REGULATION OF CORONARY MICROVESSEL PERMEABILITY

无数的冠状动脉血管功能改变以适应运动训练的需要。在PROJECT 4中，重点是健康心脏的微血管交换如何适应运动训练的代谢需求。以及运动训练是否能改善高脂血症的影响。普遍的假设是，运动引起的冠状动脉交换容量的增加反映了微血管通透性（Ps）的功能变化。采用荧光显微荧光法对正常饲粮和高脂肪饲粮（久坐不动（SED）和运动训练（EX））猪心脏分离的微血管进行Ps评估。重要的发现是，运动训练后，小动脉对血管活性物质（如腺苷（ADO））的反应会改变方向和大小。根据这些和其他重要发现，拟议的工作有四个目标。目的1将侧重于交换屏障途径，目的2将侧重于白蛋白的机制，白蛋白是游离脂肪酸的主要载体，与其他大分子相比，通过完整的微血管壁。ADO诱导EX猪小动脉中Ps依赖no升高，SED猪小动脉中Ps降低。由于ADO可以激活cAMP依赖通路，NO可以激活cGMP依赖通路，Aim 3将重点关注cAMP和cGMP在介导微血管Ps中的作用。在Aim 4中，我们将重点关注ADO受体亚型介导SED和EX猪小动脉中ADO诱导的Ps变化。PROJECT 4的数据说明了ADO在交换微血管水平上的交换协调中的新作用，增强了其在冠状动脉血流自动调节中的作用。这项研究的结果对理解运动和休息期间的溶质输送都有影响。知道训练影响溶质通量直接影响了患者的训练状态不会改变药物递送或微血管对常见冠状动脉功能介质的反应的假设。

A myriad of coronary vascular functions change to accommodate the demands of exercise training. In PROJECT 4 the focus is on how microvascular exchange in healthy hearts adapts to match the metabolic demands exercise training. And whether exercise training ameliorates the effects of hyperlipidemia. The global hypothesis is that exercise-induced increases in coronary exchange capacity reflects functional changes in microvessel permeability (Ps). Ps is assessed by fluorescence microspectrofluoremetry in microvessels isolated from the hearts of pigs on a normal diet and ho a high fat (HF) diet that are sedentary (SED) and exercise trained (EX). The important finding is that following exercise training Ps responses of arterioles to vasoactive agents, such as adenosine (ADO), change in direction and magnitude. In light of these and other significant findings, the proposed work has 4 aims. Aim 1 will focus on exchange barrier pathways and Aim 2 will focus on the mechanisms by which albumin, the primary carrier of free fatty acids, in contrast to other macromolecules, traverses the walls of intact microvessels. ADO induced an NO-dependent increases in Ps in arterioles from EX pigs and a decrease in Ps of SED pig arterioles. As ADO can activate cAMP- dependent pathways and NO can activate cGMP-dependent pathways, Aim 3 will focus on the roles of cAMP and cGMP in mediating microvessel Ps. In Aim 4, we will focus on the ADO receptor subtypes which mediate ADO-induced changes in Ps in arterioles from SED and EX pigs. The data on PROJECT 4 illustrate a new role of ADO in the coordination of exchange at the level of exchange microvasculature augmenting its well known role in autoregulation of coronary blood flow. The results of this research impact both understanding solute delivery during bouts of exercise and during rest. Knowing that training influences solute flux impacts directly on the assumption that the training status of patients does not alter drug delivery or responses to the microvasculature to common mediators of coronary function.