Role of endothelin ETB receptor in the pathogenesis of monocrotaline-induced pulmonary hypertension in rats
Role of endothelin ETB receptor in the pathogenesis of monocrotaline-induced pulmonary hypertension in rats
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DOI：
10.1016/j.ejphar.2004.06.028
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发表时间：
2004-08-02
影响因子：
5
通讯作者：
Matsumura, Y
中科院分区：
文献类型：
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作者：
Nishida, M;Okada, Y;Matsumura, Y
我们使用斑点致死 (sl) 大鼠研究了内皮素 ETB 受体在野百合碱诱导的肺动脉高压发展中的作用，该大鼠携带内皮素 ETB 受体基因天然存在的缺失。注射盐水或野百合碱（60 mg/kg，皮下注射）三周后，测定血流动力学、心脏肥大和右心室内皮素-1 水平。野百合碱会产生明显的肺动脉高压，并伴有右心室压力升高和肥厚、肺动脉中层增厚和内皮素-1 水平。与野生型大鼠相比，这些野百合碱诱导的改变在 ETB 缺陷的纯合子大鼠中往往会增强。使用选择性 ETA 受体拮抗剂 ABT-627 [2R-(4-甲氧基苯基)-4S-(1,3-苯并二氧杂环戊烯-5-基)-1-(N,N-二(正丁基)氨基羰基-甲基)-吡咯烷-3R-羧酸]治疗 3 周（10 mg/kg/天，每天两次）几乎完全抑制了野百合碱诱导的肺动脉高压和相关器官损伤。野生型动物达到相同水平。因此，我们认为，无论 ETB 受体是否存在，ETA 受体的拮抗作用对于防止野百合碱诱导的肺动脉高压至关重要，尽管不能排除 ETB 受体介导的作用在该疾病模型发病机制中的保护作用。 (C) 2004 Elsevier B.V. 保留所有权利。
We investigated the role of endothelin ETB receptor in the development of monocrotaline-induced pulmonary hypertension, by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the endothelin ETB receptor gene. Three weeks after injection of saline or monocrotaline (60 mg/kg, s.c.), hemodynamics, cardiac hypertrophy and endothelin-1 levels in right ventricle were determined. Monocrotaline produced a marked pulmonary hypertension associated with increases in right ventricular pressure and hypertrophy, pulmonary arterial medial thickening and the endothelin-1 levels. These monocrotaline-induced alterations tended to be enhanced in ETB-deficient homozygous rats, compared with cases in wild-type rats. The treatment with the selective ETA receptor antagonist ABT-627 [2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid] for 3 weeks (10 mg/kg/day, twice daily) almost completely suppressed the monocrotaline-induced pulmonary hypertension and related organ damage both in ETB-deficient and wild-type animals to the same levels. Thus, we suggest that the antagonism of the ETA receptor is essential for the protection from monocrotaline-induced pulmonary hypertension, irrespective of the presence of the ETB receptors, although a protective role of ETB receptor-mediated action in the pathogenesis of this disease model cannot be ruled out. (C) 2004 Elsevier B.V. All rights reserved.