Heart failure (HF), a clinical syndrome that develops as a consequence of heart disease from multiple etiologies, now affects almost six million Americans, presenting an imminent need for further research addressing the pathophysiology of this pervasive disease. One of the most damaging consequences of HF is an elevation in sympathetic nervous system (SNS) activity, which is expressed through alpha adrenergic receptors located on the vascular smooth muscle, promoting peripheral vasoconstriction. In HF patients, chronic sympathetic vasoconstriction acts to limit blood flow in the exercising muscle, promoting exercise intolerance, inactivity, and a subsequent acceleration in disease progression. Fortunately, disease-related sympathoexcitation may be remediable. Among the most influential modulators of peripheral SNS expression is the nitric oxide (NO) pathway, located at the interface between the vascular smooth muscle and the vascular endothelium. Though NO is perhaps best known for its transient vasodilator effects, recent studies have identified a clear role for this substance as an inhibitor of both central SNS activity and peripheral expression at the level of the alpha adrenergic receptor. Interventions focused on improving NO bioavailability may thus offer a new, unexplored strategy for inhibiting SNS overactivity in HF. A series of experiments using innovative methodologies are proposed to explore the contribution of the alpha adrenergic pathway to vasoconstriction in these patients and to subsequently evaluate the beneficial role of disruptions in oxidative stress (via AOx administration) on sympathetic vasoconstriction in this patient group. Specific Aim 1 will explore the hypothesis that peripheral alpha adrenergic vasoconstriction is overactive in HF. Intra-arterial drug infusions (alpha-adrenergic agonists/antagonists) will be undertaken to pharmacologically probe disease-related changes in alpha adrenergic-mediated vasoconstriction, both at rest and during exercise. Specific Aim 2 will study the direct and modulatory effects of oxidative stress on skeletal muscle vasoconstriction. It is hypothesized that acute AOx administration (intra-arterial Vitamin C) will promote vasodilation at rest and during exercise in an NO-dependent manner. We also hypothesize that chronic oral AOx administration (Vitamins C [1000mg], E [400 IU], and Alpha Lipoic Acid [600 mg], daily for 8 weeks) will reduce circulating free radical levels and subsequently improve NO bioavailability, which will in turn lessen peripheral vasoconstriction through inhibition of alpha adrenergic-mediated vasoconstriction. Successfully defining how sympathetic vasoconstriction is altered in HF is an important step towards better patient care, as we anticipate that findings from the proposed work may serve to refine current strategies for the treatment of peripheral blood flow dysregulation in HF, ultimately leading to enhanced quality of life in this cohort.