ADENOSINE AND NITRIC OXIDE INTERACTION IN VASCULAR REGULATION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。当一氧化氮（NO）机制受损时，腺苷（Ado）是血管张力代谢调节的重要代偿机制。1）确定在人中抑制NO是否导致在休息时和响应于减少的氧供应（缺血）或增加的代谢需求（剧烈运动）的Ado产生增加。2)为了验证以下假设：在动脉粥样硬化和NO机制受损的高风险患者中，基础Ado水平增加，并且响应于缺血和运动而保持Ado释放。3)确定动脉粥样硬化低风险和高风险受试者中NO和Ado对局部血管调节的贡献。4)确定老年人和黑人中NO和Ado对局部血管调节的贡献。NO对Ado释放的影响：图中给出了NO和Ado途径的简化说明。NO和Ado分别通过激活鸟苷酸环化酶和腺苷酸环化酶介导血管舒张。已知这两种介质具有相似的心血管效应（Belardinelli等人，1989; Moncada等人，1991; Schulz和Triggle，1994）。最近，独立的研究者发现，在基线条件下，NO合成的抑制增加了Ado的产生（Woolson et al. 1995）和反应性充血期间（Kostic和Schrader，1992）。拟议的机制在图表中概述。研究表明，PKC可增加5 ′-NT活性和腺苷酸的释放。相反，NO和NO供体都抑制PKC并降低5 '-核苷酸酶（NT）活性。在局部缺血期间，Ado产生的增加可被5 '-NT抑制剂减弱，PKC抑制剂减弱Ado和5'-NT活化的增加（minamino等，1995）。

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).