The neuronal norepinephrine transporter in experimental heart failure: Evidence for a posttranscriptional downregulation

An impairment of norepinephrine (NE) re-uptake by the neuronal NE transport er (NET) has been shown to contribute to the increased cardiac net-release of NE in congestive heart failure (CHF). The present study investigated whi ch mechanisms are involved in the impairment of NET. Rats with supracoronar y aortic banding characterized by myocardial hyper-trophy, elevated left ve ntricular end diastolic pressures and severe pulmonary congestion were used as an experimental model for CHF. Compared to sham-operated controls, aort ic-banded rats had enhanced plasma NE concentrations and decreased cardiac NE stores. In isolated perfused hearts of aortic-banded rats, functional im pairment of NET was indicated by a 37% reduction in [B-3]-NE-uptake. In add ition, pharmacological blockade of NET with desipramine led to a markedly a ttenuated increase in the overflow of endogenous NE from hearts of aortic-b anded rats. Determination of cardiac NET protein and of NET mRNA in the lef t stellate ganglion by [H-3]-desipramine binding and competitive RT-PCR, re spectively, revealed a 41% reduction of binding sites but no difference in gene expression, The density of sympathetic nerve fibers within the heart w as unchanged, as shown by glyoxylic acid-induced histofluorescence. In conc lusion, as impairment of intracardiac NE re-uptake by a reduction of NET bi nding sites is neither mediated by a decreased NET gene expression nor by a loss of noradrenergic nerve terminals, a posttranscriptional downregulatio n of NET per neuron is suggested in CHF. (C) 2001 Academic Press.