Bosentan Effects in Hypoxic Pulmonary Vasoconstriction: Preliminary Study in Subjects with or without High Altitude Pulmonary Edema-History

Abstract

Hypoxia-induced pulmonary vasoconstriction in patients with a medical history of high-altitude pulmonary edema (HAPE) may involve activation of the endothelin-1 (ET-1) pathway. We, therefore, compared the effect of the ETA/ETB receptor antagonist, bosentan, on pulmonary artery systolic pressure (PASP) in healthy subjects with (HS: HAPE subjects, n=5) or without a HAPE-history (CS: Control subjects, n=10). A double-blind, placebo-controlled, randomized, crossover design was performed in order to study the effects on PASP of a single oral dose of bosentan (250 mg) after 90 min exposure to normobaric hypoxia (FiO2=0.12). In normoxia, PASP, evaluated by echocardiography, was 23.4±2.7 mmHg in CS and 28±5.8 mmHg in HS (NS). During the placebo period, hypoxia induced a significant decrease in SaO2, PaO2 and PCO2 and increase in pH in both CS and HS. Pulmonary arterial systolic pressure was also significantly increased (+8.5±5.0 mmHg in CS; +13.4±3.1 mmHg in HS) and reached significantly higher levels in HS than in CS (P=0.02). Bosentan significantly but similarly blunted the hypoxia-induced increase in PASP in both CS (Bosentan: 27.0±3.3 mmHg; placebo: 32.1±3.5 mmHg; P<0.01) and HS (Bosentan: 35.0±2.9 mmHg; placebo: 41.4±7.6 mmHg; P<0.05), (CS 5.2±5.3 vs. HS −6.4±5.2 mmHg, NS). Bosentan did not have a major effect on the hypoxia-induced changes in blood gas, or on cardiac output (CO) and systemic blood pressure (SBP), which were not modified by hypoxia. Plasma ET-1 in hypoxia during the bosentan period was 2.8 times higher than during for both CS and HS. A single oral dose of bosentan similarly blunted the hypoxia-induced increase in PASP both in healthy and HAPE-susceptible subjects, without altering CO or SBP.

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Topics

Endothelin and Endothelium & Epithelium and Epithelial Transport
High Altitude and Hypoxia
Hypoxia/ Intermittent Hypoxia/ Hypoxia-Ischemia and Ischemia-Reperfusion Injury

Authors

Isabelle Pham, Grégoire Wuerzner, Jean-Paul Richalet, Séverine Peyrard, Michel Azizi

Published in:

Pulmonary Circulation Vol 2: No 1 cover image

March 2012

Pulmonary Circulation Vol 2: No 1

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