Pathophysiological role of endothelin-1 on high altitude induced pulmonary hypertension. Effects of bosentan administration

Background: High altitude pulmonary edema (HAPE) is a life threatening complication with an estimated prevalence ranging from 1% in the mountaineering population, living at > 2500m, to 10% in subjects examined after rapid ascent (within 24hours) to 4559m. Although the mechanisms responsible for HAPE are not yet fully understood, in HAPE-prone subjects were found larger increases in both endothelin(ET)-1 plasma levels and systolic pulmonary artery pressure (sPAP) than in individuals who did not develop HAPE. The aim of the study was to define the pathophysiological role of ET-1 on high altitude (HA) induced pulmonary hypertension, and to evaluate the possible benefit associated with pharmacological blockade of ET-1 receptors. Methods: In a double blind placebo controlled study we randomly assigned 16 healthy adult volunteers (3 females and 13 males, age 40±11 years), to receive placebo or bosentan (62,5 mg for 1 day and 125 mg for the following 2 days) both at sea level (SL) and after rapid ascent to HA (Queen Margherita Hut, Italy, 4559 m). Non invasive measurements of oxygen saturation (Nihon-Kohden 1523, Japan) and sPAP (Echocardiography, Caris Plus Esaote) were performed daily by the same physician both at SL and at HA. Results: At SL baseline office blood pressure (115±10/70±5 mmHg), sPAP and oxygen saturation were not modified by bosentan (ns vs placebo). Oxygen saturation at HA was markedly reduced vs SL on the first day (74±7% vs 99±1%, p< 001). This was associated with a parallel increase in sPAP by 115% (from 16±2 to 34±7 mmHg), while systemic blood pressure was 126±13/80±9 mmHg (p<0.05 vs SL). Bosentan did not significantly modify systemic blood pressure (ns vs placebo) but induced a significant reduction of sPAP and a mild increase in oxygen saturation vs placebo after one day of treatment (respectively 21±7 vs 31±11 mmHg, p<0.03 and 81±6% vs 74±12%, p=0.06). At the third day sPAP and oxygen saturation were comparable in the two groups (19±8 vs 22±6, ns and 81±8 vs 81±4, ns). Conclusion: Bosentan administration effectively reduces sPAP during acute exposure to HA. This suggests a pathophysiological role of ET-1 on HA induced pulmonary hypertension, and its possible involvement in the pathogenesis of HAPE.