title: Role of endothelin-1 in exposure to high altitude: Acute Mountain Sickness and Endothelin-1 (ACME-1) study.
abstract: 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.
  
  
  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.
authors.affiliation: Clinica Medica Generale e Cardiologia, University of Florence, Viale Morgagni 85, 50134 Florence, Italy. pamodesti@unifi.it
authors.forename: Pietro Amedeo
authors.initials: PA
authors.lastname: Modesti
authors.forename: Simone
authors.initials: S
authors.lastname: Vanni
authors.forename: Marco
authors.initials: M
authors.lastname: Morabito
authors.forename: Alessandra
authors.initials: A
authors.lastname: Modesti
authors.forename: Matilde
authors.initials: M
authors.lastname: Marchetta
authors.forename: Tania
authors.initials: T
authors.lastname: Gamberi
authors.forename: Francesco
authors.initials: F
authors.lastname: Sofi
authors.forename: Giulio
authors.initials: G
authors.lastname: Savia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Mancia
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Gensini
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Parati
mesh_terms: D000208:Acute Disease; D000222:Adaptation, Physiological; D000328:Adult; D000531:Altitude; D000532:Altitude Sickness / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control; D001127:Arginine Vasopressin / Q000037:antagonists & inhibitors; D000077300:Bosentan; D003404:Creatinine / Q000097:blood; D004231:Diuresis / Q000187:drug effects; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000502:physiology* / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology*; D000860:Hypoxia / Q000209:etiology / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D009994:Osmolar Concentration; D010100:Oxygen / Q000097:blood; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D011651:Pulmonary Artery / Q000503:physiopathology; D011654:Pulmonary Edema / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D017466:Receptors, Endothelin / Q000502:physiology; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D024642:Potassium Channels, Voltage-Gated; D017466:Receptors, Endothelin; D013449:Sulfonamides; D001127:Arginine Vasopressin; D003404:Creatinine; D000077300:Bosentan; D010100:Oxygen