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

心衰（HF）患者和所有HF动物模型均表现出交感神经激活增加，这增加了心衰期间死亡的风险。这些异常背后的主要机制尚不清楚。我们之前观察到，心衰患者心室神经网络内支配交感神经流出的中枢一氧化氮（NO）机制发生改变。随后，我们确定通过γ -氨基丁酸（GABA）机制（代表抑制机制）的NO在HF中增强。最近，我们发现了HF患者PVN内涉及谷氨酸能和血管紧张素能（也受NO影响）的增强兴奋机制。综上所述，涉及NO和GABA的抑制机制以及涉及PVN内谷氨酸能和血管紧张素能通路的兴奋机制的改变（涉及NO的两种机制之间的相互作用）可能参与了这种交感神经兴奋。本研究证实，恢复PVN内的神经元一氧化氮合酶（nNOS）增强了抑制性gaba能机制，降低了导致心衰交感神经驱动增强的兴奋性谷氨酸能和血管紧张素能机制。我们建议确定；首先，如果恢复降低的nNOS水平（使用基因转移）恢复钝化的抑制机制（NO/GABA）并改善PVN中增加的兴奋性（谷氨酸能和血管紧张素能）系统；第二，哪些因素（血管紧张素和/或去甲肾上腺素）导致HF大鼠PVN中nNOS的下调；第三，运动训练是否使其正常化

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.