Published Online
on September 18, 2006

A more recent version of this article appeared on September 26, 2006

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Submitted on December 1, 2005
Revised on June 23, 2006
Accepted on July 1, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: pamodesti{at}unifi.it.

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.

Key words: endothelin • altitude • hypoxia • lung • oxygen • pulmonary heart disease • pressure

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