Hypoxia and vascular nitric oxide bioavailability
: Hypoximplications for the pathophysiology of high-altitude illness

  • Kevin Andrew Evans

    Student thesis: Doctoral Thesis


    Introduction: Nitric oxide (NO) is an integral molecule implicated in the control of vascular function. It has been suggested that vascular dysfunction may lead to the development of acute mountain sickness (AMS), high-altitude cerebral oedema (HACE) and high-altitude pulmonary oedema (HAPE), though data to date remains scarce. Therefore, there is a clear need for further work to address the role of NO in the pathogenesis of high-altitude illness.Aims: There were two primary aims of the current work: (1) To examine whether hypoxia mediated changes in systemic NO metabolism are related to the development of AMS andsub-clinical pulmonary oedema and (2) to examine whether hypoxia mediated changes in the trans-cerebral exchange kinetics of NO metabolites are related to the development of AMSand headache.Hypothesis: We hypothesise that hypoxia will be associated with an increase in reactive oxygen species (ROS) formation, resulting in a decrease in vascular NO bioavailability (O2•-+ NO → ONOO•-, k = 109 M.s-1). The reduction in NO will lead to vascular dysfunction and impaired oxygen (O2) delivery. Subsequent hypoxaemia will result in pulmonary vascularvasoconstriction and the development of sub-clinical pulmonary oedema within and mild brain swelling. Symptoms and reductions in NO bioavailability will be more pronounced in those who develop AMS since they are typically more hypoxaemic. Alternatively, a hypoxia mediated increase in NO, during vasodilatation, specifically across the cerebral circulation,may activate the trigminovascular system resulting in headache and by consequence, AMS.Methods: Study 1 – AMS symptoms, systemic venous NO concentration and nasal potential difference (NPD), used as a surrogate biomarker of extravascular lung oedema, werequantified in normoxia, after a 6hr passive exposure to 12% oxygen (O2) and immediately following a hypoxic maximal exercise challenge (≈6.5 hrs). Final measurements were 2 obtained two hours into (hypoxic) recovery. Study 2 – AMS, radial arterial and internal jugular venous NO metabolite concentrations and global cerebral blood flow (CBF), usingthe Kety-Schmidt technique, were assessed in normoxia and after a 9hr passive exposure to 12.9% O2. AMS was diagnosed if subjects presented with a combined Lake Louise score of≥5 points and an Environmental Symptoms Questionnaire – Cerebral score of ≥0.7 points.Results: Hypoxia was associated with a reduction in total plasma NO, primarily due to a reduction in nitrate (NO3•) and a compensatory increase in red blood cell (RBC)-bound NO(P < 0.05 vs. normoxia) in both studies. Study 1 – Exercise reduced plasma nitrite (NO2•) (P< 0.05 vs. normoxia) whereas RBC-bound NO did not change. NO was not different in those who developed AMS (AMS+) compared to those who remained comparatively more healthy (AMS-) (P < 0.05). NPD was not affected by hypoxia or exercise and was not different between AMS+ and AMS- (P > 0.05). Study 2 – Hypoxia decreased arterial concentration of total plasma NO due primarily to a reduction in NO2•- and nitrate (NO3•-). Hypoxia did not alter the cerebral metabolism of RSNO, whereas the formation of RBC-bound NO increased. Discussion: These findings suggest that alterations in systemic or trans-cerebral NO metabolism are not implicated in the pathophysiology of AMS or sub-clinical pulmonary oedema. However, hypoxia was associated with an overall reduction in the total NO pool (NOx), whereas, selected alterations in more vasoactive NO metabolites were observed. Reductions in the partial pressure of O2 (pO2) were thought to be a key regulator in these changes. Overall net increases in RBC NO and corresponding reductions in plasma NO2• in the face of no alterations in NOx indicates that rather than being simply consumed, NO is reapportioned to other NO metabolites and this may be implicated in the pathophysiology of AMS.
    Date of AwardDec 2009
    Original languageEnglish


    • Hypoxia
    • high-altitude illness
    • acute mountain sickness
    • AMS
    • high-altitude cerebral oedema
    • HACE
    • Nitric Oxide

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