FUNCTION OF PVN IN HEART FAILURE: ROLE OF NO AND NMDA

心力衰竭（HF）患者和所有HF动物模型均表现出交感神经激活增加，这增加了HF期间的死亡风险。这些异常的中枢机制还知之甚少。我们以前已经观察到，中央一氧化氮（NO）的机制，在室旁核内，决定交感神经流出的HF改变。随后，我们确定，NO通过γ-氨基丁酸（GABA）机制，代表抑制机制，在HF中增加。最近，我们发现了增强的兴奋机制，涉及血管紧张素能和血管紧张素能（也受到NO的影响）在室旁核在HF。这些数据一起表明，改变抑制机制，涉及NO和GABA和兴奋机制，涉及在PVN（与涉及NO的两种机制之间的相互作用）的血管紧张素能和血管紧张素能通路可能参与这种交感神经兴奋。该提议检验了以下假设：在PVN内恢复神经元型一氧化氮合酶（nNOS）增强抑制性GABA能机制，并减少兴奋性多巴胺能和血管紧张素能机制，这些机制有助于HF中交感神经驱动的增加。我们建议确定;首先，如果恢复降低的nNOS水平（使用基因转移），则恢复钝化的抑制机制（NO/GABA）并改善PVN中增加的兴奋性（血管紧张素能和血管紧张素能）系统;其次，哪些因素（血管紧张素和/或去甲肾上腺素）负责HF大鼠PVN中nNOS的下调;第三，如果运动训练，则恢复正常 水平的nNOS和抑制系统，也减少了增强的神经递质， 血管紧张素能兴奋性驱动。nNOS和NMDA NR 1受体和AT 1受体之间的关系（细胞机制）将在体外研究中使用神经元细胞培养物（NG 108细胞系）进一步检查。预计恢复PVN内的nNOS可改善HF期间通常观察到的改变的神经抑制（NO/GABA机制）和兴奋系统（谷氨酸/Ang II）。这些结果将提供重要的新信息，中枢机制的交感神经兴奋，特别是参与的NO/GABA和血管紧张素II/NMDA系统的PVN内，在HF状态。了解中枢机制在交感神经驱动增加中的作用，将提高我们治疗HF及其心血管并发症的能力。

Patients with heart failure (HF) and all animal models of HF exhibit an increased sympathetic neural activation, which increases the risk of mortality during HF. The central mechanisms that underlie these abnormalities are poorly understood. We have previously observed that central nitric oxide (NO) mechanisms within the PVN that dictate sympathetic outflow are altered in HF. Subsequently, we determined that NO via a gamma -amino butyric acid (GABA) mechanism, representing an inhibitory mechanism, is augmented in HF. Recently we uncovered enhanced excitatory mechanisms involving glutamatergic and angiotensinergic (also influenced by NO) within the PVN in HF. These data taken together suggest that altered inhibitory mechanisms involving NO and GABA and excitatory mechanisms involving glutamatergic and angiotensinergic pathways within the PVN (with interactions between the two mechanisms involving NO) may be involved in this sympatho-excitation. This proposal tests the hypothesis that restoring neuronal nitric oxide synthase (nNOS) within the PVN enhances the inhibitory GABAergic mechanisms and reduces the excitatory glutamatergic and angiotensinergic mechanisms that contribute to the increased sympathetic drive in HF. We propose to determine; first, if restoring the reduced levels of nNOS (using gene transfer) restores the blunted inhibitory mechanisms (NO/GABA) and ameliorates increased excitatory (glutamatergic and angiotensinergic) systems in the PVN; second, which factors (angiotensin and/or norepinephrine) are responsible for the down-regulation of nNOS in the PVN of rats with HF and third, if exercise training, which normalizes levels of nNOS and the inhibitory system, also reduces the augmented glutamatergic and angiotensinergic excitatory drive in HF. The relationship (cellular mechanisms) between nNOS and NMDA NR1 receptors and AT1 receptors will be further examined using neuronal cell cultures (NG108 cell line) in inin vitrole studies. It is anticipated that restoring nNOS within the PVN improves the altered neural inhibitory (NO/GABA mechanisms) and excitatory systems (glutamate/Ang II) commonly observed during HF. The results will provide significant new information regarding central mechanisms of sympatho-excitation, specifically involvement of the NO/GABA and Ang II/NMDA systems within the PVN, in the HF state. Understanding the role of central mechanisms, not studied to date, in the increased sympathetic neural drive will enhance our ability to treat the HF condition and its cardiovascular complications.