The neuronal norepinephrine transporter in experimental heart failure: evidence for a posttranscriptional downregulation.
An impairment of norepinephrine (NE) re-uptake by the neuronal NE transporter (NET) has been shown to contribute to the increased cardiac net-release of NE in congestive heart failure (CHF). The present study investigated which mechanisms are involved in the impairment of NET. Rats with supracoronary aortic banding characterized by myocardial hypertrophy, elevated left ventricular end diastolic pressures and severe pulmonary congestion were used as an experimental model for CHF. Compared to sham-operated controls, aortic-banded rats had enhanced plasma NE concentrations and decreased cardiac NE stores. In isolated perfused hearts of aortic-banded rats, functional impairment of NET was indicated by a 37% reduction in [(3)H]-NE-uptake. In addition, pharmacological blockade of NET with desipramine led to a markedly attenuated increase in the overflow of endogenous NE from hearts of aortic-banded rats. Determination of cardiac NET protein and of NET mRNA in the left stellate ganglion by [(3)H]-desipramine binding and competitive RT-PCR, respectively, revealed a 41% reduction of binding sites but no difference in gene expression. The density of sympathetic nerve fibers within the heart was unchanged, as shown by glyoxylic acid-induced histofluorescence. In conclusion, as impairment of intracardiac NE re-uptake by a reduction of NET binding sites is neither mediated by a decreased NET gene expression nor by a loss of noradrenergic nerve terminals, a posttranscriptional downregulation of NET per neuron is suggested in CHF.
Backs
J
J
Department of Cardiology, University of Heidelberg, Bergheimer Str. 58, 69115 Heidelberg, Germany.
Haunstetter
A
A
Gerber
S H
SH
Metz
J
J
Borst
M M
MM
Strasser
R H
RH
Kübler
W
W
Haass
M
M
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006706:Homeostasis; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009474:Neurons; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012323:RNA Processing, Post-Transcriptional; D051381:Rats; D017208:Rats, Wistar; D013233:Stellate Ganglion / Q000378:metabolism; D027981:Symporters; D018487:Ventricular Dysfunction, Left / Q000378:metabolism / Q000503:physiopathology; D017725:Ventricular Pressure
D002352:Carrier Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; D027981:Symporters; D009638:Norepinephrine