Effects of acute exposure to hypobaric hypoxia at high altitude on pulmonary hemodynamics and water sodium balance: Effects of endothelin-1 antagonism

The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related with increased plasma ET-1. A further increase in ET-1 release seems to occur in subjects prone to high altitude pulmonary edema (HAPE). While this suggests a possible advantage of ET-1 blockade in acute mountain sickness, the effects of ET-1 antagonism on pulmonary hypertension and renal water and sodium balance under acute and prolonged exposure to high altitude-associated hypoxia have not been explored yet. Aim of our study was to specifically investigate this issue Methods: In a double blind placebo controlled study 16 healthy adult volunteers were randomly assigned to receive placebo or bosentan (62,5 mg for 1 day and 125 mg for the following 2 days) at sea level and after rapid ascent to Regina Margherita hut (RMH, monte Rosa, Italian Alps, 4559 m). Collection of urine and plasma samples and non invasive measurements of arterial oxygen saturation (SaO2) and systolic pulmonary-artery pressure (SAP, echocardiography) (Caris Plus, Esaote, Italy) were performed daily over 3 days both at sea level and at high altitude. Results: At sea level bosentan did not induce any significant changes in hemodynamic and renal parameters. At RMH, on Day 1 SaO2 was reduced to 74±7% (vs 99±1% at the sea level, p<0.01) and SAP increased from 16±2 to 34±7 mmHg (p<0.01). At RMH Bosentan induced a significant reduction of SAP and a mild increase in SaO2 vs placebo already after one day treatment (respectively 21±7 vs 31±11 mmHg, p<0.03 and 81±6% vs 74±12%, p=0.06). On day 3 SAP and SaO2 were comparable in the two groups (19±8 vs 22±6 mmHg, ns, and 81±8 % vs 81±4%, ns). Ascent to RMH was associated with a significant increase in urinary flow rate (from 1250±597 to 1706±539 ml) and free water clearance (ClH2O) (from -1.14±0.41 to -0.22±0.27, p<0.01) which in untreated subjects remained elevated after 3 days at high altitude (1613±586 ml and -0.22±0.42 ml/min respectively). Conversely, both urinary volume and ClH2O were significantly reduced after 3 days of ET-1 antagonism at RMH (1096±205 ml and -0.72±0.41 ml/min, p<0.05 vs placebo for both). Sodium clearance and segmental tubular function were not significantly affected by bosentan administration. Conclusion: Although bosentan administration effectively reduces pulmonary SAP during acute and prolonged exposure to high altitude, mixed ETA/ETB antagonism might limit early volume adaptation to high altitude by blunting the increase in free water excretion. These findings may have implications to prevention and treatment of acute mountain sickness and HAPE.