Bosentan Decreases Pulmonary Vascular Resistance and Improves Exercise Capacity in Acute Hypoxia

Background: Altitude exposure is associated with mild pulmonary hypertension and decreased exercise capacity. We tested the hypothesis that pulmonary vascular resistance (PVR) contributes to decreased exercise capacity in hypoxic health), subjects. Methods: An incremental cycle ergometer cardiopulmonary exercise test and echocardiographic estimation of pulmonary artery pressure (Ppa) and cardiac output to calculate total PVR were performed in 11 healthy volunteers in normoxia and after 1 h of hypoxic breathing (12% O-2). The measurements were performed in a random order at 1-week intervals after the receiving either a placebo or bosentan, following a double-blind randomized crossover design. Bosentan was administered twice a day for 3 days, 62.5 mg on the first day and 125 mg on the next 2 days. Results: Hypoxic breathing decreased the mean (+/- SE) pulse oximetric saturation (Spo(2)) from 99 +/- 1% to 3 +/- 1% and increased the mean PVR from 5.6 +/- 0.3 to 7.2 +/- 0.5 mm Hg/L/min/m(2), together with a decrease in mean maximum 02 uptake ((v) over dotO(2) max) from 47 +/- 2 to 35 +/- 2 mL/kg/min. Bosentan had no effect on normoxic measurements and did not affect hypoxic Spo(2), but decreased PVR to 5.6 +/- 0.3 min Hg/L/min/m(2) (p < 0.01)and increased (v) over doto(2)max to 39 +/- 2 mL/kg/min (p < 0.01) in hypoxia. Bosentan therapy, on average, restored 30% of the hypoxia-induced decrease in (v) over doto(2)max. Bosentan-induced changes in Ppa and (v) over dot(2)max correlated (p = 0.01). Conclusions: We conclude that hypoxic pulmonary hypertension partially limits exercise capacity in healthy subjects, and that bosentan therapy can prevent it. (CHEST 2009; 135:1215-1222)