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Faoro, Vitalie, Michel Lamotte, Gael Deboeck, Adriana Pavelescu, Sandrine Huez, Hervé Guenard, Jean-Benoît Martinot, and Robert Naeije. Effects of sildenafil on exercise capacity in hypoxic normal subjects. High Alt. Med. Biol. 8:155–163, 2007.—The phosphodiesterase-5 inhibitor sildenafil has been reported to improve hypoxic exercise capacity, but the mechanisms accounting for this observation remain incompletely understood. Sixteen healthy subjects were included in a randomized, double-blind, placebo-controlled, cross-over study on the effects of 50-mg sildenafil on echocardiographic indexes of the pulmonary circulation and on cardiopulmonary cycle exercise in normoxia, in acute normobaric hypoxia (fraction of inspired O₂ , 0.1), and then again after 2 weeks of acclimatization at 5000 m on Mount Chimborazo (Ecuador). In normoxia, sildenafil had no effect on maximum V_O2 or O₂ saturation. In acute hypoxia, sildenafil increased maximum V_O2from 27 ± 5 to 32 ± 6 mL/min/kg and O₂ saturation from 62% ± 6% to 68% ± 9%. In chronic hypoxia, sildenafil did not affect maximum V_O2 or O₂ saturation. Resting mean pulmonary artery pressure increased from 16 ± 3 mmHg in normoxia to 28 ± 5 mmHg in normobaric hypoxia and 32 ± 6 mmHg in hypobaric hypoxia. Sildenafil decreased pulmonary vascular resistance by 30% to 50% in these different conditions. We conclude that sildenafil increases exercise capacity in acute normobaric hypoxia and that this is explained by improved arterial oxygenation, rather than by a decrease in right ventricular afterload.