The endothelin receptor antagonist bosentan prevents and reverses
hypoxia induced pulmonary hypertension in the rat.
Chen, Shi-Juan, Yiu-Fai Chen, Qing Cheng Meng, Joan Durand, Vick S.
Dicarlo, Suzanne Oparil.
Vascular Biology and Hypertension Program, Division of
Cardiovascular Disease, University of Alabama at Birmingham,
Birmingham, Alabama 35294
APStracts 2:0337A, 1995.
The current study examined the effects of bosentan, an orally active
antagonist of endothelin-A (ETA) and ETB 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/day, x 2 days, per gavage) completely blocked the
pulmonary vasoconstrictor response to acute hypoxia. Chronic bosentan
treatment (100 mg/kg/day, p.o. in food) instituted 48hrs prior to
hypoxic exposure prevented the subsequent development of pulmonary
hypertension, attenuated the associated right heart hypertrophy, and
prevented the remodeling of small (50-100[mu]m) pulmonary arteries
without altering systemic arterial pressure. Institution of bosentan
treatment (for 4 wks) after 2 wks of hypoxia produced 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 ET-1 plays a major
role in hypoxic pulmonary vasoconstriction/hypertension, right heart
hypertrophy and pulmonary vascular remodeling and suggest that ET
receptor blockade may be useful in the treatment of hypoxic pulmonary
hypertension in humans.
Received 13 April 1995; accepted in final form 17 July 1995.
APS Manuscript Number A409-5.
Article publication pending Journal of Applied Physiology.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 10 August 1995.