VASCULAR REGULATION BY FLOW VELOCITY/ENDOTHELIUM

本项目的总体目标是确定 负责减少冠状动脉血管一氧化氮合成 这发生在心力衰竭的发展过程中。 而且我们 将确定NO生产损失对 调节血管阻力和氧消耗， 心 为了确保这些结果适用于人类疾病状态， 它们适用于导致心力衰竭的疾病，我们 将研究人类冠状动脉微血管和主动脉狭窄的狗， 以及快速起搏引起的扩张性肌病 最后是药理学 分子生物学技术将用于确定改变的 参与减少NO生产的机制。我们将确定 NO产生的改变对心肌氧控制的影响 消耗在体内和体外，并将扩大我们的研究， 微血管NO生成量增加至从衰竭中分离的微血管 人类的心脏。 一个重要的控制机制， 冠状动脉微血管中NO的产生是局部形成 激肽 这将在我们的体外研究中得到重视，因为ACE 抑制剂抑制激肽分解，并在临床上用于 心力衰竭的治疗 与Wolin博士合作（项目1） 我们会和凯利博士一起研究线粒体功能的改变 （项目4）改变体外微血管的流动依赖性调节; 并与Anversa博士（项目3）一起研究了NO作为参与信号的作用 心脏重塑 Sessa博士将参加，以延长我们的 以前的研究表明，内皮细胞NOS基因表达的改变， 大血管内皮细胞转移到微血管内皮细胞，因为这是 控制心脏阻力和血流的血管。 我们将 测量水溶液或血浆中的亚硝酸盐和硝酸盐， 项目的所有组成部分。 我们的研究将解决的作用 在心脏发生时减少冠状循环中的NO产生 在控制良好的动物模型和人类心脏中也失败了。

The overall goal of this project is to determine the mechanisms responsible for the reduction in coronary vascular nitric oxide synthesis which occurs during the development of heart failure. Furthermore, we will determine the implications of the loss of NO production to the regulation of both vascular resistance and oxygen consumption in the heart. To insure that these results apply to human disease states and that they are applicable to diseases which result in heart failure, we will study human coronary microvessels and dogs with an aortic stenosis as well as a dilated myopathy caused by rapid pacing. Finally pharmacologic and molecular biology techniques will be used to determine the altered mechanisms involved in the reduced production of NO. We will determine the impact of altered NO production on the control of myocardial oxygen consumption in vivo and in vitro and will extend our studies of coronary microvessel NO production to microvessels isolated from the failing explanted human heart. An important control mechanism governing the production of NO in coronary microvessels is the local formation of kinins. This will receive emphasis in our studies in vitro since ACE inhibitors inhibit kinin breakdown and are used clinically in the treatment of heart failure. In collaboration with Dr. Wolin (Project 1) we will investigate altered mitochondrial function, with Dr. Kaley (Project 4) altered flow dependent regulation of microvessels in vitro; and with Dr. Anversa (Project 3) the role of NO as a signal involved in cardiac remodeling. Dr. Sessa will participate in order to extend our previous studies of alterations of endothelial NOS gene expression from large vessel endothelium to microvessel endothelium since this is the vessel which controls resistance and blood flow in the heart. We will measure nitrite and nitrate in aqueous solution or plasma as a service to all the program project components. Our studies will address the role of reduced NO production in the coronary circulation in the genesis of heart failure in well controlled animal models and also in the human heart.