Chen Y F, Li H, Elton T S, Yang R H, Jin H, Oparil S
Department of Medicine, University of Alabama at Birmingham 35294.
Chin J Physiol. 1994;37(3):165-83.
The goal of our studies is to elucidate the role of atrial natrluretic peptide (ANP) and endothelin-1 (ET-1) and their receptor mechanisms in hypoxia-induced pulmonary hypertension and the control of pulmonary artery pressure in patients with pulmonary hypertension. Our experimental model is the male Sprague-Dawley rat subjected to normobaric hypoxia (10% O2, 1 atm) x 4 weeks or less. Our hypothesis is that ET-1 and ANP gene expression are enhanced by exposure to hypoxia and that the ET-1 and ANP so generated have causal and protective, respectively, effects on the development of hypoxia-induced pulmonary hypertension. Results from our studies demonstrated that ANP gene expression and ANP secretion in the heart, and the sensitivity to both endogenous and exogenous ANP in the pulmonary vasculature of hypoxia adapted rats are enhanced during hypoxic exposure. These data defined a role for ANP as a modulator hormone that protects against the development of acute hypoxic pulmonary vasoconstriction and chronic hypoxic pulmonary hypertension. Our studies also demonstrated that ET-1 and endothelin-A receptor (ET-AR) gene expression were selectively enhanced in the pulmonary vasculature by exposure to hypoxia, and that the ET-1 so generated is an important mediator in acute and chronic hypoxia-induced pulmonary hypertension. These results suggest that the intrapulmonary ET-1, acting on ET-AR receptors in the pulmonary vasculature mediates the hypoxia-induced pulmonary vasoconstriction and hypertension. In addition, our recent experiments have demonstrated that administration of BQ-123, a selective ET-AR antagonist, abolished the pulmonary vasoconstrictor response to acute (0-90 min) and chronic (2 weeks) hypoxia, further suggesting that ET-1 plays an important role in the pathogenesis of hypoxia-induced pulmonary hypertension in the rat. Results from our studies also indicate that selective ANP analogs and ET-AR antagonists may be clinically useful for the treatment of pulmonary hypertension.
我们研究的目的是阐明心房利钠肽（ANP）和内皮素-1（ET-1）及其受体机制在缺氧诱导的肺动脉高压以及肺动脉高压患者肺动脉压控制中的作用。我们的实验模型是雄性Sprague-Dawley大鼠，使其在常压缺氧（10%氧气，1个大气压）环境下暴露4周或更短时间。我们的假设是，暴露于缺氧环境会增强ET-1和ANP基因的表达，并且如此产生的ET-1和ANP分别对缺氧诱导的肺动脉高压的发展具有因果作用和保护作用。我们研究的结果表明，在缺氧暴露期间，缺氧适应大鼠心脏中的ANP基因表达和ANP分泌，以及肺血管对内源性和外源性ANP的敏感性均增强。这些数据确定了ANP作为一种调节激素的作用，可预防急性缺氧性肺血管收缩和慢性缺氧性肺动脉高压的发展。我们的研究还表明，暴露于缺氧环境会使肺血管中的ET-1和内皮素-A受体（ET-AR）基因表达选择性增强，并且如此产生的ET-1是急性和慢性缺氧诱导的肺动脉高压中的重要介质。这些结果表明，肺内ET-1作用于肺血管中的ET-AR受体，介导了缺氧诱导的肺血管收缩和高血压。此外，我们最近的实验表明，给予选择性ET-AR拮抗剂BQ-123可消除对急性（0 - 90分钟）和慢性（2周）缺氧的肺血管收缩反应，进一步表明ET-1在大鼠缺氧诱导的肺动脉高压发病机制中起重要作用。我们研究的结果还表明，选择性ANP类似物和ET-AR拮抗剂在临床上可能对肺动脉高压的治疗有用。
