Effects of desipramine on norepinephrine clearance in congestive heart failure

Elevated plasma norepinephrine (NE) in congestive heart failure (CHF) is caused by increased NE spillover and decreased NE clearance. To evaluate the effects of neuronal uptake blockade on NE clearance, we studied NE kinetics during steady-state infusions of [³H]NE, before and after oral desipramine (DMI, 50 mg) in 11 patients with CHF and 8 normal volunteers. Baseline plasma NE was greater in the CHF group (637 ± 56 vs. 271 ± 32 pg/ml; P < 0.001), NE clearance was lower in CHF (1.31 ± 0.21 vs. 1.94 ± 0.17 l · min^-1 · m^-2; P = 0.026), and NE spillover was greater in CHF (4.71 ± 0.78 vs. 3.04 ± 0.35 nmol · min^-1 · m^-2; P = 0.054). After DMI, plasma NE rose significantly in CHF (778 ± 67; P = 0.008), and NE clearance decreased further in CHF (0.97 ± 0.16; P = 0.024), but neither changed in normal subjects. NE spillover did not change in either group. There appears to be an enhanced effect of DMI on NE clearance in CHF patients. Two general mechanisms may be responsible for this finding, an increased concentration of drug, possibly caused by a decreased volume of distribution, and an increased sensitivity of neuronal amine pumps to DMI. Both mechanisms may reflect a more general abnormality of clearance of drugs and hormones related to abnormalities of tissue perfusion in CHF.