REGULATION OF CORONARY MICROVESSEL PERMEABILITY

为了适应运动训练的需要，无数的冠状动脉血管功能发生了变化。在项目4中，重点是健康心脏中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效果。全球假说是，运动诱导的冠状动脉交换能力的增加反映了微血管通透性(Ps)的功能变化。用荧光显微荧光分光光度法对正常饲料和高脂饲料(SED)和运动训练(EX)的猪心脏分离的微血管PS进行了评估。重要的发现是，在运动训练之后，小动脉对血管活性物质如腺苷(ADO)的反应在方向和幅度上发生了变化。根据这些和其他重要发现，拟议的工作有4个目标。目标1将侧重于交换屏障途径，目标2将侧重于白蛋白--游离脂肪酸的主要载体，与其他大分子不同--穿过完整微血管壁的机制。ADO使前猪小动脉的Ps增加，而SED猪的小动脉的Ps降低。由于ADO可以激活cAMP依赖的通路，而NO可以激活cGMP依赖的通路，目标3将重点介绍cAMP和cGMP在介导微血管Ps中的作用。在目标4中，我们将重点介绍介导ADO诱导的SED和EX猪小动脉Ps变化的ADO受体亚型。项目4的数据显示了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众所周知的作用。这项研究的结果影响了对运动和休息期间溶质输送的理解。了解训练影响溶质流动的直接影响是假设患者的训练状态不会改变药物输送或对微血管系统对常见冠脉功能介质的反应。

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.