Role of Endothelin-1 in Exposure to High Altitude

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. 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; nϭ10) or placebo (nϭ10) 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 (21Ϯ7 versus 31Ϯ7 mm Hg, PϽ0.03) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment. However, both urinary volume and free water clearance (H 2 OCl/glomerular filtration rate) were significantly reduced versus placebo after 2 days of ET-1 antagonism (1100Ϯ200 versus 1610Ϯ590 mL; Ϫ6.7Ϯ3.5 versus Ϫ1.8Ϯ4.8 mL/min, PϽ0.05 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.

Pulmonary artery pressure limits exercise capacity at high altitude

“…Circulating endothelin-1 has been previously shown to be increased at high altitudes, in relation to increased Ppa and decreased arterial blood oxygenation [10,20]. Endothelin-1 appears to play a role in hypoxia-induced pulmonary hypertension.…”

“…and nonselective endothelin A and B receptor blockers prevent and reverse hypoxic pulmonary hypertension in experimental animals [23,24]. In healthy humans at high altitude, systolic Ppa is increased, and this has been shown to be partly reversed by the administration of the nonselective endothelin receptor antagonist bosentan [10]. A partial inhibition of normobaric hypoxic pulmonary vasoconstriction by the preventive intake of bosentan has been reported in healthy subjects [8].…”

“…In the present study, we tested the hypothesis that inhibition of hypoxic pulmonary vasoconstriction by the selective endothelin A receptor antagonist sitaxsentan [9] would allow for a persistent improvement in aerobic exercise in normal subjects at high altitudes. We also investigated the effects of sitaxsentan on renal function, as a decreased free water clearance has been reported after the intake of bosentan at high altitudes [10].…”

Improvement in lung diffusion by endothelin A receptor blockade at high altitude

“…No side effects of sitaxsentan were noted in the present study. Highaltitude exposure is associated with a release of endothelin-1 that is correlated to increased PAP (32). Endothelin-1 acts on the renal distal tubules and collecting ducts by inhibiting endothelin B receptor-mediated reabsorption of sodium and water (28).…”

“…Part of this improvement in exercise capacity could have been related to improved lung diffusing capacity, either as a consequence of decreased pulmonary vascular pressures (34) or inhibition of some negative effect of endothelin-1 at the alveolocapillary membrane (32). The latter would be unlikely after sitaxsentan, since there is experimental evidence that endothelin inhibits the alveolar epithelial transport of sodium and water but through the specific interaction with endothelin B receptors (5,11).…”