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且至关重要的问题。 在过去的20年里，该实验室一直在研究CHF动物模型中心血管功能的异常神经体液控制机制。 我们已经清楚地表明，增强交感神经流出，这是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，我们建议调查两种交感神经流出的体液介质在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，下调的神经元亚型的一氧化氮合酶（nNOS）在特定的中央网站有助于下调的神经元亚型的一氧化氮合酶（nNOS）在特定的中央网站有助于增加交感神经流出与起搏诱导的CHF兔。 此外，我们认为，中央血管紧张素II的增加有助于这种交感神经兴奋。 在具体的目标1中，我们将确定血管紧张素II和一氧化氮的相互作用的调节休息和反射介导的变化，肾交感神经活动（RSNA）在清醒的兔子与CHF。 这些研究将通过脑室内给药NO供体、拮抗剂和Ang II受体拮抗剂，同时引起动脉压力反射和心肺反射来完成。 在具体目标2中，我们将评估血管紧张素II对心肺反射中nNOS压力感受器反射的作用。 在具体目标2中，我们将通过测量nNOS mRNA和蛋白来评估Ang II对脑中nNOS产生的作用。 此外，我们将确定慢性治疗与血管紧张素受体拮抗剂对nNOS的表达和蛋白质在有和没有CHF的兔子的影响。 另外的初步证据表明，CHF中的运动调节（EXC）不仅可以逆转交感神经兴奋状态，而且可以上调脑中的nNOS mRNA和蛋白。 因此，在具体目标3中，我们将确定EXC对静息RSNA和RSNA的压力反射和心肺反射控制的作用，以及确定EXC对nNOS mRNA和蛋白质的中枢表达的影响。 这些研究将提供重要的新信息，在CHF的交感神经流出的调节和运动可能是有益于这种疾病的患者的机制之一。

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.