Heart failure (HF) is associated with increased cardiac and renal sympathetic drive, which are both independent predictors of poor prognosis. A candidate mechanism for the centrally mediated sympatho-excitation in HF is reduced synthesis of the inhibitory neuromodulator nitric oxide (NO), resulting from down-regulation of neuronal NO synthase (nNOS). We therefore investigated the effects of increasing the levels of NO in the brain, or selectively in the PVN, on cardiac sympathetic nerve activity (CSNA) and baroreflex control of CSNA and heart rate in ovine pacing-induced HF. The resting level of CSNA was significantly higher in the HF than the normal group, but the resting level of RSNA was unchanged. Intracerebroventricular (ICV) infusion of the NO donor sodium nitroprusside (SNP; 500 μg/mL/hr) in conscious normal sheep and HF sheep inhibited CSNA and restored baroreflex control of heart rate, but there was no change in RSNA. Microinjection of SNP into the PVN did not cause a similar cardiac sympatho-inhibition in either group, although the number of nNOS positive cells was decreased in the PVN of sheep in HF. Reduction of endogenous NO with ICV infusion of N-nitro-L-arginine methyl ester decreased CSNA in normal but not HF sheep, and caused no change in RSNA in either group. These findings indicate that endogenous NO in the brain provides tonic excitatory drive to increase resting CSNA in the normal state, but not in HF. In contrast, exogenously administered NO inhibited CSNA in both normal and HF groups via an action on sites other than the PVN.