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

在正常状态下负责调节交感神经流出的机制已经研究了很多年，并且被广泛接受为涉及外周反射反馈以及髓质经典升压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清楚。我们先前的研究沿着在本资助申请中描述的初步数据表明，在慢性心力衰竭（CHF）中产生交感兴奋的重要成分是物质血管紧张素II（Ang II）和一氧化氮（NO）。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通路间接起作用。我们的初步数据表明，活性氧化剂（ROS）是重要的贡献者的交感神经兴奋状态在CHF。在这一建议中，我们假设，在CHF状态下，Ang II的许多中枢交感神经兴奋作用是通过激活促氧化酶NAD（P）H氧化酶介导的。本研究拟采用新的方法学手段，探讨CHF家兔静息状态下和Ang Ⅱ诱导下ROS和NAD（P）H氧化酶在交感神经兴奋中的作用，评价CHF家兔中枢神经系统中NO和Ang Ⅱ的相互作用，确定运动训练对CHF家兔交感神经兴奋的影响 对血管紧张素Ⅱ的交感神经兴奋反应和NAD（P）H氧化酶参与这些反应的影响。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学操作。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，这些研究将提供新的信息的作用，活性氧在交感神经兴奋和发病机制的CHF。有可能减少中央ROS影响的干预措施将是这些实验的另一个重要成果。最后，该项目与本PPG中的其他3个项目高度互动。

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.