Endothelin-1 and the pulmonary vascular response to altitude: a new therapeutic target?

Ascent to high altitude is normally associated with a modest increase in pulmonary artery pressure.1 The increased right ventricular afterload, coupled with hypobaric hypoxia-induced reductions in blood oxygen content, may lead to diminished peripheral oxygen delivery and result in dyspnea, fatigue, and exercise intolerance.2 The predominant mechanism responsible for the increase in pulmonary artery pressure at altitude is hypoxic pulmonary vasoconstriction, which is mediated through an oxygensensitive pulmonary artery smooth muscle cell voltage-gated K channel.3 The primary site of hypoxic pulmonary vasoconstriction is the small (50 to 200 m) muscular pulmonary arteries, although the pulmonary venous circuit may contribute up to 20% of the pressor response.4 A more clinically significant and potentially fatal cardiovascular consequence of exposure to altitude is the development of high-altitude pulmonary edema (HAPE). Risk factors for HAPE include gender, rate of altitude ascent, recent respiratory infection, and prior acclimatization5; a genetic susceptibility also has been suggested.6 Although the mechanisms responsible for the development of HAPE remain unclear, it is associated with greater increases in pulmonary artery pressure and increased pulmonary capillary pressure, which results in hydrostatic pulmonary edema.7 The increased capillary pressure despite normal left ventricular function suggests that an exaggerated pulmonary venoconstrictor response may play a critical role. A variety of vasoactive substances are elaborated in the pressor response to altitude and in particular HAPE, including endothelin-1 (ET-1), a potent pulmonary arterial and venous constrictor.8 In this issue of Circulation, Modesti and colleagues9 provide further evidence of the contribution of ET-1 to the pulmonary vascular responses to altitude by demonstrating that the administration of bosentan, a dual ETA and ETB receptor antagonist that is approved for the treatment of chronic pulmonary arterial hypertension,10 attenuated the pressor response in normal subjects at altitude.