CORONARY VASCULAR RESPONSE TO ISCHEMIA

本提案中的研究旨在深入了解 冠状动脉微血管系统的反应机制， 影响缺血心肌的灌注。这些研究的目的 是定义冠状动脉阻力的功能反应 血流限制性冠状动脉远端心肌区域中的血管 动脉狭窄或侧支通道灌注的区域， 可以影响心肌缺血的发展， 可能会受到治疗干预。研究将 在长期使用仪器的犬中进行，其中冠状动脉 用多普勒流量计测量血流， 收缩功能用超声微晶体评估。 用微球测量心肌灌注;主动脉和 冠状静脉导管将允许测量一氧化氮 (NO)由冠状血管系统产生。初步研究将 确定运动是否刺激NO的产生，以及是否 在冠状动脉狭窄的情况下进行运动， 心肌缺血导致NO产生的进一步增加。一 后续研究将检查代谢之间的相互作用 K+ATP通道开放介导的冠状动脉舒张机制 和腺苷，以确定是否阻断代谢 血管扩张机制增加冠状动脉NO的产生。第二 一组研究将检查冠状动脉阻力的反应， 血管通过络脉灌注。抵押品 反复短暂冠状动脉扩张将诱导血管发育 闭塞或通过在左侧放置Ameroid缩窄器 冠状动脉前降支初步研究将 确定ACIA-核苷是否可以选择性地增加腺苷 在侧支心肌中产生，从而增强 运动时侧支依赖区的灌注。一 第二项研究将测量侧支血管的NO产生， 在体内通过侧支灌注的远端冠状血管系统， 确定冠状血管中NO的产生是否减少 通过络脉灌注。第三协议 将决定是否基础或刺激NO的生产， 从侧支分离的冠状动脉微血管减少- 依赖性心肌区最终的协议将决定 是否存在组成性内皮细胞的表达减少， NO合酶mRNA或蛋白质在侧支依赖区，和 侧支依赖区是否表现出 诱导型NO合酶mRNA或蛋白。

The studies in this proposal are designed to provide insight into mechanisms by which responses of the coronary microvasculature can affect perfusion of ischemic myocardium. The goal of these studies is to define functional responses of the coronary resistance vessels in myocardial regions distal to a flow limiting coronary artery stenosis or in regions perfused by collateral channels that can influence the development of myocardial ischemia and which might be amenable to therapeutic intervention. Studies will be performed in chronically instrumented dogs in which coronary artery flow is measured with a Doppler flowmeter while regional systolic contractile function is assessed with ultrasonic microcrystals. Myocardial perfusion is measured with microspheres; aortic and coronary venous catheters will allow measurement of nitric oxide (NO) production by the coronary vasculature. Initial studies will determine whether exercise stimulates NO production, and whether exercise in the presence of a coronary stenosis which results in myocardial ischemia causes a further increase in NO production. A subsequent study will examine-interactions between metabolic coronary vasodilator mechanisms mediated by K+ATP channel opening and adenosine to determine whether blockade of metabolic vasodilator mechanisms augments coronary NO production. A second group of studies will examine responses of coronary resistance vessels which are perfused through collateral channels. Collateral vessel development will be induced with repeated brief coronary occlusions or by placement of an ameroid constrictor on the left anterior descending coronary artery. An initial study will determine whether ACIA-riboside can selectively increase adenosine production in collateralized myocardium, thereby augmenting perfusion of the collateral-dependent region during exercise. A second study will measure NO production by collateral vessels and distal coronary vasculature perfused by collaterals in vivo, to determine whether NO production is decreased in coronary vessels which are perfused through collateral channels. A third protocol will determine whether basal or stimulated NO production is decreased in coronary microvessels isolated from a collateral- dependent myocardial region. A final protocol will determine whether there is decreased expression of constitutive endothelial NO synthase mRNA or protein in the collateral-dependent region, and whether the collateral-dependent region demonstrates expression of inducible NO synthase mRNA or protein.