C-type natriuretic peptides (CNP) was originally identified in the porcine brain and is considered the predominant neuropeptide of the nervous systems, however expression has also been identified in extra-neuronal tissue including the heart and vasculature. Recent data has identified a cardioprotective role for B-type natriuretic peptide (BNP) during cardiac hypertrophy and heart failure specifically acting via the NPR-A receptor. CNP is the ligand for the NPR-B receptor, and its levels are also elevated during heart failure (Kalra, et. al. 2003). The expression pattern of NPR-B within cardiac autonomic innervation and the role of CNP in cardiac neural control currently remains unclear. We hypothesised that CNP, like BNP, would inhibit sympathetic neurotransmission. Immunohistochemistry demonstrated co-staining of NPR-B with tyrosine hydroxylase (TH) positive neurons cultured from stellate ganglia of the SD rat. Peak calcium current density in cultured stellate ganglia neurons was measured using whole cell patch clamp recordings. A reduction in Ca2+ current was observed with CNP (250nM; 21.7± 2.7%, n=3). Intracellular Ca2+ transients in response to transient cell depolarisation (50mM KCl, 30 sec) measured using ratiometric fluorescent imaging (fura-2AM) were also significantly (p<0.01) reduced by CNP (250nM; n=9). In isolated atria organ bath preparations CNP (250nM; n=8) significantly reduced tritiated norepinephrine (3H-NE) release, in response to 5Hz field stimulation, as well as the heart rate response to stimulation of the right stellate ganglion (250nM; n=8). This study provides evidence for the sympatho-inhibitory role of CNP, which may be cardio- protective during chronic heart failure. CNP reduces noradrenaline release and the heart rate response to sympathetic stimulation via a reduction in neuronal calcium signalling through the NPR-B receptor.