To examine changes in renal sympathetic outflow in response to cardiac unloading with nitroglycerin (GTN) in patients with chronic heart failure (CHF) and healthy subjects (HS).Renal (RNAsp) and total body (TBNAsp) noradrenaline (NA) spillover were measured with radiotracer methods in 16 patients with CHF (50±3 years, LVEF 20±1%) and nine HS (57±2 years) during right heart and renal vein catheterisation. Low dose GTN decreased mean pulmonary artery pressure (PAm: CHF −7±2 mm Hg, HS −4±1 mm Hg, p<0.05 vs. baseline) but not mean arterial pressure (MAP: CHF −2±1 mm Hg, HS −2±1 mm Hg) and did not affect RNAsp in any of the study groups. High dose GTN lowered MAP (CHF −12±1 mm Hg, HS −12±2 mm Hg, p<0.05 vs. baseline) and PAm (CHF −13±2 mm Hg, HS −5±1 mm Hg, p<0.05 vs. baseline) and was accompanied by a significant reduction in RNAsp only in CHF (1.3±0.1 nmol/min baseline to 0.9±0.2 nmol/min, p<0.05), whereas RNAsp in HS remained unchanged.In spite of a reduction in both arterial pressure and cardiac filling pressures, renal sympathetic activity decreased in CHF and did not increase in HS. These findings suggest that the altered loading conditions resulting from high-dose GTN infusion have renal sympathoinhibitory effects.