Interaction of a neutral endopeptidase inhibitor with an ANP-C receptor ligand in anesthetized dogs.

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.