Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, C23

Oral Communications

Exercise-induced oxidative-nitrosative stress is associated with impaired dynamic cerebral autoregulation and blood-brain barrier integrity

D. M. Bailey1,2, K. A. Evans1, J. McEneny3, I. S. Young3, D. A. Hullin4, P. E. James5, S. Ogoh6, P. N. Ainslie7, M. Culcasi2, S. Pietri2, D. Janigro8

1. Faculty of Health, Science and Sport, University of Glamorgan, South Wales, United Kingdom. 2. Sondes Moleculaires en Biologie, CNRS-Universite de Provence, Marseilles, France. 3. Centre for Clinical and Population Sciences, Queen’s University Belfast, Belfast, Ireland. 4. Department of Medical Biochemistry, Royal Glamorgan Hospital, Llantrisant, United Kingdom. 5. Wales Heart Research Institute, Cardiff University, Cardiff, United Kingdom. 6. Department of Biomedical Engineering, Toyo University, Saitama, Japan. 7. Department of Human Kinetics, University of British Columbia Okanagan, Kelowna, British Columbia, Canada. 8. Department of Medicine, Cleveland Clinic-Lerner College of Medicine, Cleveland, Ohio, United States.

Background and hypothesis: Cerebral autoregulation (CA) is a homeostatic mechanism that serves to maintain cerebral blood flow (CBF) constant over a wide range of perfusion pressures. It is especially important for the human brain given its reliance on oxygen and glucose to support the metabolic demands of neuronal activity and need to protect tissue from hypo/hyper-perfusion (Willie et al., in-the-press). In rodents, subdural perfusion with the superoxide anion impaired the dynamic rate of CA (dCA) (Zagorac et al., 2005) though human data are lacking. Given that acute exercise is an established stimulus for oxidative-nitrosative (OX-NOX) stress (Bailey et al., 2010), the current study examined if intense exercise would increase blood brain-barrier (BBB) permeability subsequent to impaired dCA. Methods: Eight healthy males were examined at rest and after an incremental bout of semi-recumbent cycling exercise to exhaustion. Changes in a dCA index [ARI (Tiecks et al., 1995)] were determined during the recovery period from continuous recordings of blood flow velocity in the middle cerebral artery (MCAv, trans-cranial Doppler ultrasound) and mean arterial pressure (finger photoplethysmography) during transiently induced hypotension (Aaslid et al., 1989). Electron paramagnetic resonance spectroscopy combined with ex-vivo spin trapping and ozone-based chemiluminescence were employed for direct detection of spin-trapped free radicals and nitric oxide (NO) respectively in venous blood. Neuron-specific enolase (NSE), S100β, and 3-nitrotyrosine (3-NT) were determined by Enzyme-Linked Immuno-Sorbent Assay. Following confirmation of distribution normality using Shapiro-Wilk W tests, data were analysed using paired samples t-tests and relationships determined with Pearson Product Moment Correlations. Significance was established at P ≤ 0.05 and data expressed as mean ± standard deviation (SD). Results: While exercise did not alter MCAv (rest: 49 ± 6 vs. 47 ± 8 cm/sec, P > 0.05), it caused a mild reduction in ARI [6.9 ± 0.6 arbitrary units (AU) to 5.5 ± 0.9 AU, P < 0.05]. This reduction correlated directly against the exercise-induced increase in the ascorbate radical (global free radical flux), 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide and α-phenyl-tert-butylnitrone-adducts (identified through simulation as a mixture of primary hydroxyl and secondary alkoxyl-alkyl radicals), 3-NT and S100β (r = -0.66 to -0.81, P ≤ 0.05). In contrast, no changes in NSE or (total) NO were observed. Conclusion: These findings are the first to suggest that intense exercise has the potential to disrupt the BBB without causing structural brain damage subsequent to a free radical-mediated impairment in dCA.

Where applicable, experiments conform with Society ethical requirements