NEURO-CIRCULATORY FUNCTION IN CHRONIC HEART DISEASE

描述（由申请人提供）： 该项目资助（PPG）更新描述了4名高级研究人员的一系列研究。本申请的总体目标是进一步了解慢性心力衰竭（CHF）状态的神经体液兴奋特征所涉及的各种机制。在前一个资助期间，我们已经提出证据表明，中央交感神经流出强烈调节血管紧张素II（Ang II）和一氧化氮（NO）之间的相互作用。基于新的初步数据，我们现在提出，额外的中枢和外周机制有助于CHF的交感神经兴奋。这些包括活性氧（ROS）的作用和谷氨酸受体的参与和异常γ氨基丁酸（GABA）的机制在下丘脑NO信号转导。 项目I-III是延续项目，项目IV是一个新项目，我们认为它非常符合本项目规划的总体主题。在项目I中，我们提出，中央Ang II介导交感神经流出和压力反射重调定的增加，凭借它对NAD（P）H氧化酶和超氧阴离子的产生的刺激作用。超氧阴离子的增加提供了一种机制，减少NO的生物利用度，从而缺乏中枢交感神经抑制途径。我们认为，运动训练（EX）改善交感兴奋性CHF状态，通过上调清除酶，如超氧化物歧化酶（SOD）。在项目II中，将研究室旁核（PVN）中谷氨酸和GABA在CHF大鼠交感兴奋中的作用。将研究Ang II和NO在与NR 1、AT 1和NMDA受体相关的过程中的参与。EX对谷氨酸和GABA反应改变的作用也将在本项目中进行研究。项目III继续研究CHF状态下动脉化学反射功能增强的细胞机制。在这个项目中，NO对血管球细胞离子通道缺陷的作用将在CHF中进行研究。此外，Ang II，NO和活性氧的作用将在分离的细胞和完整的动物中进行检查。EX将是该项目的一个额外组成部分。项目四是本项目规划补助金的新增项目。在这个项目中，我们将检查的作用，血管紧张素Ⅱ，一氧化氮和活性氧的心脏交感传入反射的作用，在交感兴奋的发生在CHF。本课题还将研究EX对心交感传入反射功能的影响。所有项目将使用新的遗传技术（基因转移和反义管理）和最先进的血流动力学，细胞和分子技术，以促进所提出的问题的答案。

DESCRIPTION (provided by applicant): This program project grant (PPG) renewal describes a series of studies from 4 senior investigators. The global objective of this application is to further our understanding of the various mechanisms that are involved in the neurohumoral excitation characteristic of the chronic heart failure (CHF) state. During the previous funding period we have produced evidence that central sympathetic outflow is strongly modulated by the interplay between angiotensin II (Ang II) and nitric oxide (NO). Based on novel preliminary data we now propose that additional central and peripheral mechanisms contribute to the sympatho-excitation in CHF. These include the role of reactive oxygen species (ROS) and the involvement of glutamate receptors and abnormal gamma amino butyric acid (GABA) mechanisms in NO signaling in the hypothalamus. Projects I-III are continuation projects and Project IV is a new project that we believe fits well with the overall theme of this PPG. In Project I we propose that central Ang II mediates increases in sympathetic outflow and baroreflex resetting by virtue of it stimulatory effect on NAD(P)H oxidase and production of superoxide anion. The increase in superoxide anion provides a mechanism for the reduction in NO bioavailability and thus the lack of a central sympatho-inhibitory pathway. We propose that exercise training (EX) ameliorates the sympatho-excitatory CHF state by up regulating scavenging enzymes such as superoxide dismutase (SOD). In Project II, the role of glutamate and GABA in the paraventricular nucleus (PVN) will be investigated in the sympatho-excitation of rats with CHF. The involvement of both Ang II and NO in the processes associated with NR1, AT1 and NMDA receptors will be investigated. The role of EX on the alterations in glutamate and GABA responses will also be examined in this project. Project III continues to investigate the cellular mechanisms that are responsible for augmented arterial chemoreflex function in the CHF state. In this project the role of NO on glomus cell ion channel defects will be investigated in CHF. In addition, the roles of Ang II, NO and reactive oxygen species will be examined in both isolated cells and intact animals. EX will be an additional component of this project. Project IV is a new addition to this PPG. In this project we will examine the role of Ang II, NO and ROS on the role of the cardiac sympathetic afferent reflex in the genesis of sympatho-excitation in CHF. The role of EX on cardiac sympathetic afferent reflex function will also be investigated in this project. All projects will use novel genetic techniques (gene transfer and antisense administration) and state of the art hemodynamic, cellular and molecular techniques to facilitate answers to the questions posed.