EXERCISE--CORONARY RESERVE-CORONARY HEART DISEASE

锻炼--冠状动脉储备-冠心病

• 批准号: 6242384
• 负责人: M HAROLD LAUGHLIN
• 金额: $ 26.17万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 1998-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6242384
• 关键词: blood flow measurement; bradykinin; calcium flux; coronary disorder; disease /disorder model; exercise; heart circulation; immunocytochemistry; microcirculation; miniature swine; nitric oxide synthase; substance P; vascular resistance; vascular smooth muscle; vasodilation; vasodilators; vasomotion; western blottings

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.

运动训练的心脏冠状动脉血流量增加 (EX)猪，部分原因是冠状血管的控制改变 阻力 项目3的目标是阐明 这些训练引起的变化。 血管反应性和 内皮介导的控制机制将在体外进行检查， 离体冠状动脉阻力（近阻力：150 - 250 μ m 直径，ID和阻力动脉：50至150微米直径，ID） 安装在玻璃微量移液管和微血管肌描记器上。 研究 为目标1提出的建议将决定训练诱导的机制是否 孤立的冠状动脉阻力动脉中的肌源性反应性增加 包括：a）微血管内皮对 管腔内压力的变化，B）增加牵张诱导的Ca 2 + 血管平滑肌（VSM）细胞中的释放和/或流入，和/或c） 增强牵张诱导的VSM收缩细胞Ca 2+敏感性增加 元素 目标2和3的核心假设是， 冠状动脉内皮介导的血管舒张反应 EX猪的微循环是由训练引起的， 内皮中一氧化氮合酶（ecNOS）的组成形式。 目标2中提出的实验使用对以下各项的反应的测量： 内皮依赖性血管扩张剂，P物质，缓激肽，和 管腔内血流以确定内皮介导的血管舒张 在运动后的整个冠状动脉微循环中增强 训练 目的3将确定是否有增加ecNOS在 来自EX猪的冠状动脉阻力动脉。 ecNOS活性将是 体外测定，用Western blot检测ecNOS含量 分析，ecNOS的分布将被检查， 免疫组化 如果ecNOS没有增加，我们将测试 增强内皮介导的血管舒张反应的假说 这是由训练引起的抗氧化剂的增加造成的。 目标4是 旨在确定训练诱导适应的时间过程。 目标5将测量肌源性反应和血流之间的相互作用- 在从EX和SED分离的阻力动脉中诱导血管舒张 猪 为目标6设计的研究将确定内皮细胞是否- 介导的血管舒张在完整的冠状动脉中产生更大的血流量 与SED相比，EX猪的循环。 研究完成 在项目3中提出的将：A）阐明细胞/分子机制 调节冠状动脉微循环中的VSM和内皮，B） 确定负责训练诱导的肌源性变化的机制， 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 冠状动脉微循环中的控制和血管交换，D） 确定训练诱导的冠状动脉血增加的机制 流量 这项研究将为以下方面提供坚实的基础： 了解训练对正常冠状动脉血管的影响 功能 这种理解对概念的发展至关重要 关于运动训练、高脂血症和 冠状动脉微循环疾病。