Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats.
The current study examined the effects of bosentan, an orally active antagonist of endothelin-A and -B receptors, on the development and maintenance of hypoxia (10% O2)-induced pulmonary hypertension and vascular remodeling in the rat. Pretreatment with bosentan (100 mg.kg-1.day-1, 1 gavage/day for 2 days) completely blocked the pulmonary vasoconstrictor response to acute hypoxia. Chronic bosentan treatment (100 mg.kg-1.day-1 po in the food) instituted 48 h before hypoxic exposure prevented the subsequent development of pulmonary hypertension, attenuated the associated right heart hypertrophy, and prevented the remodeling of small (50-100 microns) pulmonary arteries without altering systemic arterial pressure. Institution of bosentan treatment (for 4 wk) after 2 wk of hypoxia produced a significant reversal of established hypoxia-induced pulmonary hypertension (from 36 +/- 1 to 25 +/- 1 mmHg), right heart hypertrophy, and pulmonary vascular remodeling despite continuing hypoxic exposure. These findings support the hypothesis that endogenous endothelin-1 plays a major role in hypoxic pulmonary vasoconstriction and/or hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that endothelin-receptor blockade may be useful in the treatment of hypoxic pulmonary hypertension humans.
Chen
S J
SJ
Division of Cardiovascular Disease, University of Alabama at Birmingham 35294, USA.
Chen
Y F
YF
Meng
Q C
QC
Durand
J
J
Dicarlo
V S
VS
Oparil
S
S
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D006339:Heart Rate / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000517:prevention & control*; D000860:Hypoxia / Q000188:drug therapy* / Q000517:prevention & control*; D008297:Male; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D013449:Sulfonamides; D000077300:Bosentan