CONTRIBUTION OF ENDOGENOUS ENDOTHELIN-1 TO THE PROGRESSION OF CARDIOPULMONARY ALTERATIONS IN RATS WITH MONOCROTALINE-INDUCED PULMONARY-HYPERTENSION
CONTRIBUTION OF ENDOGENOUS ENDOTHELIN-1 TO THE PROGRESSION OF CARDIOPULMONARY ALTERATIONS IN RATS WITH MONOCROTALINE-INDUCED PULMONARY-HYPERTENSION
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DOI：
10.1161/01.res.73.5.887
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发表时间：
1993-11-01
影响因子：
20.1
通讯作者：
GOTO, K
中科院分区：
文献类型：
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作者：
MIYAUCHI, T;YORIKANE, R;GOTO, K
已知内皮素-1（ET-1）对血管平滑肌细胞具有有效的收缩和增殖作用，并且已知其诱导心肌细胞肥大。我们研究了内源性ET-1在野百合碱诱导的肺动脉高压大鼠中的病理生理作用。对4周龄大鼠单次皮下注射60 mg/kg野百合碱（MCT大鼠）或生理盐水（对照大鼠），并在6、10、14、18和25天后处死。在MCT大鼠中，右心室收缩压进行性升高，右心室肥大以平行方式发展。静脉血浆ET-1浓度也进行性增加，这种增加之前的肺动脉高压的发展。MCT大鼠离体肺动脉在第25天对ET-1的反应明显减弱，但在第6天和第14天没有。在MCT大鼠中，通过北方印迹分析测量的prepro ET-1 mRNA的表达在第18天和第25天在心脏中显著增加，而在肺中逐渐减少。肺动脉高压期肺组织ET-1肽水平明显降低。ET-1前体mRNA的表达在第6天仅在肾脏中增加。应用渗透泵持续输注选择性ETA受体拮抗剂BQ-123（14.3 mg/天/大鼠，持续18天）显著抑制肺动脉高压的进展，（右心室收缩压，77.8 ± 4.2 [平均值± SEM] mm Hg [n=10] vs 52.3 ± 2.4 mm Hg [n = 7]; P <0.01）和右心室肥大（右心室/[左心室+/-室间隔]，0.56 +/- 0.03 [n=10]对0.41 +/- 0.02 [n = 71; P <0.01）。组织学检查显示，BQ-123也有效地防止肺动脉中膜增厚。BQ-123抑制右心室肥厚的作用除可预防肺动脉高压外，还可部分归因于阻断ET-1对心脏的过度刺激。目前的研究结果表明，内源性ET-1有助于与MCT诱导的肺动脉高压大鼠的心肺变化的进展。
Endothelin-1 (ET-1) is known to have potent contractile and proliferative effects on vascular smooth muscle cells and is known to induce myocardial cell hypertrophy. We studied the pathophysiological role of endogenous ET-1 in rats with monocrotaline-induced pulmonary hypertension. Four-week-old rats were given a single subcutaneous injection of 60 mg/kg monocrotaline (MCT rats) or saline (control rats) and were killed after 6, 10, 14, 18, and 25 days. In the MCT rats, right ventricular systolic pressure progressively increased and right ventricular hypertrophy developed in a parallel fashion. The venous plasma ET-1 concentration also progressively increased, and this increase preceded the development of pulmonary hypertension. The isolated pulmonary artery exhibited a significantly weaker response to ET-1 in the MCT rats on day 25 but not on days 6 and 14. In the MCT rats, the expression of prepro ET-1 mRNA as measured by Northern blot analysis significantly increased in the heart on days 18 and 25, whereas it gradually decreased in the lungs. The peptide level of ET-1 in the lungs also significantly decreased in the pulmonary hypertensive stage. The expression of prepro ET-1 mRNA had increased by day 6 only in the kidneys. Continuous infusion of BQ-123, a selective ETA receptor antagonist, by an osmotic minipump (14.3 mg per day per rat for 18 days) significantly inhibited the progression of both pulmonary hypertension (right ventricular systolic pressure, 77.8 +/- 4.2 [mean +/- SEM] mm Hg [n=10] versus 52.3 +/- 2.4 mm Hg [n = 7]; P < .01) and right ventricular hypertrophy (right ventricle/[left ventricle +/- septum], 0.56 +/- 0.03 [n=10] versus 0.41 +/- 0.02 [n = 71; P < .01). Histological examination revealed that BQ-123 also effectively prevented pulmonary arterial medial thickening. The inhibition of right ventricular hypertrophy by BQ-123 may be partly ascribed to the blockade of excessive stimulation of the heart by ET-1, in addition to the prevention of pulmonary hypertension. The present findings suggest that endogenous ET-1 contributes to the progression of cardiopulmonary alterations in rats with MCT-induced pulmonary hypertension.