cyclic-gmp and sacubitril

The significant morbidity and mortality associated with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in the regulation of cardiovascular function. This pathway is disrupted in HF resulting in decreased protection against myocardial injury. The sGC activator cinaciguat increases cGMP levels by direct, NO-independent activation of sGC, and may be particularly effective in conditions of increased oxidative stress and endothelial dysfunction, and then reduced NO levels, but this comes at the expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat and vericiguat) enhance sGC sensitivity to endogenous NO, and then exert a more physiological action. The phase 3 VICTORIA trial found that vericiguat is safe and effective in patients with HFrEF and recent HF decompensation. Therefore, adding vericiguat may be considered in individual patients with HFrEF, particularly those at higher risk of HF hospitalization; the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF is currently unknown.

Topics: Aminobutyrates; Biphenyl Compounds; Cyclic GMP; Heart Failure; Heterocyclic Compounds, 2-Ring; Humans; Nitric Oxide; Pyrimidines; Soluble Guanylyl Cyclase; Stroke Volume

Aldosterone is a critical pathological driver for cardiac and renal diseases. We recently discovered that mutant atrial natriuretic peptide (MANP), a novel atrial natriuretic peptide (ANP) analog, possessed more potent aldosterone inhibitory action than ANP in vivo. MANP and natriuretic peptide (NP)-augmenting therapy sacubitril/valsartan are under investigations for human hypertension treatment. Understanding the elusive mechanism of aldosterone inhibition by NPs remains to be a priority. Conflicting results were reported on the roles of the pGC-A (particulate guanylyl cyclase A receptor) and NP clearance receptor in aldosterone inhibition. Furthermore, the function of PKG (protein kinase G) and PDEs (phosphodiesterases) on aldosterone regulation are not clear.. In the present study, we investigated the molecular mechanism of aldosterone regulation in a human adrenocortical cell line H295R and in mice.. We first provided evidence to show that pGC-A, not NP clearance receptor, mediates aldosterone inhibition. Next, we confirmed that MANP inhibits aldosterone via PDE2 (phosphodiesterase 2) not PKG, with specific agonists, antagonists, siRNA silencing, and fluorescence resonance energy transfer experiments. Further, the inhibitory effect is mediated by a reduction of intracellular Ca2+ levels. We then illustrated that MANP directly reduces aldosterone synthase CYP11B2 (cytochrome p450 family 11 subfamily b member 2) expression via PDE2. Last, in PDE2 knockout mice, consistent with in vitro findings, embryonic adrenal CYP11B2 is markedly increased.. Our results innovatively explore and expand the NP/pGC-A/3',5', cyclic guanosine monophosphate (cGMP)/PDE2 pathway for aldosterone inhibition by MANP in vitro and in vivo. In addition, our data also support the development of MANP as a novel ANP analog drug for aldosterone excess treatment.

Topics: Aldosterone; Aminobutyrates; Animals; Atrial Natriuretic Factor; Biphenyl Compounds; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Cytochrome P-450 CYP11B2; Humans; Mice; Mice, Knockout; Natriuretic Peptides