CORONARY VASCULAR RESPONSE TO ISCHEMIA

这项建议中的研究旨在提供对 冠脉微血管反应的机制 影响缺血心肌的血流灌注。这些研究的目标是 是为了定义冠状动脉阻力的功能反应 血流受限冠脉远端心肌区的血管 动脉狭窄或在经络灌流的区域 会影响心肌缺血的发展，而 可能要接受治疗干预。研究将会是 在慢性器械犬中进行，在其中冠状动脉 当局部收缩时，用多普勒流量计测量流量 用超声微晶评价其收缩功能。 心肌血流灌注用微球测量；主动脉和 冠状静脉导管将允许测量一氧化氮 (否)冠状血管系统产生。初步研究将 确定运动是否刺激NO产生，以及是否 在存在冠状动脉狭窄的情况下进行锻炼 心肌缺血会进一步增加NO的生成。一个 后续研究将检验-代谢之间的相互作用 K+-ATP通道开放介导的冠状动脉扩张剂机制 和腺苷来确定是否阻断代谢 血管扩张剂机制增加冠脉一氧化氮的产生。一秒钟 一组研究将检查冠状动脉阻力的反应 通过络脉灌流的血管。抵押品 反复短暂冠脉病变可诱导血管发育 闭塞或通过在左侧放置无肌样缩窄器 冠状动脉前降支。初步研究将 确定相思核苷是否可以选择性地增加腺苷 在侧支心肌中产生，从而增加 运动时侧支依赖区域的灌流。一个 第二项研究将测量侧枝血管和 冠状动脉远端血管由活体侧支灌流，以 确定冠脉中一氧化氮的产生是否减少 它们通过侧支通道进行灌流。第三项议定书 将决定基础或刺激NO产量是 从侧支分离的冠脉微血管减少- 依赖心肌区。最终协议将确定 构成血管内皮细胞表达是否减少 在侧支依赖区域没有合酶mRNA或蛋白，以及 抵押品依赖区是否表现出 诱导型NO合酶基因或蛋白。

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.