Sakai S, Miyauchi T, Sakurai T, Yamaguchi I, Kobayashi M, Goto K, Sugishita Y
Department of Internal Medicine, University of Tsukuba, Japan.
J Am Coll Cardiol. 1996 Nov 15;28(6):1580-8. doi: 10.1016/s0735-1097(96)00336-1.
The purpose of this study was to investigate whether 1) endothelin-1, a potent vasoconstrictor peptide, is involved in progression of pulmonary hypertension caused by congestive heart failure (CHF); and 2) whether long-term treatment with BQ-123, an endothelin receptor antagonist, ameliorates pulmonary hypertension caused by CHF.
Congestive heart failure accompanies pulmonary hypertension, and the severity of pulmonary hypertension is an important determinant of prognosis. Although we reported that production of endothelin-1 is increased in the failing heart in rats with CHF, it is not known whether production of endothelin-1 in the lung is altered by CHF.
Congestive heart failure was induced by coronary artery ligation in rats. Expression of preproendothelin-1 messenger ribonucleic acid (mRNA) in the lung and kidney was determined. Endothelin-1 staining (immunoreactivity) in the lung was studied by immunohistochemical analysis. Effects of long-term BQ-123 treatment on the rats were studied.
Two weeks postoperatively, CHF accompanied by pulmonary hypertension developed in the rats (CHF rats). Expression of preproendothelin-1 mRNA in the lung was markedly higher in the CHF rats than in the sham-operated rats, whereas that in the kidney did not differ between the two groups. Endothelin-1 staining on the pulmonary vascular endothelial cells was more intense in the CHF rats. BQ-123 treatment over a 2-week period in the CHF rats greatly reduced right ventricular systolic pressure and central venous pressure, but it did not affect blood pressure or left ventricular contractility (peak positive first derivative of left ventricular pressure) in these rats.
Long-term BQ-123 treatment greatly ameliorated pulmonary hypertension in the CHF rats. The present study suggests that endothelin-1 plays an important role in the progression of pulmonary hypertension caused by CHF and that an endothelin receptor antagonist may be a new therapeutic agent for CHF-induced pulmonary hypertension.
本研究旨在探讨：1）内皮素-1，一种强效血管收缩肽，是否参与了由充血性心力衰竭（CHF）引起的肺动脉高压的进展；2）内皮素受体拮抗剂BQ-123的长期治疗是否能改善由CHF引起的肺动脉高压。
充血性心力衰竭伴有肺动脉高压，而肺动脉高压的严重程度是预后的重要决定因素。尽管我们报道过在CHF大鼠的衰竭心脏中内皮素-1的产生增加，但尚不清楚CHF是否会改变肺中内皮素-1的产生。
通过冠状动脉结扎在大鼠中诱导充血性心力衰竭。测定肺和肾中前内皮素-1信使核糖核酸（mRNA）的表达。通过免疫组织化学分析研究肺中内皮素-1染色（免疫反应性）。研究了长期BQ-123治疗对大鼠的影响。
术后两周，大鼠出现伴有肺动脉高压的CHF（CHF大鼠）。CHF大鼠肺中前内皮素-1 mRNA的表达明显高于假手术大鼠，而两组肾中的表达无差异。CHF大鼠肺血管内皮细胞上的内皮素-1染色更强。CHF大鼠接受2周的BQ-123治疗可大大降低右心室收缩压和中心静脉压，但不影响这些大鼠的血压或左心室收缩力（左心室压力的峰值正向一阶导数）。
长期BQ-123治疗可大大改善CHF大鼠的肺动脉高压。本研究表明内皮素-1在CHF引起的肺动脉高压进展中起重要作用，内皮素受体拮抗剂可能是治疗CHF诱导的肺动脉高压的新型治疗药物。
