NEURO-CIRCULATORY FUNCTION IN CHRONIC HEART DISEASE

描述(由申请人提供)： 这项计划项目拨款(PPG)续期描述了4名高级研究人员的一系列研究。这项应用的总体目标是加深我们对慢性心力衰竭(CHF)状态的神经体液兴奋特征的各种机制的理解。在之前的资助期间，我们已经提出证据表明，中枢交感神经流出受到血管紧张素II(Ang II)和一氧化氮(NO)之间相互作用的强烈调节。基于新的初步数据，我们现在提出，在CHF中，额外的中枢和外周机制有助于交感兴奋。其中包括活性氧(ROS)的作用、谷氨酸受体和异常的伽马氨基丁酸(GABA)机制在下丘脑NO信号转导中的作用。项目一-三是续展项目，项目四是一个新项目，我们认为它非常符合本项目小组的总体主题。在项目I中，我们提出中枢Ang II通过刺激NAD(P)H氧化酶和超氧阴离子的产生而调节交感神经流出和压力感受性反射的重置。超氧阴离子的增加为NO生物利用度的降低提供了一种机制，从而缺乏中枢交感神经抑制途径。我们认为运动训练可通过上调超氧化物歧化酶等清除酶来改善交感兴奋性心力衰竭状态。在项目II中，我们将研究室旁核(PVN)谷氨酸和GABA在CHF大鼠交感神经兴奋中的作用。Ang II和NO在与NR1、AT1和NMDA受体相关的过程中的作用将被研究。EX在谷氨酸和GABA反应的改变中的作用也将在这个项目中被研究。项目III继续研究导致CHF状态下动脉化学反射功能增强的细胞机制。在本项目中，我们将研究一氧化氮在慢性心力衰竭患者血管球体细胞离子通道缺陷中的作用。此外，还将在分离的细胞和完整的动物中检测Ang II、NO和活性氧物种的作用。EX将是该项目的一个额外组成部分。第四个项目是这个PPG的新成员。在这个项目中，我们将研究Ang II、NO和ROS在心交感传入反射在心力衰竭交感神经兴奋发生中的作用。本项目还将研究EX对心脏交感传入反射功能的影响。所有项目都将使用新的基因技术(基因转移和反义管理)以及最先进的血液动力学、细胞和分子技术，以便于回答所提出的问题。

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.