Purpose: 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. Elevated B-type natriuretic peptide (BNP) is regarded as an early compensatory response to hypertension and heart failure. However, the use of a recombinant BNP agonist in clinical trials has proved disappointing, with some suggesting it actually enhances cardiac sympathetic activity. Our previous data shows that BNP decreases cardiac sympathetic neurotransmission by attenuating activation of neuronal calcium channels and the intracellular calcium transient via a cGMP-PKG pathway. Emerging evidence suggests that overactivity of phosphodiesterase 2A (PDE2A) may impair the efficacy of BNP to regulate the intracellular calcium concentration ([Ca2+]i) in CNS neurons. Therefore we tested whether PDE2A was directly involved in modulating Ca2+ handling in cardiac sympathetic neurons from pre-hypertensive spontaneously hypertensive rats (SHRs) that show an enhanced Ca2+ phenotype.Methods and Results: Rats were humanely killed by an approved Home Office schedule 1 method and the cardiac stellate ganglia were enzymatically isolated. Calcium current was measured using the whole cell configuration of the patch-clamp technique. Currents were evoked by test pulses to -10 mV from a holding potential of -90 mV. [Ca2+]i transient was measured by ratiometric fluorescence imaging using fura-2AM in cultured cardiac sympathetic 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. 100 nM & 250 nM BNP significantly reduced the magnitude of the Ca2+ transients and calcium current in normotensive Wistar-Kyoto (WKY) rats, but not in SHR sympathetic neurons. Type 2 PDE2-specific inhibitor Bay 60-7550 (1 µM) restored the capacity for both concentrations of BNP to reduce intracellular Ca2+ transients in the SHR. Overexpression of PDE2A using a viral vector (Ad.CMV-mCherry.PDE2A) on the sympathetic neurons abrogated the response to 250 nM BNP in the WKY. This was reversed by PDE2 inhibition. Conclusion: These data demonstrate that attenuation of [Ca2+]i and the neuronal calcium current by BNP is impaired in the SHR, and this may be associated with apparent over activity of PDE2A. Our results suggest that neuronal PDE2 may play a potential role as a pharmacological target to restore the efficacy of BNP to decrease sympathetic neurotransmission.Key words: B-type natriuretic peptide, Phosphodiesterase 2A, calcium, sympathetic neuron