The factors controlling cardiac sympathetic nerve activity (CSNA) in the normal state and those causing the large increase in activity in heart failure (HF) remain unclear. We hypothesized, from previous clinical findings, that activation of cardiac mechanoreceptors by the increased blood volume in HF may stimulate SNA, particularly to the heart via cardio-cardiac reflexes. To investigate the effect of volume expansion and depletion on CSNA we have made multiunit recordings of CSNA in conscious normal sheep and sheep paced into HF. In HF sheep (n=9), compared to normal sheep (n=9), resting levels of CSNA were significantly higher (21±1 vs. 11±2 spikes/s; P<0.05), mean arterial pressure was lower (76±3 vs. 87±2 mmHg; P<0.05) and central venous pressure (CVP) was greater (3.0±1.0 vs. 0.0±1.0 mmHg; P<0.05). In normal sheep (n=6), hemorrhage (400 mL over 30 min) was associated with a significant increase in CSNA (179±16%) with a decrease in CVP (2.7±0.7 mmHg). Volume expansion (400 mL Gelofusine over 30 min) significantly decreased CSNA (35±12%) and increased CVP (4.7±1.0 mmHg). In HF sheep (n=6), the responses of CSNA to both volume expansion and hemorrhage were severely blunted, with no significant changes in CSNA or heart rate with either stimulus. In summary, these studies in a large conscious mammal demonstrate that in the normal state directly recorded CSNA increased with volume depletion and decreased with volume loading. In contrast, both these responses were severely blunted in HF, with no significant changes in CSNA during either hemorrhage or volume expansion.