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

在正常状态下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经典延髓升压区和降压区神经传递的激素中介。处于共鸣-兴奋状态的情况并不清楚。我们之前的研究以及本赠款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途径间接发挥作用。我们的初步数据表明，反应性氧化剂物种(ROS)是CHF交感兴奋状态的重要贡献者。在这一建议中，我们假设Ang II在CHF状态下的许多中枢交感兴奋作用是由促氧化剂酶NAD(P)H氧化酶的激活所介导的。我们建议使用新的方法学工具来了解ROS和NAD(P)H氧化酶在CHF兔安静状态和Ang II反应中的交感兴奋作用，评估CHF兔中枢神经系统中NO和Ang II的相互作用，确定运动训练的效果 血管紧张素Ⅱ的交感兴奋反应及NAD(P)H氧化酶参与这些反应。为了进行这些实验，我们将同时使用超氧化物歧化酶和NAD(P)H氧化酶的药理和遗传操作。我们将确定血管紧张素Ⅱ1型受体在介导这些反应中的作用，以及它在CHF状态下ROS慢性变化中的作用。总之，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，这个项目与PPG中的其他3个项目具有很强的互动性。

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.