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

Healthy subjects exposed to acute hypobaric hypoxia at high altitude experience an acute increase in pulmonary blood pressure, which suggests a possible advantage of ET-1 blockade in acute mountain sickness. However, ET-1 plays a also role in water and sodium handling in the kidney. The effects of ET-1 antagonism on 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 the ET-1 blocker Bosentan (62,5 mg for 1 day and 125 mg for the following 2 days) at sea level and after rapid ascent to Queen Margherita hut (QMH, 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 (SPAP, 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 change in hemodynamic and renal parameters. At QMH, on Day 1 SaO2 was reduced to 74±7% (vs 99±1% at the sea level, p<0.01) and SPAP increased from 16±2 to 34±7 mmHg (p<0.01). At QMH Bosentan induced a significant reduction of SPAP 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 SPAP and SaO2 were comparable in the two groups (19±8 vs 22±6 mmHg, ns, and 81±8 % vs 81±4%, ns). Ascent to QMH 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 QMH (1096±205 ml and -0.72±0.41 ml/min, p<0.05 vs placebo for both). Sodium clearance was not significantly affected by bosentan administration. Conclusion: The present results indicate that the early beneficial effect of mixed ETA/ETB antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation during the following days. These findings have to be considered for the prevention and treatment of acute mountain sickness and HAPE.