Natriuretic peptides (NPs) are a family of peptide hormones known to be potent regulators of the cardiovascular system. They play a pivotal role in the regulation of intravascular volume by modulating blood vessel tone and renal function. However, their effects on sympathetic neurons remain poorly understood considering that NP receptors are present on neurons. We aimed to elucidate the effects of brain natriuretic peptide (BNP) on calcium transients in sympathetic neurons, and on neurotransmission in isolated atria tissue. Four week old SD rats were humanely killed by an approved Home Office schedule 1 method, and the stellate ganglia enzymatically isolated. Immunofluorescent staining and RT-PCR were used to determine NP receptor expression. Intracellular free Ca2+ concentration ([Ca2+]i) was measured by ratiometric fluorescence imaging using fura-2/AM in neurons. The evoked [Ca2+]i transient was evaluated following 30 sec exposure to 50 mM KCl in the Tyrode solution. Fura-2/AM was excited alternately at 350 nm and 380 nm and the emitted fluorescence measured at 510 nm. Natriuretic peptide receptor (NPR) type A and B were expressed in sympathetic neurons. BNP significantly reduced the depolarization evoked [Ca2+]i transient (100 nM BNP: -21.15 ± 4.90 %, n=18, P<0.01; 250 nM BNP: -23.89 ± 6.42 %, n=12, P<0.05). The action of BNP was significantly reduced by the PKG inhibitor (5 μM RP-8-Br-PET-cGMP, n=11, P<0.05) and NPR-A inhibitor (10 μM Isatin, n=15, P<0.01). BNP (250 nM) decreased [3H]-noradrenaline release from isolated spontaneously beating atrial in response to 5Hz field stimulation (n=6), and also significantly reduced the heart rate (HR) responses to sympathetic nerve stimulation (1-7Hz) in- vitro compared to control (n=10). We conclude that BNP reduces cardiac sympathetic neurotransmission by decreasing [Ca2+]i and subsequent noradrenaline release via a pGC-cGMP-PKG coupled pathway downstream from the NPR.