AGE-RELATED CHANGES IN THE CARDIAC RESPONSE TO ENDOTHELIN-1 AND THE RECEPTOR IN RAT VENTRICULAR MYOCARDIUM.

大鼠心室心肌内皮素-1 和受体的心脏反应与年龄相关的变化。

基本信息

批准号：
08838001
负责人：
KATANO Yumi
金额：
$ 1.41万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

Endothelin (ET) is an endogenous potent vasoconstrictor, which may be involved in the pathogenesis of various cardiovascular diseases. It has been known that a high density of ET receptors is found in mammalian myodardium and myocardial ET receptors are up-regulated in some pathologic states. We have found that ET-1-induced coronary vasoconstriction increased with age and myocardial ET receptors are up-regulated in aged rat in compare with young rat.In this study we examined the mechanisms of the age-related changes in the cardiac response to ET-1 and gene expression of ET^A-and ET^B-receptors as well as age-related changes in the binding characteristics of ET receptor in rat ventricular myocardium.Results : In experiments with isolated papillary muscles, ET-1 elicited a positive inotropic effect in the young rat, but not in aged rat. A SR-Ca-ATP ase inhibitor, cyclopiazonic acid, concentration-dependently inhibited the positive inotropic effects in the young rat. Receptor assay showed that the affinity of ET-receptor was not age-related differences, but the density (Bmax) of ET-binding was significantly increased in aged rats. Gene expression of both ET^A-and ET^B-receptors determined by Northern blotting analysis or semiquantitative RT-PCR increased in aged rats, but not significantly. The ratio of ET^A-and ET^B-receptors mRNA was not changed, suggesting that the alteration of responsiveness to ET is not due to the change in the ratio of ET^A-and ET^B-receptors. These findings suggest that the decrease in the function of SR Ca-ATP ase may be responsible for the marked attenuation of the ET-induced positive inotropic effects in the aged rat. Alternatively the increase in ET-receptor in aged rats may be an adaptation to decreased cardiac responsiveness to ET-1.

内皮素（ET）是一种内源性强效血管收缩剂，可能参与多种心血管疾病的发病机制。众所周知，哺乳动物心肌中存在高密度的ET受体，并且心肌ET受体在某些病理状态下上调。我们发现，与年轻大鼠相比，ET-1诱导的冠状血管收缩随着年龄的增长而增加，并且老年大鼠心肌ET受体的调节上调。在这项研究中，我们检查了心脏对ET反应的年龄相关变化的机制。 -1 和 ET^A-和 ET^B-受体的基因表达以及大鼠心室心肌 ET 受体结合特征的年龄相关变化。结果：在离体乳头肌的实验中， ET-1 对年轻大鼠产生正性肌力作用，但对老年大鼠则不然。 SR-Ca-ATP 酶抑制剂环匹阿尼酸可浓度依赖性地抑制幼鼠的正性肌力作用。受体测定表明，ET受体的亲和力与年龄无关，但老年大鼠ET结合密度（Bmax）显着增加。通过Northern印迹分析或半定量RT-PCR测定，老年大鼠中ET^A-和ET^B-受体的基因表达增加，但不显着。 ET^A-和ET^B-受体mRNA的比率没有改变，这表明对ET反应性的改变不是由于ET^A-和ET^B-受体比率的变化。这些发现表明，SR Ca-ATP酶功能的下降可能是老年大鼠中ET诱导的正性肌力作用显着减弱的原因。或者，老年大鼠 ET 受体的增加可能是对心脏对 ET-1 反应性降低的适应。