Our purpose is to determine the mechanisms responsible for the increased plasma norepinephrine (NE) levels in congestive heart failure (CHF). The following hypotheses are to be tested: 1) that increased NE levels in heart failure are the result of both decreased NE clearance and increased spillover of NE from sympathetic nerves into the circulation; 2) that reduced NE clearance is due to a reduction in beta adrenergic receptor mediated non-neuronal uptake, and decreased blood flow to the splanchnic circulation; 3) that enhanced NE spillover comes from many organs and may be related to an increased number of rapidly turning over small vesicles in noradrenergic terminals due to excessive sympathetic nerve traffic which is facilitated and reinforced by high plasma norepinephrine levels. These hypotheses will be tested by studying humans with CHF, a rat aortocaval shunt model of CHF, and 2 dog CHF models, coronary microsphere embolization and chronic tachycardia. Studies will characterize in CHF patients the patterns of NE clearance and spillover using the 3H NE constant infusion technique at rest and with physiologic stress (head up tilt and exercise), and following transient pharmacologic interventions designed to alter separately neuronal and non-neuronal NE uptake, and regional organ NE clearance and spillover. The tail artery in the CHF rat will be used to analyze vascular NE uptake (of 3H-NE under basal conditions and during selective uptake blockade) and NE release with and without prior preincubation with 3H-NE (evoked by tyramine and potassium). NE turnover in this preparation will be assessed by varying incubation time and substrate concentration during uptake studies, by evaluating presynaptic receptor function, and by evaluating the conversion of 3H precursors to norepinephrine. The CHF dogs will be used to determine the sequence of events leading to abnormalities of NE kinetics noted in humans, and how this can be modified by interventions which cannot be used in humans. Since high NE levels may cause CHF to progress, knowledge of how and why NE levels are high may suggest ways to interrupt the process.
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