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(Circulation. 2006;114:1410-1416.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Role of Endothelin-1 in Exposure to High Altitude

Acute Mountain Sickness and Endothelin-1 (ACME-1) Study

Pietro Amedeo Modesti, MD, PhD; Simone Vanni, MD, PhD; Marco Morabito, PhD; Alessandra Modesti, BS, PhD; Matilde Marchetta, BS; Tania Gamberi, BS, PhD; Francesco Sofi, MD, PhD; Giulio Savia, MD; Giuseppe Mancia, MD; Gian Franco Gensini, MD; Gianfranco Parati, MD, PhD

From Clinica Medica Generale e Cardiologia (P.A.M., S.V., M. Morabito, A.M., M. Marchetta, T.G., F.S., G.F.G.), University of Florence, Florence, Italy; Don Carlo Gnocchi Foundation (P.A.M., G.F.G.), Onlus IRCCS, Florence, Italy; and Department of Clinical Medicine, Prevention and Applied Biotechnologies (G.S., G.M., G.P.), University of Milano-Bicocca and Istituto Auxologico Italiano, Milan, Italy.

Correspondence to Professor Pietro Amedeo Modesti, MD, PhD, Clinica Medica Generale e Cardiologia, University of Florence, Viale Morgagni 85, 50134 Florence, Italy. E-mail pamodesti{at}unifi.it

Received December 1, 2005; revision received June 23, 2006; accepted July 1, 2006.

Background— The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related to increased plasma endothelin (ET)-1. The aim of the present study was to investigate the effects of ET-1 antagonism on pulmonary hypertension, renal water, and sodium balance under acute and prolonged exposure to high-altitude–associated hypoxia.

Methods and Results— In a double-blind fashion, healthy volunteers were randomly assigned to receive bosentan (62.5 mg for 1 day and 125 mg for the following 2 days; n=10) or placebo (n=10) at sea level and after rapid ascent to high altitude (4559 m). At sea level, bosentan did not induce any significant changes in hemodynamic or renal parameters. At altitude, bosentan induced a significant reduction of systolic pulmonary artery pressure (21±7 versus 31±7 mm Hg, P<0.03) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment. However, both urinary volume and free water clearance (H₂OCl/glomerular filtration rate) were significantly reduced versus placebo after 2 days of ET-1 antagonism (1100±200 versus 1610±590 mL; –6.7±3.5 versus –1.8±4.8 mL/min, P<0.05 versus placebo for both). Sodium clearance and segmental tubular function were not significantly affected by bosentan administration.

Conclusions— The present results indicate that the early beneficial effect of ET-1 antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation. These findings must be considered for the prevention and treatment of acute mountain sickness.

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