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 γ-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. We have subsequently shown that; first, restoring the reduced levels of nNOS (using gene transfer) restores the blunted inhibitory mechanisms (NO/GABA) and ameliorates increased excitatory (glutamatergic) systems in the PVN; second, exercise training restores the levels of nNOS within the PVN and restores the enhanced sympathoexcitation observed in chronic heart failure. Understanding the role of central mechanisms, in the increased sympathetic neural drive will enhance our ability to treat the HF condition and its cardiovascular complications.

Location:	B448-49 Life Sciences Building [map]
Price:	free
Sponsor:	Dept of Pharmacology & Toxicology
Contact:	Diane Hummel phm@msu.edu 353-9616
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