809-3 Desipramine Attenuates the Cardiac Sympathetic Nerve Terminal Abnormalities in Congestive Heart Failure

Abstract

We have shown that cardiac norepinephrine (NE) reuptake activity and tyrosine hydroxylase (TH), a rate-limiting enzyme for NE synthesis, are reduced in congestive heart failure (CHF). To determine whether the changes of TH are caused by neurotoxic effects of NE, we administered the neuronal uptake inhibitor desipramine (DMI, 225 mg/day) to pacing-induced CHF and sham-operated (SHAM) dogs for 6 weeks. CHF was characterized by tachycardia, low aortic pressure, elevated left atrial pressure, decreased left ventricular dP/dt and reduced cardiac output. DMI produced no hemodynamic effects. The effects of OMI on left ventricular NE uptake activity (fmol/mg/15 min) and immunocytochemical TH profiles were: Group NE uptake TH SHAM (n = 12) 133 ± 9 813 ± 43 SHAM + OMI (n = 6) 49 ± 11 * 769 ± 14 CHF (n = 12) 64 ± 8 * 409 ± 42 * CHF + OMI (n = 7) 40 ± 9 * , † 642 ± 49 * , † Values are mean ± SE * p < 005 vs. SHAM: † P < 0.05 vs. CHF As expected, DMI reduced NE uptake activity in both SHAM and CHF animals, but its actions on TH differed between the two groups. While it exerted no effect on TH in SHAM animals, DMI reduced the decrease in TH that occurred in CHF. The results suggest that the cardiac sympathetic changes that occur in CHF may be caused by excessive NE, and that the neurotoxic effect of NE on TH involves the NE reuptake mechanism.