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.
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