Altered free radical metabolism in acute mountain sickness: implications for dynamic cerebral autoregulation and blood-brain barrier function

Abstract

We tested the hypothesis that dynamic cerebral autoregulation (CA) and blood-brain barrier (BBB) function would be compromised in acute mountain sickness (AMS) subsequent to a hypoxia-mediated alteration in systemic free radical metabolism. Eighteen male lowlanders were examined in normoxia (21% O(2)) and following 6 h passive exposure to hypoxia (12% O(2)). Blood flow velocity in the middle cerebral artery (MCAv) and mean arterial blood pressure (MAP) were measured for determination of CA following calculation of transfer function analysis and rate of regulation (RoR). Nine subjects developed clinical AMS (AMS+) and were more hypoxaemic relative to subjects without AMS (AMS-). A more marked increase in the venous concentration of the ascorbate radical (A(*-)), lipid hydroperoxides (LOOH) and increased susceptibility of low-density lipoprotein (LDL) to oxidation was observed during hypoxia in AMS+ (P < 0.05 versus AMS-). Despite a general decline in total nitric oxide (NO) in hypoxia (P < 0.05 versus normoxia), the normoxic baseline plasma and red blood cell (RBC) NO metabolite pool was lower in AMS+ with normalization observed during hypoxia (P < 0.05 versus AMS-). CA was selectively impaired in AMS+ as indicated both by an increase in the low-frequency (0.07-0.20 Hz) transfer function gain and decrease in RoR (P < 0.05 versus AMS-). However, there was no evidence for cerebral hyper-perfusion, BBB disruption or neuronal-parenchymal damage as indicated by a lack of change in MCAv, S100beta and neuron-specific enolase. In conclusion, these findings suggest that AMS is associated with altered redox homeostasis and disordered CA independent of barrier disruption.

Figure 1

Typical electron paramagnetic resonance (EPR) spectra of the ascorbate free radical (g= 2.00518; a^H4= 1.76 Gauss) detected in the venous circulation of one subject without (AMS–) and a separate subject with (AMS+) acute mountain sickness in normoxia and following 6 h passive exposure to hypoxia (12% O₂). All spectra were filtered and scaled identically. Simulation spectrum also illustrated.

Figure 2

Relationship between the change (delta: hypoxia minus normoxia) in arterial haemoglobin oxygen saturation and the ascorbate free radical (A^•−: A), lipid hydroperoxides (LOOH: B) and low density lipoprotein (LDL)-oxidation (C) in subjects with (•) and without (^) acute mountain sickness.

Figure 3

Relationship between the change (delta: hypoxia minus normoxia) in the rate of regulation (RoR, A) and low frequency (LF) transfer function gain (B) and increase in headache scores measured using a visual analog scale (VAS) in subjects with acute mountain sickness.