The long-term objective of this project is to investigate the hypothesis that adenosine functions as a negative-feedback regulator of catecholamine-elicited responses in the mammalian heart.
One specific aim i s to reveal the importance of extracellular (interstitial) adenosine in the antiadrenergic actions of the nucleoside in isolated working hearts. Another specific aim is to investigate the ability of adenosine to modulate intracellular calcium of adult primary cultured ventricular myocytes using an intracellular calcium sensitive fluorescent indicator. Finally, and of primary importance are the studies designed to investigate the membrane biochemical mechanisms by which adenosine, upon interaction with its inhibitory receptor, manifests its antiadrenergic actions in the myocardial cell. For the last series of studies cultured ventricular myocytes and ventricular membranes will be utilized. The knowledge gained from this project should contribute significantly to the physiological characterization of the antiadrenergic action of adenosine in the normal working heart. The new knowledge should also provide insight into the way in which mechanisms regulating myocardial contractile state are altered in the failing and hypoxic heart, such as in conditions of cardiac and coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL022828-13
Application #
3485798
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1978-07-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
13
Fiscal Year
1990
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
Monahan, T S; Sawmiller, D R; Fenton, R A et al. (2000) Adenosine A(2a)-receptor activation increases contractility in isolated perfused hearts. Am J Physiol Heart Circ Physiol 279:H1472-81
Fenton, R A; Dickson, E W; Meyer, T E et al. (2000) Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol 32:1371-5
Norton, G R; Woodiwiss, A J; McGinn, R J et al. (1999) Adenosine A1 receptor-mediated antiadrenergic effects are modulated by A2a receptor activation in rat heart. Am J Physiol 276:H341-9
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
Woodiwiss, A J; Honeyman, T W; Fenton, R A et al. (1999) Adenosine A2a-receptor activation enhances cardiomyocyte shortening via Ca2+-independent and -dependent mechanisms. Am J Physiol 276:H1434-41
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
Sawmiller, D R; Fenton, R A; Dobson Jr, J G (1998) Myocardial adenosine A1-receptor sensitivity during juvenile and adult stages of maturation. Am J Physiol 274:H627-35
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
Dobson Jr, J G; Fenton, R A; Sawmiller, D R (1996) The contractile response of the ventricular myocardium to adenosine A1 and A2 receptor stimulation. Ann N Y Acad Sci 793:64-73

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