ADENOSINE AND NITRIC OXIDE INTERACTION IN VASCULAR REGULATION

腺苷和一氧化氮在血管调节中的相互作用

• 批准号: 7375567
• 负责人: Italo Biaggioni
• 金额: $ 0.08万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7375567
• 关键词: ADENOSINE; NITRIC; OXIDE; INTERACTION; VASCULAR

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).

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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。具体目的1)确定在人体中抑制NO是否会导致静息状态下以及在氧气供应减少(缺血)或代谢需求增加(剧烈运动)时产生更多的ADO。2)验证动脉粥样硬化高危和NO机制受损的患者基础ADO水平升高，ADO释放在缺血和运动中保持不变的假说。3)在动脉粥样硬化高危和低危人群中，确定NO和Ado在局部血管调节中的作用。4)在老年人和黑人中，确定NO和ADO对局部血管调节的贡献。NO对ADO释放的影响：图中提供了NO和ADO途径的简化图解。NO和ADO分别通过激活鸟苷环化酶和腺苷环化酶来介导血管扩张。已知这两种调节剂具有相似的心血管效应(Belardinelli等人。1989年；Moncada等人。1991年；Schulz and Trigger，1994)。最近，独立研究人员发现，在基线条件下，抑制NO合成增加了ADO的产生(Woolson et at.)和反应性充血期间(Kostic和Schrader，1992)。建议的机制如图所示。已有研究表明，PKC可增加5‘-NT活性和Ao-Ado的释放。相反，NO供体和NO供体都抑制PKC并降低5‘-核苷酸酶(NT)的活性。在缺血期间，腺苷生成的增加可以被5‘-NT抑制剂钝化，而PKC抑制剂可以钝化两者，腺苷和5’-NT激活的增加(Mininoet al.1995年)。