SYMPATHETIC OUTFLOW IN HEART FAILURE: ANG II, NO AND ROS

心力衰竭中的交感神经流出：ANG II、NO 和 ROS

基本信息

批准号：
6928281
负责人：
Irving H Zucker
金额：
$ 35.93万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6928281
关键词：
NAD(P)H dehydrogenase angiotensin II angiotensin receptor autonomic reflex baroreflex electrophysiology exercise free radical oxygen gene expression heart conduction system heart electrical activity heart failure heart innervation hypothalamic pituitary adrenal axis immunocytochemistry laboratory rabbit neurohormones neuroregulation nitric oxide nitric oxide synthase pathologic process rest superoxide dismutase sympathetic nervous system transfection western blottings

NAD(P)H dehydrogenase angiotensin II angiotensin receptor autonomic reflex baroreflex electrophysiology exercise free radical oxygen gene expression heart conduction system heart electrical activity heart failure heart innervation hypothalamic pituitary adrenal axis immunocytochemistry laboratory rabbit neurohormones neuroregulation nitric oxide nitric oxide synthase pathologic process rest superoxide dismutase sympathetic nervous system transfection western blottings

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项目摘要

The mechanisms that are responsible for modulating sympathetic outflow in the normal state have been investigated for many years and are widely accepted as those which involve peripheral reflex feedback as well as hormonal mediation of neurotransmission in classical pressor and depressor areas of the medulla. The situation in sympatho-excitatory states is not as clear. Our previous studies along with the preliminary data described in this grant application indicate that important components in the generation of sympatho-excitation in chronic heart failure (CHF) are the substances angiotensin II (Ang II) and nitric oxide (NO). While these substances may have direct effects on central synaptic function they also may act indirectly by activation of additional pathways. Our preliminary data suggest that reactive oxidant species (ROS) are important contributors to the sympatho-excitatory state in CHF. In this proposal we hypothesize that many of the central sympatho-excitatory actions of Ang II in the CHF state are mediated by activation of the pro-oxidant enzyme NAD(P)H oxidase. We propose experiments using novel methodological tools to understand the role of ROS and NAD(P)H oxidase in sympatho-excitation at rest and in response to Ang II in rabbits with CHF, evaluate the interaction between NO and Ang II in the central nervous system of rabbits with CHF, determine the effects of exercise training on the sympatho-excitatory responses to Ang II and on the involvement of NAD(P)H oxidase in these responses. In order to carry out these experiments we will use both pharmacological and genetic manipulations of superoxide dismutase and NAD(P)H oxidase. We will determine the role of the Ang II type 1 receptor in mediating these responses and its role in chronic changes of ROS in the CHF state. Overall, these studies will provide new information on the role of ROS in the sympatho-excitation and pathogenesis of CHF. Interventions that are likely to reduce the influence of central ROS will be another important outcome of these experiments. Finally, this project is highly interactive with the other 3 projects in this PPG.

多年来已经研究了负责调节正常状态的交感神经流出的机制，并被广泛接受为涉及外围反射反馈以及在髓质的经典压力和抑郁症区域中神经传递的激素介导的机制。同情兴奋状态的情况并不清楚。我们先前的研究以及本赠款应用中描述的初步数据表明，慢性心力衰竭（CHF）产生交感神经激发的重要组成部分是物质血管紧张素II（ANG II）和一氧化氮（NO）。尽管这些物质可能对中央突触功能有直接影响，但它们也可能通过激活其他途径而间接起作用。我们的初步数据表明，反应性氧化剂物种（ROS）是CHF中交感神经兴趣状态的重要因素。在此提案中，我们假设ANG II在CHF状态中的许多中心交感神经作用都是通过激活促氧化酶NAD（P）H氧化酶来介导的。我们提出了使用新型方法学工具来了解ROS和NAD（P）H氧化酶在静止和响应CHF的兔子中的ANG II中的作用的实验，评估NO和ANG II之间的相互作用与CHF的兔子中央神经系统中的相互作用，确定运动训练的效果，确定运动训练的影响关于对ANG II的交感神经反应以及NAD（P）H氧化酶参与这些反应。为了进行这些实验，我们将使用超氧化物歧化酶和NAD（P）H氧化酶的药理和遗传操作。我们将确定ANG II 1型受体在介导这些反应及其在CHF状态ROS慢性变化中的作用中的作用。总体而言，这些研究将提供有关ROS在CHF交感神经激发和发病机理中作用的新信息。可能会减少中央ROS影响的干预措施将是这些实验的另一个重要结果。最后，该项目与该PPG中的其他3个项目具有很高的交互性。