Endothelin receptors blockade blunts hypoxia-induced increase in PAP in humans.
BACKGROUND
Activation of the endothelin-1 (ET-1) pathway may be involved in hypoxia-induced pulmonary vasoconstriction, increase in pulmonary pressure and high altitude pulmonary oedema. Thus, we investigated the effect of the ETA/ETB receptor antagonist, bosentan, on pulmonary artery systolic pressure (PASP) in healthy subjects (n = 10).


METHODS
We used a double-blind, placebo-controlled, randomized, cross-over design to study the effects of a single oral dose of bosentan (250 mg) on PASP after 90-min-exposure to normobaric hypoxia (FiO(2) = 0.12). We measured PASP and cardiac output by echocardiography, systolic arterial blood pressure, arterial O(2) saturation (SaO(2)), and blood gases at rest and during a sub-maximal exercise.


RESULTS
PASP in normoxia at rest was 23.5 +/- 2.7 and during exercise 39.8 +/- 11.6 mmHg (P < 0.0001). During the placebo period, hypoxia induced a significant decrease in SaO(2), PaO(2) and PCO(2) and increase in pH. PASP at rest increased significantly: 32.1 +/- 3.5 mmHg (P < 0.001 vs. normoxia). Bosentan significantly blunted the hypoxia-induced increase in PASP: bosentan: 27.0 +/- 3.3 mmHg, P = 0.002 vs. placebo at rest, but not during exercise: bosentan 39.8 +/- 11.6 vs. placebo 43.0 +/- 8.5 mmHg, ns. Bosentan had no effect on the hypoxia-induced changes in blood gases, or on cardiac output and systolic arterial blood pressure, which were not modified by hypoxia.


CONCLUSIONS
A single oral dose of bosentan blunted an acute hypoxia-induced increase in PASP in healthy subjects, without altering cardiac output or systemic blood pressure.
Pham
I
I
Université Paris 13-UFR SMBH, EA 2363, Bobigny, France. isabelle.pham@jvr.aphp.fr
Wuerzner
G
G
Richalet
J-P
JP
Peyrard
S
S
Azizi
M
M
D000284:Administration, Oral; D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects*; D000077300:Bosentan; D002302:Cardiac Output / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004452:Echocardiography; D065128:Endothelin Receptor Antagonists; D015444:Exercise / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan; D010100:Oxygen