NEURO-CIRCULATORY FUNCTION IN CHRONIC HEART DISEASE

慢性心脏病的神经循环功能

• 批准号: 7085383
• 负责人: Irving H Zucker
• 金额: $ 206.53万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-05 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085383
• 关键词: autonomic reflex; chronic disease /disorder; heart failure; neuroregulation

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.

描述（由申请人提供）： 该计划项目赠款（PPG）续约描述了来自4位高级研究人员的一系列研究。该应用的全球目标是进一步了解慢性心力衰竭（CHF）状态的神经肿瘤激发特征所涉及的各种机制。在上一个资金期间，我们产生了证据表明，血管紧张素II（ANG II）和一氧化氮（NO）之间的相互作用强烈调节中心交感神经流出。基于新的初步数据，我们现在建议其他中央和外围机制有助于CHF的交感神经激发。其中包括活性氧（ROS）的作用以及谷氨酸受体和异常伽马氨基丁酸（GABA）机制在下丘脑中无信号传导中的作用。 I-III项目是延续项目，IV项目是一个新项目，我们认为与该PPG的整体主题非常吻合。在项目I中，我们建议中央ANG II介导，通过对NAD（P）H氧化酶的刺激作用和超氧化物阴离子的产生，交感神经流出和压力反射重置的增加。超氧化阴离子的增加为降低无生物利用度的机制提供了一种机制，因此缺乏中央交汇途径。我们建议通过调节诸如超氧化物歧化酶（SOD）等清除酶来改善同情兴奋的CHF状态。在项目II中，将研究谷氨酸和GABA在室室核（PVN）中的作用。将研究ANG II和NO在与NR1，AT1和NMDA受体相关的过程中的参与。在该项目中，还将检查EX在谷氨酸和GABA反应改变的作用。项目III继续研究CHF状态下负责增强动脉化学反射功能的细胞机制。在该项目中，NO在CHF中将研究NO在Glomus细胞离子通道缺陷中的作用。另外，将在孤立的细胞和完整动物中检查ANG II的作用，NO和活性氧。 EX将是该项目的另一个组成部分。 IV项目是该PPG的新成员。在这个项目中，我们将研究ANG II，NO和ROS在心脏交感神经反射中的作用中的作用。在该项目中，还将研究EX在心脏交感传入反射功能上的作用。所有项目都将使用新颖的遗传技术（基因转移和反义给药）以及艺术血流动力学，细胞和分子技术的状态来促进对提出问题的答案。