Cardiac sympathetic neuroprotective effect of desipramine in tachycardia-induced cardiomyopathy.
Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic neurotransmitters was associated with increased interstitial norepinephrine (NE) and reactive oxygen species in congestive heart failure (CHF), using a microdialysis technique and salicylate to detect .OH generation. Rabbits with and without rapid ventricular pacing (340 beats/min) were randomized to receive desipramine (10 mg/day) or placebo for 8 wk. Rapid pacing produced left ventricular dilation and systolic dysfunction. The failing myocardium also showed reduced tissue contents of NE and tyrosine hydroxylase protein and activity. In contrast, myocardial interstitial NE was increased in CHF (0.89 +/- 0.11 ng/ml) compared with the sham-operated animals (0.26 +/- 0.03 ng/ml). In addition, cardiac oxidative stress was increased in CHF animals as measured by myocardial interstitial .OH radical, tissue oxidized glutathione, and oxidized mitochondrial DNA. Desipramine treatment produced significant NE uptake inhibition as evidence by an exaggerated pressor response and a greater increase of myocardial interstitial NE in response to intravenous NE infusion but no significant effects on cardiac function or hemodynamics in sham-operated or CHF animals. However, desipramine treatment attenuated the reductions of tissue NE and tyrosine hydroxylase protein and activity in CHF. Desipramine also prevented the reduction of tyrosine hydroxylase produced by NE in PC12 cells. Thus the reduction of cardiac sympathetic neurotransmitters is related to the increased interstitial NE and tissue oxidative stress in CHF. Also, normal neuronal uptake of NE is required for NE or its oxidized metabolites to exert their neurotoxic effects.
Liang
Chang-Seng
CS
Department of Medicine, Cardiology Division, University of Rochester Medical Center, Box 679, 601 Elmwood Ave., Rochester, New York 14642, USA. chang-seng_liang@urmc.rochester.edu
Mao
Weike
W
Iwai
Chikao
C
Fukuoka
Shuji
S
Stevens
Suzanne Y
SY
D000818:Animals; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects; D009202:Cardiomyopathies / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D003891:Desipramine / Q000008:administration & dosage*; D006321:Heart / Q000187:drug effects / Q000294:innervation; D018696:Neuroprotective Agents / Q000008:administration & dosage; D009638:Norepinephrine / Q000378:metabolism*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism*; D013610:Tachycardia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D003891:Desipramine; D009638:Norepinephrine