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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL036964-02
Application #
3352385
Study Section
Cardiovascular Study Section (CVA)
Project Start
1986-07-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Lorbar, M; Fenton, R A; Dobson Jr, J G (1999) ATP as a source of interstitial adenosine in the rat heart. Can J Physiol Pharmacol 77:579-88
Lorbar, M; Fenton, R A; Duffy, A J et al. (1999) Effect of aging on myocardial adenosine production, adenosine uptake and adenosine kinase activity in rats. J Mol Cell Cardiol 31:401-12
Ethier, M F; Dobson Jr, J G (1997) Adenosine stimulation of DNA synthesis in human endothelial cells. Am J Physiol 272:H1470-9
Dobson Jr, J G; Fenton, R A (1997) Adenosine A2 receptor function in rat ventricular myocytes. Cardiovasc Res 34:337-47
Romano, F D; Dobson Jr, J G (1996) Adenosine attenuation of isoproterenol-stimulated adenylyl cyclase activity is enhanced with aging in the adult heart. Life Sci 58:493-502
Dobson Jr, J G; Fenton, R A (1993) Adenosine inhibition of beta-adrenergic induced responses in aged hearts. Am J Physiol 265:H494-503
Ethier, M F; Chander, V; Dobson Jr, J G (1993) Adenosine stimulates proliferation of human endothelial cells in culture. Am J Physiol 265:H131-8
Fenton, R A; Dobson Jr, J G (1993) Hypoxia enhances isoproterenol-induced increase in heart interstitial adenosine, depressing beta-adrenergic contractile responses. Circ Res 72:571-8
Fenton, R A; Dobson Jr, J G (1992) Fluorometric quantitation of adenosine concentration in small samples of extracellular fluid. Anal Biochem 207:134-41
George, E E; Dobson Jr, J G (1992) Lack of oscillations in cyclic AMP, cAMP-protein kinase and glycogen phosphorylase during the cardiac cycle in perfused rat hearts. J Mol Cell Cardiol 24:477-84

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