RESUMO
We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500 mg) plus ambrisentan (5 mg) in normoxic volunteers. Subsequently, a placebo-controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267 m). No serious adverse events occurred. Drug interaction was minimal or absent. Aminophylline alleviated hypoxia-induced headaches. Aminophylline, ambrisentan, and their combination all significantly (P < 0.05 vs. placebo) improved submaximal hypoxic exercise performance (19.5, 20.6, and 19.1% >placebo). Single-dose ambrisentan increased blood oxygenation in resting, hypoxic subjects. We conclude that combined aminophylline and ambrisentan offer promise to safely increase exercise capacity in hypoxemic humans without relying on increasing blood oxygen availability.