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控是一个复杂而重要的问题。在过去的20年里，该实验室一直在研究CHF动物模型中异常的神经-体液控制心血管功能的机制。我们已经清楚地表明，增强的交感神经流出是CHF状态的特征，是一个多因素的过程，涉及缓冲反射和交感神经流出中枢调节的改变。根据初步数据和本实验室最近发表的研究，我们建议研究两种体液介质在交感神经流出在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有助于起搏诱导的心力衰竭家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神经兴奋。在具体目的1中，我们将确定Ang II和NO对有意识CHF家兔静息和反射介导的肾交感神经活动（RSNA）变化的调节作用。这些研究将通过在脑室内给药NO供体、拮抗剂和Ang II受体拮抗剂来完成，同时唤起动脉压力反射和心肺反射。在具体目的2中，我们将评估angii在心肺反射中对nNOS气压反射的作用。在具体目标2中，我们将通过测量nNOS mRNA和蛋白质来评估Ang II在脑内nNOS产生中的作用。此外，我们将确定血管紧张素受体拮抗剂慢性治疗对有和无CHF家兔nNOS表达和蛋白的影响。进一步的初步证据表明，运动调节（EXC）在CHF中不仅可以逆转交感神经兴奋状态，还可以上调脑内nNOS mRNA和蛋白的表达。因此，在具体的目的3中，我们将确定EXC对静息RSNA和RSNA的气压反射和心肺反射控制的作用，以及确定EXC对nNOS mRNA和蛋白中枢表达的影响。这些研究将为CHF患者交感神经流出的调节提供重要的新信息，并为运动可能对该疾病患者有益的机制之一提供信息。

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.