Introduction: B-type natriuretic peptide (BNP) is regarded as an early compensatory response to cardiac myocyte hypertrophy. However, the use of a recombinant BNP (Nesiritide) in clinical trials proved disappointing in the treatment of hypertension and heart failure1, with some suggesting it actually enhances cardiac sympathetic activity. Our previous work showed that BNP decreases cardiac sympathetic neurotransmission by attenuating activation of neuronal calcium channels and the intracellular calcium transient via a cGMP-protein kinase G (PKG)-phosphodiesterase 2 (PDE2A) coupled pathway. Emerging evidence suggests that myocardial PDE2A expression and activity is up-regulated in heart failure. Therefore we tested whether PDE2A was directly involved in modulating cardiac neurotransmitter release from pre-hypertensive spontaneously hypertensive rats (SHRs) that show an enhanced Ca2+ phenotype. Methods & Results: Four week old pre-hypertensive SHR and the age matched normotensive Wistar-Kyoto (WKY) rats were humanely killed with schedule 1 method in accordance with the Home Office Animals (Scientific Procedures) Act 1986 (UK). PDE2A activity in the SHR (n=8) was higher (~60%) than in WKY stellate ganglia tissue (n=8). [3H] labelled noradrenaline (NA) release was measured from isolated spontaneously beating atrial in response to 5Hz field stimulation for 1 minute at the 16th (S1, control) and 40th (S2, with 250nM BNP) minutes. All data are expressed as mean+SEM. Comparison within groups are performed using the paired t-test. We demonstrated that the BNP caused a ~35% reduction of [3H]-NA release in the WKY (S1:+0.92±0.09%, S2: +0.59±0.09%, n=10, P<0.05), whereas it failed to reduce [3H]-NA release in the SHR (S1:+1.34±0.34%, S2: +1.16±0.23%, n=10, P=0.45). Overexpression of PDE2A using a viral vector (Ad.PDE2A) which transduced to the right atria abrogated the response to BNP in the WKY (S1:+1.71±0.18%, S2: +1.78±0.22%, n=7, P=0.61). Interestingly, BNP produced a ~50% reduction in [3H]-NA release in the SHR that was transduced with an adenoviral vector expressing catalytically inactive PDE2A (dominant negative PDE2A, S1:+1.16±0.12%, S2: +0.54±0.11%, n=9, P<0.05). Conclusions: These data support the hypothesis that higher PDE2A expression in the SHR abolishes the capacity of BNP to reduce neurotransmitters release in stimulated right atrium. 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.