Endothelin-1 in Pulmonary Hypertension Associated With High-Altitude Exposure

Abstract

Background Endothelin-1 is involved in chronic pulmonary hypertension. Its role in acute pulmonary hypertension due to hypoxia in humans is not clear. We therefore studied the influence of hypoxia caused by exposure to high altitude on plasma endothelin-1 levels, arterial blood gases, and pulmonary arterial pressure in subjects taking nifedipine or placebo. Methods and Results Twenty-two healthy volunteers were investigated at low altitude (490 m) and high altitude (4559 m). Arterial blood gases were analyzed immediately, endothelin-1 was measured by radioimmunoassay, and pulmonary artery pressure was assessed by Doppler echocardiography. After baseline investigations, the mountaineers were allocated in a randomized double-blind fashion to receive either placebo or nifedipine (20 mg TID) during rapid ascent to high altitude within 22 hours. Tests were repeated at the high-altitude research laboratories located in the Capanna “Regina Margherita” (Italy, 4559 m). Plasma endothelin-1 was increased twofold at high altitude (5.9±2.2 pg/mL compared with 2.9±1.1 pg/mL, P <.05), was inversely related to arterial P o 2 ( r =−.46, P <.001), and correlated with pulmonary artery pressure ( r =.52, P <.002). At high altitude, arterial endothelin-1 was lower (4.3±1.6 pg/mL) than venous endothelin-1 (5.9±2.2 pg/mL, P <.001), indicating either predominant production in the venous vasculature or pronounced clearance in the pulmonary circulation. The calcium antagonist nifedipine, which lowered pulmonary artery pressure at high altitude (32±5 versus 42±11 mm Hg, P <.05), had no influence on plasma endothelin-1 levels. The administration of 35% O 2 at high altitude normalized arterial P o 2 , tended to decrease endothelin-1, and decreased pulmonary artery pressure accordingly. Conclusions We conclude that plasma endothelin-1 is increased at high altitude, but whether or not it represents an important pathogenetic factor for pulmonary hypertension remains to be investigated.