PDE2A activity was significantly higher in stellate ganglia from patients with sympathetic hyperactivity compared to donors, and PDE2A inhibition restored the sympatholytic action of BNP in diseased neurons.
Does PDE2A inhibition restore the sympatholytic action of BNP in stellate ganglia neurons from models of sympathetic hyperactivity?
Upregulation of PDE2A in sympathetic neurons impairs BNP responsiveness, and targeted PDE2A inhibition restores the sympatholytic effects of BNP, offering a potential therapeutic strategy for sympathetic hyperactivity.
Absolute Event Rate: 134.6% vs 75.6%
p-value: p=0.028
Elevated levels of brain natriuretic peptide (BNP) are regarded as an early compensatory response to cardiac myocyte hypertrophy, although exogenously administered BNP shows poor clinical efficacy in heart failure and hypertension. We tested whether phosphodiesterase 2A (PDE2A), which regulates the action of BNP-activated cyclic guanosine monophosphate (cGMP), was directly involved in modulating Ca2+ handling from stellate ganglia (SG) neurons and cardiac norepinephrine (NE) release in rats and humans with an enhanced sympathetic phenotype. SG were also isolated from patients with sympathetic hyperactivity and healthy donor patients. PDE2A activity of the SG was greater in both spontaneously hypertensive rats (SHRs) and patients compared with their respective controls, whereas PDE2A mRNA was only high in SHR SG. BNP significantly reduced the magnitude of the calcium transients and ICaN in normal Wistar Kyoto (WKY) SG neurons, but not in the SHRs. cGMP levels stimulated by BNP were also attenuated in SHR SG neurons. Overexpression of PDE2A in WKY neurons recapitulated the calcium phenotype seen in SHR neurons. Functionally, BNP significantly reduced 3H-NE release in the WKY rats, but not in the SHRs. Blockade of overexpressed PDE2A with Bay 60-7550 or overexpression of catalytically inactive PDE2A reestablished the modulatory action of BNP in SHR SG neurons. This suggests that PDE2A may be a key target in modulating the action of BNP to reduce sympathetic hyperactivity.
Liu et al. (Wed,) conducted a other in Sympathetic hyperactivity. PDE2A inhibition (Bay 60-7550) and BNP vs. Control / Vehicle was evaluated on cGMP-PDE2A specific activity in human left stellate ganglia (pmol/mg/min) (p=0.028). PDE2A activity was significantly higher in stellate ganglia from patients with sympathetic hyperactivity compared to donors, and PDE2A inhibition restored the sympatholytic action of BNP in diseased neurons.