An impairment of cardiac norepinephrine (NE) re-uptake via the neuronal NE transporter (NET) enhances the effects of increased cardiac NE release in heart failure patients. Increasing evidence suggests that aldosterone and endothelins promote sympathetic overstimulation of failing hearts. Salt-sensitive Dahl rats (DS), fed on a high-salt diet, developed arterial hypertension and diastolic heart failure as well as elevated plasma levels of endothelin-1 and NE. Cardiac NE re-uptake and NET binding sites, as assessed by clearance of bolus-injected [³H]-NE in isolated perfused rat hearts and [³H]-mazindol binding, were reduced. Treatment of DS with the mineralocorticoid receptor antagonist spironolactone preserved the plasma levels of endothelin-1 and NE, cardiac NE re-uptake and myocardial NET density. Moreover, ventricular function and survival of spironolactone-treated DS were significantly improved compared with untreated DS. The ₁-inhibitor prazosin decreased the blood pressure in DS similar to spironolactone-treatment, but did not normalize the plasma levels of endothelin-1 and NE, NE re-uptake or ventricular function. In a heart failure-independent model, Wistar rats, that were infused with aldosterone and fed on a high-salt diet, developed also an impaired cardiac NE re-uptake. Treatment of these rats with the endothelin A receptor antagonist darusentan attenuated the impairment of NE re-uptake. In conclusion, spironolactone preserves NET-dependent cardiac NE re-uptake in salt-dependent heart failure. Evidence is provided that aldosterone inhibits NET function through an interaction with the endothelin system. Selective antagonism of the mineralocorticoid and/or the endothelin A receptor might represent therapeutic principles to prevent cardiac sympathetic overactivity in salt-dependent heart failure.