maximal power output in hypoxia and equivalent relative and absolute intensities in normoxia. Blood was sampled from the brachial artery (a), internal jugular and femoral veins (v) for non-enzymatic antioxidants (HPLC), ascorbate radical (A●-, electron paramagnetic resonance spectroscopy), lipid hydroperoxides (LOOH) and low density lipoprotein (LDL) oxidation (spectrophotometry). Cerebral and femoral venous blood flow was evaluated by transcranial Doppler ultrasound (CBF) and constant infusion thermodilution (FBF). With 3 participants lost to follow up (final n = 4♂, 3♀), hypoxia increased CBF and FBF (P = 0.041 vs. normoxia) with further elevations in FBF during exercise (P = 0.002 vs. rest). Cerebral and femoral ascorbate and α-tocopherol consumption (v < a) was accompanied by A●-/LOOH formation (v > a) and increased LDL oxidation during hypoxia (P < 0.043 to 0.049 vs. normoxia) implying free radical-mediated lipid peroxidation subsequent to inadequate antioxidant defense. This was pronounced during exercise across the femoral circulation in proportion to the increase in local O2 uptake (r = -0.397 to -0.459, P = 0.037 to 0.045) but unrelated to any reduction in PO2. These findings highlight considerable regional heterogeneity in the oxidative stress response to hypoxia that may be more attributable to local differences in O2 flux than to O2 tension. Since arterial hypoxaemia is a hallmark feature of circulatory disease, mapping the dynamic transvascular interplay of free radicals as a function of changing O2 demand may help define sensitive biomarkers of vascular health and monitor the success of interventions designed to optimise tissue oxygenation in the critically ill.

Where applicable, experiments conform with Society ethical requirements