Interaction of a Neutral Endopeptidase Inhibitor with an ANP-C Receptor Ligand in Anesthetized Dogs

Abstract

Inhibition of important degradative pathways of atrial natriuretic peptide (ANP) in vivo could be a valuable therapeutic tool for regulating endogenous levels of ANP. The aim was to investigate the in vivo effects of both blockade of atrial natriuretic peptide clearance receptor and inhibition of neutral endopeptidase 24.11, an enzyme shown to be involved in ANP breakdown. Therefore, we infused a specific neutral endopeptidase inhibitor ((S)-thiorphan) and an ANP-C receptor ligand (AP 811) alone or in combination into anaesthetized beagle dogs. Compared with vehicle controls, coadministration of (S)-thiorphan and AP 811 (100 micrograms/kg/min and 10 micrograms/kg/min, resp.) had greater effects on endocrine and renal parameters than administration of either substance alone. Coadministration of both compounds increased urinary excretion of volume and sodium, cGMP and ANP. We found also increased plasma cGMP, plasma ANP and decreased plasma renin activity. No effects were observed with respect to blood pressure, left ventricular pressure or heart rate during the infusion period of 2 h. We conclude from these investigations, that blocking both degrading pathways of ANP with the ANP-C receptor ligand AP 811 and the neutral endopeptidase inhibitor (S)-thiorphan is more effective than inhibition of either system alone. Such a combination might therefore be a useful therapeutic tool in cardiovascular diseases.

Natriuretic peptide metabolism, clearance and degradation

“…Oral neprilysin inhibitors elevate natriuretic peptide concentrations in humans and animal models, and increase sodium excretion during heart failure, consistent with neprilysin or another enzyme that is blocked by neprilysin inhibitors contributing to natriuretic peptide degradation [56,59–62]. Natriuretic peptide levels have not been reported in mice lacking neprilysin, but these mice show no obvious signs of increased natriuretic peptide receptor activation, consistent with other degradation pathways compensating for the loss of neprilysin activity in this species [63].…”

Blockade of the natriuretic peptide clearance receptor attenuates proteinuria in a mouse model of focal segmental glomerulosclerosis

“…Thus, the effects of ANP(4‐23) might be mediated, at least in part, by stimulating NPRC. Future studies could address this possibility by studying other high affinity, specific NPRC ligands such as AP‐811 (Koyama et al, 1994 ; Nishizawa et al, 2017 ; Veale et al, 2000 ; William et al, 2008 ) which does not act as an agonist at the NPRC receptor (Becker et al, 2014 ; William et al, 2008 ) but effectively inhibits NP clearance from the circulation in vivo (Wegner et al, 1995 ).…”

Neutral Endopeptidase Inhibition Potentiates the Effects of Natriuretic Peptides in Renin Transgenic Rats.

“…In rats with experimentally induced congestive heart failure (aortovenocaval fistula rats) acute treatment with ecadotril increased the plasma levels of endogenous ANP without having any effect in their sham-operated controls (21). In addition, acute administration of various NEP inhibitors has been shown to increase plasma ANP in various animal models of hypertension when the ANP was already elevated, e.g., in NaCI-sensitive spontaneously hypertensive rats (22) and in DOCAlsalt hypertensive rats (23), whereas NEP inhibitors failed to modify plasma ANP in intact normotensive rats (3), dogs (24), and humans (25). In hypertensive patients, NEP inhibition raised ANP levels (26) and a small decrease in blood pressure was observed (15,27,28).…”