(a) Arrows in top chart indicate location and timing of exercise testing and blood sampling. Breathing frequency and heart rate before and after a standardized 2-min step exercise protocol and resting blood pressure were recorded daily for all members of the Core Team (see Methods for details). (b) Changes in haematocrit, plasma osmolality and protein concentration were quantified together with circulating levels of interleukin-6 (IL-6) tumor necrosis factor alpha (TNF-α), creatinine and erythropoietin (EPO). (c) Variables affecting oxygen delivery included partial pressure of oxygen (black bars), arterial oxygen saturation at rest (dark grey bars), haemoglobin concentration (light grey bars), and arterial oxygen content (open bars). (d) Effects of hypoxia on exercise performance, expressed as rates of oxygen consumption at the lactate threshold (LaT) and at maximal work rate (VO₂max). Results are means ± SEM; n = 24.

(a) Effects of hypoxia on oxidative stress biomarkers are expressed as differences in plasma concentration of 8-iso-prostaglandin-F_2α (8-iso-PGF; F₂-isoprostanes), 4-hydroxy-2-nonenal (HNE), and the ratio of reduced to oxidized glutathione (GSH/GSSG) at the indicated altitudes from normoxic concentrations at sea level (75 m, London, UK); (b) Circulating concentrations of the nitric oxide related metabolites, nitrite (NO₂⁻) and nitrate (NO₃⁻) as well as the second messenger cyclic guanosine 3', 5'-monophosphate (cGMP) are elevated in hypoxia while plasma S-nitrosothiols (RSNOs) experienced a dramatic drop compared to sea level conditions on arrival at Kathmandu (1,300 m) before progressively increasing. In contrast, pro atrial natriuretic peptide (proANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) variations are minimal. Plasma concentrations at each altitude correspond to time of exercise testing; means ± SEM (n = 24). (c) Correlations between NO metabolites and variables of oxygen delivery and consumption at sea level (all variables log-transformed).

(a) Directional change in associations between peak oxygen consumption (VO₂peak) and plasma nitrite at different altitudes (log-transformed values) along with an association matrix of altitude-dependent changes in NO metabolites with net efficiency at 40W. (b) Correlations between microvascular blood flow in small and medium-sized vessels and plasma nitrite as well as cyclic guanosine 3', 5'-monophosphate (cGMP; insets) concentrations. (c) Subgroup analyses for nitrate, cGMP and erythropoietin (EPO) levels in lab staff (n = 10) and climbers (n = 14); means ± SEM.