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）是一种内源性有效的血管收缩剂，可能与各种心血管疾病的发病机理有关。众所周知，在哺乳动物肌心肌中发现了高密度的ET受体，在某些病理状态下，心肌ET受体被上调。 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分离的乳头肌肉的实验ET-1引起了年轻大鼠的阳性肌力作用，但在老年大鼠中没有引起阳性。 SR-CA-ATP ASE抑制剂环皮二唑酸浓度依赖性地抑制了年轻大鼠的阳性肌力作用。受体分析表明，ET受体的亲和力不是与年龄相关的差异，但是老年大鼠的ET结合的密度（BMAX）显着增加。通过北印迹分析或半定量RT-PCR确定的ET^a和et^b受体的基因表达在老年大鼠中增加，但没有显着。 Et^a-and et^b受体mRNA的比率没有改变，这表明对ET的反应性的改变不是由于Et^a-and et^b受体比率的变化所致。这些发现表明，SR CA-ATP ASE功能的下降可能是造成ET诱导的老年大鼠阳性正性效应的明显衰减的原因。或者，老年大鼠ET受体的增加可能是对降低对ET-1的心脏反应性的适应性。