ADENOSINE AND BETA-ADRENERGIC ACTION IN THE AGING HEART

老年心脏对β-肾上腺素能刺激的反应减弱， 与年轻人的心脏相比。 初步研究表明， 老年心脏比年轻的成年心脏产生更多的腺苷。 从我们以前的工作中，众所周知，腺苷具有 心脏中的抗肾上腺素作用。 建议的总体目的 项目是研究腺苷在降低反应性中的作用， 老年人心脏对β-肾上腺素能刺激的反应。 将灌注来自逐渐老化的成年大鼠的心脏以研究 衰老、腺苷产生和腺苷减少之间的关系 β-肾上腺素能收缩（压力发展的程度和速率）和 代谢（环腺苷酸，环腺苷酸依赖性蛋白激酶，蛋白 磷酸化、糖原磷酸化酶）变量。 腺苷的作用 老年人心脏对β-肾上腺素能受体的反应降低 刺激将通过以下方式进行探索：1）确定 衰老的心脏腺苷，2）减少腺苷的积累， 衰老心脏的血管和间质液空间，3）确定 衰老的心脏对缺氧的脆弱性及其产生 腺苷，以及4）确定腺苷的间质水平如何 随着年龄和β-肾上腺素能刺激而变化。 老龄化的重要性 对5 '-核苷酸酶和腺苷脱氨酶活性的影响， 分别负责腺苷的形成和分解， 在灌注心脏、离体肌细胞、血管平滑肌中研究 和毛细血管内皮。 衰老对细胞内 腺苷水平、β-肾上腺素能受体结合特征和 将研究激素敏感腺苷酸环化酶。 这个项目代表了一种新的方法，旨在阐明一个新的， 这是一个重要的机制，负责为什么衰老的成年人的心脏不像 对β-肾上腺素能刺激的反应与年轻时一样。

The aged heart has a diminished response to Beta-adrenergic stimulation as compared to the young adult heart. Preliminary studies indicate that the aged heart produces much more adenosine than does the young adult heart. From our previous work it is well known that adenosine has an antiadrenergic action in the heart. The overall purpose of the proposed project is to study the role of adenosine in the reduced responsiveness of the aged adult heart to Beta-adrenergic stimulation. Hearts from progressively aged adult rats will be perfused to investigate the relationship between aging, adenosine production and the diminution of Beta-adrenergic contractile (extent and rate of pressure development) and metabolic (cyclic AMP, cyclic AMP-dependent protein kinase, protein phosphorylation, glycogen phosphoylase) variables. The role of adenosine in the decreased response of the aging adult heart to Beta adrenergic stimulation will be explored by, 1) determining the sensitivity of the aging heart to adenosine, 2) curtailing the build-up of adenosine in the vascular and interstitial fluid spaces of the aging heart, 3) ascertaining the vulnerability of the aging heart to hypoxia and its ability to produce adenosine, and 4) determining how the interstitial levels of adenosine change with aging and Beta-adrenergic stimulation. The importance of aging on the activities of 5'-nucleotidase and adenosine deaminase, the enzymes responsible for adenosine formation and breakdown, respectively, will be investigated in perfused hearts, isolated myocytes, vascular smooth muscle and capillary endothelium. Also the effect of aging on intracellular adenosine levels, Beta-adrenergic receptor binding characteristics and hormone sensitive adenylate cyclase will be studied. This project represents a new approach designed to elucidate a novel and important mechanism responsible for why the aging adult heart is not as responsive to Beta-adrenergic stimulation as its younger counterpart.