Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats
Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats
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DOI：
10.1152/jappl.1995.79.6.2122
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发表时间：
1995-12-01
影响因子：
3.3
通讯作者：
Oparil, S
中科院分区：
文献类型：
--
作者：
Chen, SJ;Chen, YF;Oparil, S
本研究检测了波生坦（一种内皮素-A和-B受体的口服活性拮抗剂）对大鼠缺氧（10% O-2）诱导的肺动脉高压和血管重塑的发展和维持的影响。波生坦（100 mg . kg（-1）。第（-1）天，1次灌胃/天，持续2天）完全阻断对急性缺氧的肺血管收缩反应。慢性波生坦治疗（100 mg . kg（-1）。在低氧暴露前48小时开始的第（-1）天口服食物）预防了随后肺动脉高压的发展，减弱了相关的右心肥大，并预防了小（50-100 μ m）肺动脉的重塑，而不改变全身动脉压。缺氧2周后开始波生坦治疗（持续4周）可显著逆转已建立的缺氧诱导的肺动脉高压（从36 +/- 1至25 +/- 1 mmHg）、右心肥大和肺血管重塑，尽管持续缺氧暴露。这些发现支持了内源性内皮素-1在缺氧性肺血管收缩和/或高血压、右心肥大和肺血管重塑中起主要作用的假设，并表明内皮素受体阻断剂可能在治疗人类缺氧性肺动脉高压中有用。
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% O-2)-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 mu m) 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 in humans.