This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 (Belardinelli et al. 1989; Moncada et al. 1991; Schulz and Triggle, 1994). Recently, independent investigators found that inhibition of NO synthesis increases Ado production under baseline conditions (Woolson et at. 1995) and during reactive hyperemia (Kostic and Schrader, 1992). 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).
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