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

• 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
• 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

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.

正常状态下负责调节交感神经流出的机制已被研究多年，并被广泛接受为涉及外周反射反馈以及髓质经典升压区和降压区神经传递的激素介导的机制。交感神经兴奋状态的情况并不那么清楚。我们之前的研究以及本次拨款申请中描述的初步数据表明，慢性心力衰竭 (CHF) 中产生交感神经兴奋的重要成分是血管紧张素 II (Ang II) 和一氧化氮 (NO) 物质。虽然这些物质可能对中枢突触功能有直接影响，但它们也可能通过激活其他途径间接发挥作用。我们的初步数据表明，活性氧化剂（ROS）是 CHF 交感神经兴奋状态的重要贡献者。在该提议中，我们假设 CHF 状态下 Ang II 的许多中枢交感神经兴奋作用是由促氧化剂 NAD(P)H 氧化酶的激活介导的。我们建议使用新的方法工具进行实验，以了解 ROS 和 NAD(P)H 氧化酶在静息交感神经兴奋中的作用以及对患有 CHF 的兔子对 Ang II 的反应，评估中枢神经系统中 NO 和 Ang II 之间的相互作用患有 CHF 的兔子，确定运动训练的效果 Ang II 的交感兴奋反应以及 NAD(P)H 氧化酶在这些反应中的参与。为了进行这些实验，我们将使用超氧化物歧化酶和 NAD(P)H 氧化酶的药理学和遗传操作。我们将确定 Ang II 1 型受体在介导这些反应中的作用及其在 CHF 状态下 ROS 慢性变化中的作用。总的来说，这些研究将为 ROS 在交感神经兴奋和 CHF 发病机制中的作用提供新的信息。可能减少中枢活性氧影响的干预措施将是这些实验的另一个重要成果。最后，这个项目与PPG中的其他3个项目互动性很强。