High-altitude pulmonary hypertension is associated with a free radical-mediated reduction in pulmonary nitric oxide bioavailability

Abstract

High altitude (HA)-induced pulmonary hypertension may be due to a free radical-mediated reduction in pulmonary nitric oxide (NO) bioavailability. We hypothesised that the increase in pulmonary artery systolic pressure (PASP) at HA would be associated with a net transpulmonary output of free radicals and corresponding loss of bioactive NO metabolites. Twenty-six mountaineers provided central venous and radial arterial samples at low altitude (LA) and following active ascent to 4559 m (HA). PASP was determined by Doppler echocardiography, pulmonary blood flow by inert gas re-breathing, and vasoactive exchange via the Fick principle. Acute mountain sickness (AMS) and high-altitude pulmonary oedema (HAPE) were diagnosed using clinical questionnaires and chest radiography. Electron paramagnetic resonance spectroscopy, ozone-based chemiluminescence and ELISA were employed for plasma detection of the ascorbate free radical (A(·-)), NO metabolites and 3-nitrotyrosine (3-NT). Fourteen subjects were diagnosed with AMS and three of four HAPE-susceptible subjects developed HAPE. Ascent decreased the arterio-central venous concentration difference (a-cv(D)) resulting in a net transpulmonary loss of ascorbate, α-tocopherol and bioactive NO metabolites (P < 0.05 vs. LA). This was accompanied by an increased a-cv(D) and net output of A(·-) and lipid hydroperoxides (P < 0.05 vs. sea level, SL) that correlated against the rise in PASP (r = 0.56-0.62, P < 0.05) and arterial 3-NT (r = 0.48-0.63, P < 0.05) that was more pronounced in HAPE. These findings suggest that increased PASP and vascular resistance observed at HA are associated with a free radical-mediated reduction in pulmonary NO bioavailability.

Figure 1

A, oxidation of the ascorbate monoanion (AH⁻) by an initiating species (R^·) with a one electron reduction potential (E°′) greater than +282 mV to yield the domesticated ascorbate radical (A^·−). The unpaired electron is delocalised over a highly conjugated tricarbonyl system rendering it resonance-stabilised, thus facilitating direct detection by electron paramagnetic resonance (EPR) spectroscopy. B, typical changes in the EPR spectral intensity of A^·− in a healthy control and subject with high-altitude pulmonary oedema (HAPE) who presented with the highest PASP value by HA-20h (66 mmHg) and most severe radiographic score (12 points) with oedema present in all 4 quadrants of the lungs.

Figure 2. Relationship between changes (Δ, calculated as the value at HA-20h minus the SL control value) in pulmonary artery systolic pressure (PASP) and transpulmonary exchange of the ascorbate radical (A^·−) (A) and lipid hydroperoxides (LOOH) (B)

Filled circles represent subjects who developed HAPE (n= 3, one of whom was not identified as HAPE susceptible (HAPE-S) at SL) and open circles represent additional subjects identified as HAPE-S but who did not develop HAPE (n= 2).