VASCULAR REGULATION BY FLOW VELOCITY/ENDOTHELIUM

通过流速/内皮调节血管

• 批准号: 6316702
• 负责人: Thomas H HINTZE
• 金额: $ 39.44万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6316702
• 关键词: aortic valve stenosis; blood flow measurement; cardiovascular pharmacology; cellular respiration; coronary vessels; dogs; gene expression; heart circulation; heart failure; human tissue; kinins; microcirculation; myocardium disorder; nitric oxide; nitric oxide synthase; oxygen consumption; vascular endothelium; vascular resistance; vasomotion

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.

这个项目的总体目标是确定机制 冠脉血管一氧化氮合成减少的原因 它发生在心力衰竭的发展过程中。此外，我们 将决定不生产损失对 血管阻力和氧耗的调节 心。以确保这些结果适用于人类疾病状态和 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患有主动脉狭窄的狗 以及一种由快速起搏引起的扩张性肌病。最后是药理 分子生物学技术将被用来确定改变的 参与NO产量减少的机制。我们将决定 一氧化氮生成变化对心肌氧控制的影响 体内和体外的消耗，将扩大我们对冠状动脉的研究 从衰竭中分离的微血管产生微血管NO 解释了人类的心脏。一种重要的控制机制 冠状动脉微血管中一氧化氮的产生是局部形成的 金宁。自ACE以来，这将在我们的体外研究中受到重视 抑制剂抑制激动素的分解，临床上用于 治疗心力衰竭。与沃林博士合作(项目1) 我们将和Kaley博士一起研究线粒体功能的变化 (项目4)改变体外微血管的流量依赖性调节； 和Anversa博士(项目3)一起研究了NO作为信号参与的作用 心脏重塑。塞萨博士将参与其中，以延长我们的 血管内皮细胞一氧化氮合酶基因表达变化的研究进展 从大血管内皮到微血管内皮，因为这是 控制心脏阻力和血流的血管。我们会 作为服务，测量水溶液或血浆中的亚硝酸盐和硝酸盐 所有计划项目组件。我们的研究将涉及到 心脏发生过程中冠状循环中NO的生成减少 在控制良好的动物模型和人类心脏中都是失败的。