EXERCISE--CORONARY RESERVE-CORONARY HEART DISEASE

运动训练后心脏冠脉血流量增加 (例如)猪，部分由于冠状动脉血管控制的改变 抵抗。项目3的目标是阐明负责的机制 这些训练引起的改变。血管舒缩反应性和 血管内皮细胞介导的调控机制将在体外进行研究 离体冠脉阻力动脉(近阻力：150至250微米 直径、内径和阻力动脉：直径50到150微米(ID) 安装在玻璃微管和微血管肌图仪上。研究 为目标1提出的建议将确定培训诱导的机制 离体冠脉阻力动脉的肌源性反应性增加 包括：a)微血管内皮细胞对 管腔内压力的变化，b)拉伸诱导的钙离子增加 释放和/或流入血管平滑肌(VSM)细胞，和/或c) 增强牵张引起的VSM收缩的钙敏感性增加 元素。目标2和目标3的中心假设是增强的 冠状动脉内皮细胞介导的血管扩张剂反应 前猪的微循环是由于训练诱导的， 内皮细胞中一氧化氮合酶(EcNOS)的构成形式。 目标2中提出的实验使用对 内皮依赖性血管扩张剂、P物质、缓激肽和 血管内血流测定血管内皮细胞介导的血管扩张 在运动后冠脉微循环中得到增强 训练。目标3将确定是否存在ecNOS在 来自前猪的冠状动脉阻力动脉。EcNOS活性将会是 在体外测量，ecNOS的含量将用Western印迹法检测 分析，并将检查ecNOS的分布 免疫组织化学。如果ecNOS没有增加，我们将测试 增强内皮介导的血管扩张剂反应的假说 这是由于训练导致抗氧化剂增加所致。目标4是 旨在确定训练诱导适应的时间进程。 AIM 5将测量肌源性反应和血流之间的相互作用- 从EX和SED分离的阻力动脉诱导的血管扩张 猪。为Aim 6设计的研究将确定内皮- 介导性血管扩张在完整的冠状动脉中产生更多的血流量 与SED相比，前猪的流通情况。完成研究工作 项目3中提出的建议将：a)阐明细胞/分子机制 调节冠脉微循环中的VSM和内皮，B) 确定训练引起肌源性改变的机制 冠状动脉的反应和内皮介导的血管调节 微循环，C)提高对血流整合的理解 冠脉微循环中的控制和血管交换。 确定训练导致冠脉血流量增加的机制 流量。这项研究将为以下工作提供坚实的基础 了解训练对正常冠脉血管的影响 功能。这种理解对于概念的发展是必不可少的 关于运动训练、高脂血症和 冠脉微循环中的冠心病。

Coronary blood flow capacity is increased in hearts of exercise trained (EX) pigs due, in part to altered control of coronary vascular resistance. The goal of Project 3 is to elucidate mechanisms responsible for these training-induced alterations. Vasomotor responsiveness and endothelium-mediated control mechanisms will be examined in vitro in isolated coronary resistance arteries (near-resistance: 150 to 250 microm diameter, ID, and resistance arteries: 50 to 150 microm diameter, ID) mounted on glass micropipets and microvessel myographs. Research proposed for Aim 1 will determine whether mechanisms for training-induced increases in myogenic reactivity in isolated coronary resistance arteries include: a) increased responsiveness of microvascular endothelium to changes in intraluminal pressure, b) increased stretch-induced Ca2+ release and/or influx in vascular smooth muscle (VSM) cells, and/or c) enhanced stretch-induced increases in Ca2+ sensitivity of VSM contractile elements. The central hypothesis of Aims 2 and 3 is that enhanced endothelium-mediated vasodilator responses in the coronary microcirculation of EX pigs results from training-induced, increases in the constitutive form of nitric oxide synthase (ecNOS) in endothelium. Experiments proposed in Aim 2 use measurements of responses to endothelium-dependent vasodilator, substance-P, bradykinin, and intraluminal flow to determine whether endothelium-mediated vasodilation is enhanced throughout the coronary microcirculation after exercise training. Aim 3 will determine whether there is an increase in ecNOS in coronary resistance arteries from EX pigs. ecNOS activity will be measured in vitro, ecNOS content will be examined with Western blot analysis, and the distribution of ecNOS will be examined with immunohistochemistry. If ecNOS is not increased, we will test the hypothesis that enhanced endothelium-mediated vasodilator responses result from training-induced increases in antioxidants. Aim 4 is designed to determine the time course of training induced adaptations. Aim 5 will measure interactions between myogenic responses and flow- induced vasodilation in resistance arteries isolated from EX and SED pigs. Research designed for Aim 6 will determine whether endothelium- mediated vasodilation produces greater blood flow in the intact coronary circulation of EX pigs compared to SED. Completion of the research proposed in Project 3 will: A) elucidate cellular/molecular mechanisms that regulate VSM and endothelium in the coronary microcirculation, B) determine mechanisms responsible for training-induced changes in myogenic responses and endothelium-mediated vasoregulation in the coronary microcirculation, C) improve understanding of integration of blood flow control and vascular exchange in the coronary microcirculation., and D) Determine mechanisms for training-induced increases in coronary blood flow capacity. This research will provide a solid fundamental basis for understanding the effects of training on normal coronary vascular function. This understanding is essential to the development of concepts concerning interactions among exercise training, hyperlipidemia, and coronary disease in the coronary microcirculation.