de Bisschop C, Martinot J, Leurquin-Sterk G, Faoro V, Guénard H, Naeije R. Improvement in lung diffusion by endothelin A receptor blockade at high altitude. J Appl Physiol 112: 20 -25, 2012. First published October 6, 2011 doi:10.1152/japplphysiol.00670.2011.-Lung diffusing capacity has been reported variably in high-altitude newcomers and may be in relation to different pulmonary vascular resistance (PVR). Twenty-two healthy volunteers were investigated at sea level and at 5,050 m before and after random double-blind intake of the endothelin A receptor blocker sitaxsentan (100 mg/day) vs. a placebo during 1 wk. PVR was estimated by Doppler echocardiography, and exercise capacity by maximal oxygen uptake (V O2 max). The diffusing capacities for nitric oxide (DLNO) and carbon monoxide (DLCO) were measured using a single-breath method before and 30 min after maximal exercise. The membrane component of DLCO (Dm) and capillary volume (Vc) was calculated with corrections for hemoglobin, alveolar volume, and barometric pressure. Altitude exposure was associated with unchanged DLCO, DLNO, and Dm but a slight decrease in Vc. Exercise at altitude decreased DLNO and Dm. Sitaxsentan intake improved V O2 max together with an increase in resting and postexercise DLNO and Dm. Sitaxsentan-induced decrease in PVR was inversely correlated to DLNO. Both DLCO and DLNO were correlated to V O2 max at sea level (r ϭ 0.41-0.42, P Ͻ 0.1) and more so at altitude (r ϭ 0.56 -0.59, P Ͻ 0.05). Pharmacological pulmonary vasodilation improves the membrane component of lung diffusion in high-altitude newcomers, which may contribute to exercise capacity. altitude; hypoxia; lung diffusion; gas exchange; exercise capacity; pulmonary vascular resistance; pulmonary capillary pressure; pulmonary hypertension BOTH THE MEMBRANE AND THE capillary components of lung diffusing capacity have been shown to be increased in highaltitude residents (10,13,15,25). Increased lung diffusing capacity at high altitude allows for the preservation of gas exchange in the presence of a decreased ventilatory response at exercise (15). High-altitude newcomers do not benefit from this adaptation (10,15,25) and, accordingly, depend on increased ventilation to maintain pulmonary gas exchange (15,45).Previous studies on lung diffusing capacity at high altitudes calculated the membrane and capillary components of alveolocapillary transfer of carbon monoxide (CO) using measurements at ambient air and increased inspired PO 2 (10,13,15,25). This approach rests on the PO 2 dependence of , the blood's specific transfer conductance of CO, in the Roughton and Forster equation, which states that 1/DL CO ϭ 1/Dm ϩ 1/ Vc where DL CO is the diffusing capacity of the lung for CO, Dm its membrane component, and Vc the capillary blood volume (37). Thus changing as by increasing or decreasing inspired PO 2 allows for the calculation of Dm and Vc from a simple system of two equations with two unknowns. However, changing inspired PO 2 might also change pulmonary vascular tone, cardiac output, ...