Sildenafil for Enhanced Performance at High Altitude?

For centuries, reduced exercise tolerance at high altitudes has frustrated mountaineers and has puzzled scientists. Horace-Benedict de Saussure, who led the second ascent to Mont Blanc (altitude, 4807 m) in 1787, recorded his pulse, respirations, temperature, and symptoms and wrote:

The sort of weariness which proceeds from the rarity of the air is absolutely insurmountable; when it is at its height, the most imminent peril will not make you move a step faster. … Since the air had hardly more than half of its usual density, compensation had to be made for the lack of density by the frequency of respirations. That is the cause of the fatigue that one experiences at great heights. For while the respiration is accelerating, so is the circulation (1).

Although de Saussure correctly attributed the decreased exercise capacity at altitude to the cardiorespiratory effects of reduced atmospheric pressure, it took another century before a decreased inspired Po₂ was recognized as the underlying cause (2). Subsequent experiments performed during expeditions and in hypobaric chambers have demonstrated an altitude-related decrease in maximum oxygen consumption that parallels the decreased inspired Po₂, but whether the main limiting factor is pulmonary, cardiovascular, or muscular has remained unclear (2, 3).

In this issue, Ghofrani and colleagues provide evidence for a cardiovascular limitation of aerobic power (work per unit of time) at altitude by showing that sildenafil improved exercise capacity in both acute normobaric hypoxia and the hypobaric conditions of a base camp on Mount Everest (4). Sildenafil, a phosphodiesterase-5 inhibitor used to treat erectile dysfunction, inhibits hypoxic pulmonary vasoconstriction (5) and has been reported to improve hemodynamics and exercise capacity in various forms of chronic pulmonary artery hypertension (6-8). Ghofrani and colleagues interpreted their provocative results as showing a sildenafil-induced …