A Novel Role for B-Type Natriuretic Peptide and Phosphodiesterase 2A in Cardiac Sympathetic Neurons from Prehypertensive Rats

Abstract

Natriuretic peptides (NPs) 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, although the use of a recombinant BNP agonist in clinical trials has proved disappointing. However previous data shows that BNP decreases cardiac sympathetic neurotransmission by attenuating activation of neuronal calcium signaling via a cGMP-PKG pathway. Emerging evidence suggests that phosphodiesterase 2A (PDE2A) is upregulated in heart failure. Therefore we tested whether PDE2A was directly involved the efficiency of BNP modulation of Ca2+ handling in cardiac sympathetic neurons from pre-hypertensive spontaneously hypertensive rats (SHRs).Cardiac stellate ganglia were enzymatically isolated and cultured. Neuronal calcium current was measured using whole cell configuration of the patch-clamp technique. [Ca2+]i transient was measured by ratiometric fluorescence imaging. BNP significantly reduced the magnitude of the Ca2+ transients and calcium current in normotensive Wistar-Kyoto (WKY) rats, but not in SHR sympathetic neurons. PDE2 inhibitor Bay60-7550 restored the capacity of BNP to reduce [Ca2+]i in the SHR. Overexpression of PDE2A using a viral vector (Ad.CMV-mCherry.PDE2A) on the sympathetic neurons abrogated the response to BNP in the WKY. This was reversed by PDE2 inhibition. Interestingly, overexpression of dnPDE2A (a catalytically-dead mutant of PDE2A) using a viral vector (Ad.CMV-mCherry.dnPDE2A) rescued the BNP inhibition of the calcium handling from the SHR.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 PDE2A may play a potential role as a pharmacological target to restore the efficacy of BNP to decrease sympathetic neurotransmission.