Project: Research project

Project Details


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.
Effective start/end date12/31/896/30/92


  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute