In the proposed study the relationship between purine metabolism and myocardial function in the post-ischemic state will be examined. During myocardial ischemia regional function ceases and myocardial nucleotide pools decrease. Even if perfusion is instituted before irreversible injury occurs, myocardial function and nucleotide content require a prolonged period to be restored to normal. Because of the importance of purine nucleotides in many cellular processes it is hypothesized that the two observations are related. A model will be developed, using conscious mongrel dogs, to examine the rate of return of regional myocardial function and the rate of repletion of nucleotide pools following ischemia. 5-Amino-4-imidazolecarboxamide riboside (AICAriboside), an agent that has been demonstrated to selectively enhance purine nucleotide synthesis in vivo, will be used to determine whether repletion of nucleotide pools is both necessary and sufficient for restoration of normal myocardial function. Additional studies are proposed to further characterize the metabolism of AICAribose using fetal mouse hearts in organ culture. Another series of studies will examine possible mechanisms for delayed repletion of nucleotide pools. Enzymatic activities and substrate concentrations of both the de novo and salvage pathways of purine synthesis will be determined. Also, the possibility that prolonged myocardial dysfunction is secondary to a primary abnormality in contractile proteins will be examined in studies utilizing isolated myofibrils. Finally, the alterations in purine metabolism produced by ischemia will form the basis for the development of a diagnostic test to document myocardial ischemia. The proposed studies will examine possible mechanisms of post-ischemic myocardial dysfunction. If specific mechanisms can be identified, then interventions to improve myocardial function can be developed. These interventions may be applicable to patients with post-ischemic myocardial dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL026831-05
Application #
3338737
Study Section
Cardiovascular and Pulmonary Research B Study Section (CVB)
Project Start
1981-02-01
Project End
1987-01-31
Budget Start
1985-02-01
Budget End
1986-01-31
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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