Adenosine (Ado) is an important compensatory mechanism in the metabolic regulation of vascular tone when nitric oxide (NO) mechanisms are impaired.
SPECIFIC AIMS 1) To determine if inhibition of NO in humans results in increased Ado production at rest and in response to decreased oxygen supply (ischemia) or increased metabolic demand (intense exercise). 2) To test the hypothesis that in patients w/high risk for atherosclerosis and impaired NO mechanisms, basal levels of Ado are increased, and Ado release is preserved in response to ischemia and exercise. 3) To determine, in subjects w/low and high risk for atherosclerosis, the contribution of NO and Ado to local vascular regulation. 4) To determine, in the elderly and in blacks, the contribution of NO and Ado to local vascular regulation. Effect of NO on Ado release: A simplified illustration of NO and Ado pathways is presented in the diagram. NO and Ado can mediate vasodilation by activation of guanylate cyclase and adenylate cyclase, respectively. These two mediatiors are known to have similar cardiovascular effects. Recently, independent investigators found that inhibition of NO synthesis increases Ado production under baseline conditions and during reactive hyperemia. The proposed mechanism is outlined in the diagram. It has been shown that PKC increases 5'-NT activity and the release ao Ado. Conversely, both NO and NO donors inhibit PKC and decrease 5'-nucleotidase (NT) activity. During ischemia increases in Ado production can be blunted by a 5'-NT inhibitor, and PKC inhibitors blunt both, the increase in Ado and 5'-NT activation (minamino et al. 1995).

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
5M01RR000095-40
Application #
6409623
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Project Start
1977-12-01
Project End
2002-11-30
Budget Start
Budget End
Support Year
40
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37203
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