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髓质经典升压区和降压区神经传递的激素介导。交感神经兴奋状态的情况就不那么清楚了。我们之前的研究以及本申请中描述的初步数据表明，慢性心力衰竭（CHF）中交感神经兴奋产生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起作用。我们的初步数据表明，活性氧（ROS）是CHF交感神经兴奋状态的重要贡献者。在这个提议中，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由促氧化酶NAD(P)H氧化酶的激活介导的。我们建议使用新的方法工具来了解ROS和NAD(P)H氧化酶在CHF家兔休息时交感神经兴奋和对Ang II的反应中的作用，评估CHF家兔中枢神经系统NO和Ang II之间的相互作用，确定运动训练的效果

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.