EXERCISE--CORONARY RESERVE, CORONARY HEART DISEASE

锻炼——冠状动脉储备、冠心病

• 批准号: 3351567
• 负责人: M HAROLD LAUGHLIN
• 金额: $ 24.59万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-15 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3351567
• 关键词: acetylcholine; biological transport; caffeine; calcium channel; cardiovascular disorder prevention; coronary artery; coronary disorder; coronary vasodilator; dipyridamole; dogs; exercise; heart cell; heart circulation; heart contraction; heart pharmacology; indicator dilution test; miniature swine; myocardial ischemia /hypoxia; myocardium; oxygen transport; papaverine; radiotracer; training; vascular endothelium permeability; vascular smooth muscle; vasoactive agent; voltage gated channel

This research program has developed the adult miniature swine as an experimental model of exercise training (ET) for use in the study of ET-induced coronary vascular adaptation. We have established that ET improves the capacity of the coronary vascular bed to transport nutrients to and metabolites away from cardiac myocytes. ET increases both blood flow (BF) capacity and capillary diffusion capacity. Experiments proposed for Specific Aim 1 are designed to determine if ET-induced increases in coronary transport capacity are due to increased size and/or numbers of vessels (ie, angiogenesis) and/or to altered control of BF and its distribution. Morphometric techniques will be used to measure microvascular vessel numbers and size and to estimate capillary exchange area to provide a definitive test of the angiogenesis hypothesis. To evaluate the role of altered control of BF and its distribution, a uniquely complete set of coronary transport data will be obtained. Total and regional (microspheres) coronary BF, capillary diffusion capacity (multiple-indicator dilution technique), and systemic hemodynamics will be measured in-vivo with BF autoregulation intact and during maximal vasodilation. Transport data will be interpreted with model analysis employing available models and models of coronary transport that are being developed. We have also demonstrated that ET alters the intrinsic contractile behavior of coronary arteries. Results indicate that excitation-contraction coupling is altered in coronary arteries of ET pigs. Experiments outlined for Aim 2 will use isolated segments of coronary arteries to test the hypotheses that ET alters endothelium mediated control of vascular smooth muscle (VSM) tone and/or receptor mediated control of VSM cells. The experiments described for Aim # 3 will use isolated endothelial cells (EC) and VSM cells to test the hypothesis that ET alters the regulation of intra-cellular Ca++ (Cai) in coronary ECs and/or VSM cells. Cai will be measured with fura-2 microfluorimetry. Preliminary data indicate that the control of Cai is altered in both EC's and VSM of coronary arteries from ET pigs Aim 4 will determine if these ET-induced coronary adaptations are restricted to large epicardial arteries or also present in small arteries, near resistance sized arteries and arterioles. It appears that exercise training-induced coronary vascular adaptation involves: angiogenesis, altered neurohumoral control mechanisms and changes in the intrinsic contractile characteristics of coronary arteries. Completion of the proposed research will provide a comprehensive understanding of the mechanisms involved in training-induced coronary vascular adaptation and may provide information necessary for understanding the apparent effectiveness of ET in prevention and/or treatment of coronary disease.

这项研究计划已经开发了成年小型猪作为一个 运动训练的实验模型（ET），用于研究 ET诱导的冠状动脉血管适应。 我们已经确定ET 提高冠状血管床输送营养物质的能力 代谢物从心肌细胞排出。 ET增加血液中 流动能力（BF）和毛细扩散能力。 实验 针对特定目标1提出的建议旨在确定ET诱导的 冠状动脉运输能力的增加是由于尺寸增加和/或 血管数量（即血管生成）和/或BF控制改变， 其分布。 形态测量技术将用于测量 微血管的数量和大小，并估计毛细血管交换 区域提供了一个明确的测试血管生成假说。 到 评价了高炉改造控制的作用及其分布， 将获得唯一完整的冠状动脉传输数据集。 总 和局部（微球）冠状动脉BF，毛细血管扩散能力 （多指示剂稀释技术）和全身血流动力学将 在BF自动调节完整的情况下和在最大 血管舒张 运输数据将通过模型分析进行解释 采用现有的模型和模型的冠状动脉运输， 正在开发中。 我们还证明了ET改变了内在的 冠状动脉的收缩行为。 结果表明 ET冠状动脉兴奋-收缩偶联改变 猪 为目标2概述的实验将使用 冠状动脉，以检验ET改变内皮细胞的假设， 血管平滑肌张力和/或受体的介导控制 介导的VSM细胞的控制。 针对目标#3描述的实验 将使用分离的内皮细胞（EC）和VSM细胞来测试 假设ET改变了细胞内Ca++（Cai）的调节， 冠状动脉EC和/或VSM细胞。 将用fura-2测量Cai 显微荧光法初步数据显示， ET猪冠状动脉EC和VSM的改变 确定这些ET诱导的冠状动脉适应是否仅限于 大的心外膜动脉或也存在于小动脉中， 阻力大小的动脉和小动脉。 看来锻炼 训练诱导的冠状血管适应包括：血管生成， 改变的神经体液控制机制和内在的 冠状动脉的收缩特性。 完成拟议的研究将提供一个全面的 了解训练诱发的冠状动脉粥样硬化的机制 血管适应，并可能提供必要的信息， 了解ET在预防和/或 冠心病的治疗