ADENOSINE AND BETA-ADRENERGIC ACTION IN THE AGING HEART

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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.