The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague-Dawley rats

被引:109
作者
Chen, SJ
Chen, YF
Opgenorth, TJ
Wessale, JL
Meng, QC
Durand, J
DiCarlo, VS
Oparil, S
机构
[1] UNIV ALABAMA, DIV CARDIOVASC DIS, VASC BIOL & HYPERTENS PROGRAM, BIRMINGHAM, AL 35294 USA
[2] ABBOTT LABS, DIV PHARMACEUT, ABBOTT PK, IL 60064 USA
关键词
hypoxic response; pulmonary hypertension; vascular remodeling; endothelin; endothelin-A receptor antagonist;
D O I
10.1097/00005344-199706000-00003
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Exposure to hypoxia is associated with increased pulmonary artery pressure and plasma endothelin (ET-1) levels and with selective enhancement of ET-1 peptide and messenger RNA (mRNA) and endothelin-A (ET-A) receptor mRNA in rat lung. Our study tested the hypothesis that A-127722, an orally active antagonist of the ET-A receptor, can prevent hypoxia-induced pulmonary hypertension and vascular remodeling in the rat. Pretreatment with A-127722 (3, 10, and 30 mg/kg/day in drinking water for 2 days) caused dose-dependent inhibition of the pulmonary vasoconstrictor response to short-term hypoxia (10% O-2 90 min). Long-term A-127722 treatment (10 mg/kg/day in drinking water for 2 weeks) instituted 48 h before hypoxic exposure attenuated the subsequent development of pulmonary hypertension, the associated right atrial hypertrophy, and pulmonary vascular remodeling. Institution of A-127722 treatment (10 mg/kg/day in drinking water for 4 weeks) after 2 weeks of hypoxia retarded the progression of established hypoxia-induced pulmonary hypertension and right atrial hypertrophy and reversed the 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-A receptor blockers may be useful in the treatment and prevention of hypoxic pulmonary hypertension in humans.
引用
收藏
页码:713 / 725
页数:13
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