Chen S J, Chen Y F, Meng Q C, Durand J, Dicarlo V S, Oparil S
Division of Cardiovascular Disease, University of Alabama at Birmingham 35294, USA.
J Appl Physiol (1985). 1995 Dec;79(6):2122-31. doi: 10.1152/jappl.1995.79.6.2122.
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.
本研究检测了波生坦（一种口服活性内皮素-A和-B受体拮抗剂）对大鼠低氧（10%氧气）诱导的肺动脉高压及血管重塑的发生和维持的影响。波生坦预处理（100 mg·kg-1·天-1，每日灌胃1次，共2天）完全阻断了对急性低氧的肺血管收缩反应。在低氧暴露前48小时开始慢性波生坦治疗（食物中加入100 mg·kg-1·天-1口服）可预防随后肺动脉高压的发生，减轻相关的右心室肥厚，并防止小（50-100微米）肺动脉的重塑，而不改变体动脉压。在低氧2周后开始波生坦治疗（持续4周），尽管持续低氧暴露，已建立的低氧诱导的肺动脉高压（从36±1至25±1 mmHg）、右心室肥厚和肺血管重塑仍有显著逆转。这些发现支持以下假说：内源性内皮素-1在低氧性肺血管收缩和/或高血压、右心室肥厚和肺血管重塑中起主要作用，并提示内皮素受体阻断可能对人类低氧性肺动脉高压的治疗有用。
