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

内皮素(ET)是一种内源性的强效血管收缩因子，可能参与多种心血管疾病的发病机制。已知在哺乳动物心肌中存在高密度的ET受体，在某些病理状态下，心肌组织中的ET受体表达上调。与青年大鼠相比，老年大鼠心肌ET-1受体表达上调。本研究探讨了老年大鼠心脏对ET-1的反应和ET、A、B受体基因表达的增龄变化机制，以及与增龄相关的ET受体结合特性的变化。结果：在乳头肌分离实验中，ET-1在青年大鼠引起正性变力作用，而在老年大鼠则无此作用。SR-Ca-ATP酶抑制剂环匹安酸可浓度依赖性地抑制幼年大鼠的正性变力作用。受体分析显示，ET受体的亲和力与年龄无关，但老年大鼠的ET结合密度(Bmax)显著增加。Northern印迹分析或半定量RT-PCR检测老年大鼠脑内ET、A、B受体基因表达均增加，但差异不显著。ET^A-受体和ET^B-受体的比例没有改变，提示ET反应性的改变不是由于ET^A-受体和ET^B-受体比例的改变。提示老年大鼠肌浆网钙-三磷酸腺苷酶功能下降可能是ET正性变力作用明显减弱的原因之一。另外，老年大鼠ET受体的增加可能是对心脏对ET-1反应性降低的一种适应。

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.