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 (0.07-0.20Hz) 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, S100β and neuron-specific enolase. In conclusion, these findings suggest that AMS is associated with altered redox homeostasis and disordered CA independent of barrier disruption.

Cerebral Pressure–Flow Relationship in Lowlanders and Natives at High Altitude

“…We hypothesized that: (1) The dynamic cerebral pressure-flow relationship will be impaired at HA upon initial arrival and after acclimatization, as assessed using spontaneous TFA measures; however, when BP variability is maximized via repeated squatstand maneuvers, the pressure-flow relationship will remain intact; (2) As highlighted in well-controlled chamber studies, 7,8,19 there will be no correlation between changes in the pressure-flow relationship upon initial arrival to 5,050 m with symptoms of AMS; (3) HA natives will have intrinsic differences in pressure-flow coupling compared with acclimatized lowlanders at 5,050 m.…”

Acute high-altitude sickness

“…A further consequence of more severe hypoxaemia could be an increase in vascular permeability through a higher oxidative stress [35], low-grade inflammation [36] or increased hypoxia-inducible transcription factor-dependent expression of vascular endothelial growth factor (VEGF), which might be involved in the pathophysiology of HACE as suggested by animal experiments [37]. However, in AMS, lumbar punctures reveal an intact blood-brain barrier for large molecular weight proteins [38].…”

“…Disturbed autoregulation may occur in AMS [35,46] and could enhance pressure transduction to the brain, although findings are controversial [47]. Repeated transient increases of ICP may sensitise trigeminal nociception [48] and decrease compliance of the CNS to a variable degree, since the capacity for spatial compensation varies considerably between individuals [49].…”

Cerebral Formation of Free Radicals during Hypoxia Does Not Cause Structural Damage and is Associated with a Reduction in Mitochondrial PO2; Evidence of O2-Sensing in Humans?

“…Exactly 1 mL of plasma was injected into a highsensitivity multiple-bore sample cell (AquaX, Bruker Instruments Inc., Billerica, MA, USA) housed within a TM 110 cavity and analyzed by X-band electron paramagnetic resonance spectroscopy operating at 100 kHz modulation frequency, 0.65 Gauss (G) modulation amplitude, 10 mW microwave power, 2 Â 10 5 receiver gain, and 41 milliseconds time constant for 3 incremental scans (Bailey et al, 2009b). Spectra were filtered identically using WINEPR (Version 2.11, Bruker, Karlsruhe, Germany), and the double integral of each doublet was calculated using the Origin software (Version 5.0, OriginLab s , Northampton, MA, USA).…”

“…A clinically validated visual analog scale was used to measure headache (Iversen et al, 1989). Clinical AMS was diagnosed if a subject presented with a combined total LL score (self assessment + clinical score) of X5 points and ESQ-C score X0.7 points (Bailey et al, 2009b).…”