Heart Failure (HF) is associated with increased sympathetic nerve activity to the heart (CSNA), which is directly linked to mortality in HF patients. Previous studies indicate that HF is associated with high levels of plasma endothelin-1 (ET-1), which correlates with the severity of the disease. We hypothesized that blockade of endothelin receptors would decrease CSNA. The effects of intravenous tezosentan ((a non-selective ET_A and ET_B receptor antagonist) (8 mg/kg/h) on resting levels of CSNA, arterial pressure and heart rate were determined in conscious normal sheep (n= 6) and sheep with pacing induced HF (n= 7). HF was associated with a significant decrease in ejection fraction (from 74 ± 2% to 38 ± 1%, P < 0.001) and a significant increase in resting levels of CSNA burst incidence (from 56 ± 11 to 87 ± 2 bursts / 100 heart beats, P < 0.01). Infusion of tezosentan for 60 minutes significantly decreased resting MAP in both normal and HF sheep (-8 ± 4 mmHg and -4 ± 3 mmHg respectively; p<0.05). This was associated with a significant decrease in CSNA (by 25 ± 26% of control) in normal sheep, but there was no change in CSNA in HF sheep. Calculation of spontaneous baroreflex gain indicated significant impairment of the baroreflex control of HR after intravenous tezosentan infusion in normal animals, but no change in HF animals. These data suggest that endogenous levels of ET-1 contribute to the baseline levels of CSNA in normal animals, but this effect is absent in HF.