Effects of dietary nitrate supplementation on microvascular physiology at 4559 m altitude – A randomised controlled trial (Xtreme Alps)

Andrew F Cumpstey,Philip J Hennis,Edward T Gilbert-Kawai,Bernadette O Fernandez,Daniel Grant,William Jenner,Matthieu Poudevigne,Helen Moyses,Denny Zh Levett,Alexandra Cobb,Paula Meale,Kay Mitchell,Helmut Pöhnl,Monty G Mythen,Michael Pw Grocott,Daniel S Martin,Martin Feelisch

doi:10.1016/j.niox.2019.10.004

Abstract

Native highlanders (e.g. Sherpa) demonstrate remarkable hypoxic tolerance, possibly secondary to higher levels of circulating nitric oxide (NO) and increased microcirculatory blood flow. As part of the Xtreme Alps study (a randomised placebo-controlled trial of dietary nitrate supplementation under field conditions of hypobaric hypoxia), we investigated whether dietary supplementation with nitrate could improve NO availability and microvascular blood flow in lowlanders. Plasma measurements of nitrate, nitrite and nitroso species were performed together with measurements of sublingual (sidestream dark-field camera) and forearm blood flow (venous occlusion plethysmography) in 28 healthy adult volunteers resident at 4559 m for 1 week; half receiving a beetroot-based high-nitrate supplement and half receiving an identically-tasting low nitrate ‘placebo’. Dietary supplementation increased plasma nitrate concentrations 4-fold compared to the placebo group, both at sea level (SL; 19.2 vs 76.9 μM) and at day 5 (D5) of high altitude (22.9 vs 84.3 μM, p < 0.001). Dietary nitrate supplementation also significantly increased both plasma nitrite (0.78 vs. 0.86 μM SL, 0.31 vs. 0.41 μM D5, p = 0.03) and total nitroso product (11.3 vs. 19.7 nM SL, 9.7 vs. 12.3 nM D5, p < 0.001) levels both at sea level and at 4559 m. However, plasma nitrite concentrations were more than 50% lower at 4559 m compared to sea level in both treatment groups. Despite these significant changes, dietary nitrate supplementation had no effect on any measured read-outs of sublingual or forearm blood flow, even when environmental hypoxia was experimentally reversed using supplemental oxygen. In conclusion, dietary nitrate supplementation does not improve microcirculatory function at 4559 m.

Highlights

Atmospheric pressure, and the partial pressure of oxygen, both decrease with increasing altitude
Mean hemoglobin concentration slightly increased with altitude exposure in both groups, and this effect was not influenced by the nitrate intervention
Dietary nitrate supplementation increased plasma nitrate concentrations 4-fold compared to the placebo group, both at sea level and at altitude (p < 0.001)

Summary

Introduction

Atmospheric pressure, and the partial pressure of oxygen, both decrease with increasing altitude. Sherpas, who are renowned for their exceptional performance at extreme altitudes, display only modest levels of erythropoiesis [5,6,7,8]. Both elite high altitude mountaineers and Sherpas demonstrate significantly higher muscle capillary densities than lowlander controls, suggesting that excellent altitude performance might, at least in part, be due to differences in microcirculatory function (such as exercise-induced angiogenesis or smaller fiber atrophy) [4,9]. The proportion of capillaries supporting red blood cell flux may be even more important than muscle oxygen diffusing capacity in determining overall microvascular oxygen pressures [10]

Results

Discussion

Conclusion