SYMPATHETIC OUTFLOW IN HEART FAILURE--ANGIOTENSIN II AND NITRIC OXIDE

慢性心力衰竭(CHF)状态下交感神经活动的调节是一个复杂而重要的问题。在过去的20年里，这个实验室一直在研究CHF动物模型中异常神经体液控制心血管功能的机制。我们已经清楚地表明，作为CHF状态的特征，增强的交感神经流出是一个多因素的过程，涉及缓冲反射和交感神经流出的中枢调制的改变。基于初步数据和本实验室最近发表的研究，我们建议调查交感神经流出的两种体液介质在CHF中的作用。即血管紧张素II(Ang II)和一氧化氮(NO)。在这些研究中，我们假设特定中枢部位一氧化氮合酶(NNOS)神经元异构体的下调有助于特定中枢部位一氧化氮合酶(NNOS)神经元异构体的下调，从而导致起搏诱导的CHF兔交感神经流出增加。此外，我们认为，中枢Ang II的增加有助于这种交感兴奋。在特定目的1中，我们将研究Ang II和NO在静息和反射介导的心衰兔肾交感神经活动(RSNA)变化中的相互作用。这些研究将通过脑室内注射NO供体、拮抗剂和Ang II受体拮抗剂来完成，同时诱发动脉压力反射和心肺反射。在具体目标2中，我们将评估Ang II在心肺反射中对nNOS压力反射的作用。在特定的目标2中，我们将通过检测nNOS的mRNA和蛋白来评估Ang II对脑内nNOS产生的作用。此外，我们还将确定慢性应用血管紧张素受体拮抗剂对伴有和不伴有CHF的兔nNOS表达和蛋白的影响。更多的初步证据表明，运动条件反射(EXC)不仅可以逆转交感兴奋状态，而且可以上调脑内nNOS的mRNA和蛋白水平。因此，在特定的目标3中，我们将确定exc在静息RSNA和压力反射和心肺反射控制RSNA中的作用，以及exc对nNOS mRNA和蛋白中枢表达的影响。这些研究将提供有关CHF交感神经流出调节的重要新信息，以及运动可能对这种疾病患者有益的机制之一。

The regulation of sympathetic nerve activity in the chronic heart failure (CHF) state is a complex and critically important issue. Over the past 20 years this laboratory has been investigating mechanisms of abnormal neuro-humoral control of cardiovascular function in animal models of CHF. We have clearly shown that enhanced sympathetic outflow, which is characteristic of the CHF state, is a multi-factorial process involving alterations in both buffer reflexes and in the central modulation of sympathetic outflow. Based on preliminary data and on recent studies published from this laboratory we proposed to investigate the role of two humoral mediators of sympathetic outflow in CHF. Namely, angiotensin II (Ang II) and nitric oxide (NO). In these studies we hypothesize that a down regulation of the neuronal isoform of nitric oxide synthase (nNos) in specific central sites contributes that a down regulation of the neuronal isoform of nitric oxide synthase (nNos) in specific central sites contributes to an increase in sympathetic outflow in rabbits with pacing-induced CHF. Furthermore, we suggest that an increase in central Ang II contributes to this sympatho-excitation. In specific aim 1 we will determine the interaction of Ang II and NO on the regulation of resting and reflex mediated changes in renal sympathetic nerve activity (RSNA) in conscious rabbits with CHF. These studies will be accomplished by Intracerebroventricular administration of NO donors, antagonists and Ang II receptor antagonists while evoking the arterial baroreflex and the cardiopulmonary reflex. In specific aim 2 we will evaluate the role of Ang II on nNOS baroreflex in the cardiopulmonary reflex. In specific aim 2 we will evaluate the role of Ang II on nNOS production in the brain by measuring both nNOS mRNA and protein. In addition, we will determine the effects of chronic treatment with angiotensin receptor antagonists on nNOS expression and protein in rabbits with and without CHF. Additional preliminary evidence suggests that exercise conditioning (EXC) in CHF can not only reverse the sympatho-excitatory state but can up regulate nNOS mRNA and protein in the brain. Therefore, in specific aim 3 we will determine the role of EXC on resting RSNA and on baroreflex and cardiopulmonary reflex control of RSNA as well as determining the effects of EXC on the central expression of nNOS mRNA and protein. These studies will provide important new information on the regulation of sympathetic outflow in CHF and one of the mechanisms by which exercise may be beneficial to patients with this disease.