Tilton R G, Munsch C L, Sherwood S J, Chen S J, Chen Y F, Wu C, Block N, Dixon R A, Brock T A
Department of Cell Biology, Texas Biotechnology Corporation, Houston, Texas 77030, USA.
Pulm Pharmacol Ther. 2000;13(2):87-97. doi: 10.1006/pupt.2000.0237.
Effects of sitaxsentan (TBC11251), an orally active, highly selective antagonist of endothelin A receptors, were examined on the development and maintenance of pulmonary hypertension, pulmonary vascular remodeling, and cardiac hypertrophy in the rat. The pulmonary vasoconstrictor response to acute hypoxia (10% O(2)for 90 min) was prevented with sitaxsentan (5 mg/kg infused iv 10 min prior to the onset of hypoxia) while BQ-788 (a specific endothelin B receptor antagonist) was without effect. The same dose of sitaxsentan delivered iv 50 min after the onset of hypoxia reversed the established pulmonary vasoconstriction. In a 2-week model of hypoxia using 10% O(2), treatment with sitaxsentan (15 mg/kg per day in drinking water) attenuated pulmonary hypertension and the associated right ventricular hypertrophy, and prevented the remodeling of small pulmonary arteries (50-100 microM) without affecting systemic arterial blood pressure or heart rate. Institution of sitaxsentan treatment (15 and 30 mg/kg per day in drinking water) for 4 weeks after 2 weeks of untreated hypoxia produced a significant, dose dependent reversal of the established pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling despite continued hypoxic exposure. Sitaxsentan blocked increased plasma endothelin levels in the prevention protocol but did not affect the established elevated levels in the intervention study. Sitaxsentan dose dependently (10 and 50 mg/kg per day in the drinking water) attenuated right ventricular systolic pressure, right heart hypertrophy, and pulmonary vascular remodeling observed 3 weeks after a single subcutaneous injection of monocrotaline. These findings support the hypothesis that endothelin-1 plays a significant role in the development of pulmonary hypertension, pulmonary vascular remodeling, and the associated cardiac hypertrophy, and further suggest that specific endothelin-A receptor blockade may be useful in the treatment of pulmonary hypertension of diverse etiologies.
研究了口服活性、高选择性内皮素A受体拮抗剂西他生坦（TBC11251）对大鼠肺动脉高压的发生发展、肺血管重塑和心脏肥大的影响。西他生坦（缺氧开始前10分钟静脉注射5毫克/千克）可预防对急性缺氧（90分钟10%氧气）的肺血管收缩反应，而BQ - 788（一种特异性内皮素B受体拮抗剂）则无此作用。缺氧开始后50分钟静脉注射相同剂量的西他生坦可逆转已建立的肺血管收缩。在使用10%氧气的2周缺氧模型中，用西他生坦（饮用水中每天15毫克/千克）治疗可减轻肺动脉高压和相关的右心室肥大，并防止小肺动脉（50 - 100微米）的重塑，而不影响体动脉血压或心率。在未经治疗的缺氧2周后，给予西他生坦治疗（饮用水中每天15和30毫克/千克）4周，尽管持续缺氧暴露，但已建立的肺动脉高压、右心肥大和肺血管重塑出现了显著的、剂量依赖性的逆转。在预防方案中，西他生坦可阻断血浆内皮素水平的升高，但在干预研究中不影响已升高的水平。单次皮下注射野百合碱3周后观察到，西他生坦（饮用水中每天10和50毫克/千克）剂量依赖性地减轻右心室收缩压、右心肥大和肺血管重塑。这些发现支持了内皮素-1在肺动脉高压、肺血管重塑及相关心脏肥大的发生中起重要作用的假说，并进一步表明特异性内皮素-A受体阻断可能对多种病因的肺动脉高压治疗有用。
