During exercise, sympathetic nerve responses are accentuated in heart failure (HF) and this enhances norepinephrine (NE) release and prominent vasoconstriction. Two key pathophysiologic responses could contribute to the greater NE release: 1) increased sympathetic nerve discharge; and 2) increased NE in the neurovascular junction for a given level of sympathetic discharge. In this report we focus on the second of these two general issues and test the following hypotheses: 1) in HF for a given level of sympathetic nerve stimulation the concentration of NE in the interstitium ([NE]i, index of neurovascular NE) would be greater; and 2) the greater [NE]i would be linked to reduced NE uptake. Studies were performed in rats 8-10 weeks after induction of myocardial infarction (MI). NEi samples were collected from microdialysis probes inserted into the hindlimb muscle. Dialysate concentration of NE was determined by the HPLC method. First, [NE]i increased during electrical stimulation of the lumbar sympathetic nerves in eight control rats. An increase in [NE]i was significantly greater in ten severe MI rats. Additionally, a NE uptake 1 inhibitor (desipramine; 1 µmol/L) was injected into arterial blood supply of the muscle in six controls and in eight MI rats. Desipramine increased [NE]i by 24% in controls and by only 3% (P < 0.05 vs. control) in MI rats. In conclusion, given levels of electrical stimulation of the lumbar sympathetic nerve leads to larger NEi in HF. This effect is due, in part, to reduced NE uptake 1 in HF.