The Neuronal Norepinephrine Transporter in Experimental Heart Failure: Evidence for a Posttranscriptional Downregulation

doi:10.1006/jmcc.2000.1319

Journal of Molecular and Cellular Cardiology

Volume 33, Issue 3, March 2001, Pages 461-472

https://doi.org/10.1006/jmcc.2000.1319 Get rights and content

Abstract

An impairment of norÍepinephrine (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 [³H]-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 [³H]-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.

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^☆: Presented in part at the 72nd Scientific Sessions of the American Heart Association in November 1999 in Atlanta/Georgia.

^☆☆: Please address all correspondence to: Markus Haass, MD, Department of Cardiology, University of Heidelberg, Bergheimer Str. 58, D-69115 Heidelberg, Germany. E-mail: [email protected]

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Regular ArticleThe Neuronal Norepinephrine Transporter in Experimental Heart Failure: Evidence for a Posttranscriptional Downregulation☆,☆☆

Abstract

Am J Med

J Am Coll Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Life Sci

J Biol Chem

Mol Brain Res

Anal Biochem

J Chromatogr

Brain Res Mol Brain Res

J Biol Chem

Auton Nerv Syst

J Auton Nerv Syst

J Biol Chem

Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure

Circulation

Plasma norÍepinephrine as a guide to prognosis in patients with chronic congestive heart failure

N Engl J Med

Different relationships of spillover to release of norepinephrine in human heart, kidneys, and forearm

Am J Physiol

Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity

Circulation

Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure

Circulation

Selected aspects of presynaptic modulation of noradrenaline release from the heart

J Cardiovasc Pharmacol

Cardiac sympathetic nerve function in congestive heart failure

Circulation

Cardiac sympathetic nervous activity in congestive heart failure: evidence for increased neuronal norepinephrine release and preserved neuronal uptake

Circulation

Uptake of catecholamines by human cardiac msucle in vitro

Br Heart J

Tracer norÍepinephrine kinetics in coronary circulation of patients with heart failure secondary to chronic pressure and volume overload

J Clin Invest

Decreased adrenergic neuronal uptake activity in experimental right heart failure. A chamber-specific contributor to beta-adrenoceptor down-regulation

J Clin Invest

Cardiac noradrenergic nerve terminal abnormalities in dogs with experimental congestive heart failure

Circulation

Regular Article
The Neuronal Norepinephrine Transporter in Experimental Heart Failure: Evidence for a Posttranscriptional Downregulation☆,☆☆