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

心力衰竭患者和所有心力衰竭动物模型都表现出交感神经激活增加，这增加了心力衰竭期间死亡的风险。人们对这些异常的核心机制知之甚少。我们先前观察到，心衰时室旁核内支配交感神经流出的中枢一氧化氮(NO)机制发生了改变。随后，我们确定在HF中，NO通过伽马-氨基丁酸(GABA)机制增加，这代表了一种抑制机制。最近，我们发现心衰时室旁核内谷氨酸能和血管紧张素能(也受NO影响)的兴奋机制增强。这些结果提示，这种交感兴奋可能涉及涉及NO和GABA的抑制机制的改变以及涉及PVN内谷氨酸和血管紧张素能通路的兴奋机制(两种机制之间存在相互作用)。这一建议验证了一种假说，即在PVN内恢复神经元型一氧化氮合酶(NNOS)可以增强抑制GABA能机制，减少兴奋性谷氨酸和血管紧张素能机制，这些机制有助于HF交感神经驱动的增加。我们建议确定：第一，恢复降低的nNOS水平(使用基因转移)是否恢复了PVN中钝化的抑制机制(NO/GABA)并改善了兴奋系统(谷氨酸和血管紧张素能)的增加；第二，哪些因素(血管紧张素和/或去甲肾上腺素)导致心衰大鼠PVN中nNOS的下调；第三，如果运动训练，则使其正常化 NNOS和抑制系统的水平，也减少了增强的谷氨酸能和 心衰患者血管紧张素能兴奋性驱动。NNOS和NMDANR1受体和AT1受体之间的关系(细胞机制)将在inin vitole研究中使用神经元细胞培养(NG108细胞株)进一步研究。预计在下丘脑室旁核内恢复nNOS可以改善心衰时常见的神经抑制(NO/GABA机制)和兴奋系统(谷氨酸/血管紧张素II)的改变。这些结果将为交感神经兴奋的中枢机制提供重要的新信息，特别是在心力衰竭状态下，室旁核内NO/GABA和Ang II/NMDA系统的参与。了解中枢机制在交感神经驱动增加中的作用，将提高我们治疗心力衰竭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.