Mild
heart failure is characterized by increases in
atrial natriuretic peptide (
ANP) and
brain natriuretic peptide (BNP) in the absence of activation of the renin-angiotensin-aldosterone system (RAAS). Vasopeptidase (VP) inhibitors are novel molecules that coinhibit
neutral endopeptidase 24.11, which degrades the
natriuretic peptides (NPs) and ACE. In a well-characterized canine model of mild
heart failure produced by ventricular pacing at 180 bpm for 10 days, we defined the renal and humoral actions of acute VP inhibition with
omapatrilat (OMA, n=6) and acute ACE inhibition (n=5) alone with
fosinoprilat. We also sought to determine whether the NPs participate in the renal actions of acute VP inhibition by the administration of OMA together with an intrarenal administration of the NP receptor antagonist
HS-142-1 (n=5). OMA resulted in a greater natriuretic response than did ACE inhibition in association with increases in plasma cGMP,
ANP, BNP, urinary cGMP, urinary
ANP excretion, and glomerular filtration rate (P<0.05 for OMA versus ACE inhibition). Plasma
renin activity was increased only in the group subjected to ACE inhibition. Administration of intrarenal
HS-142-1 attenuated the renal properties of OMA in association with a decrease in urinary cGMP excretion despite similar increases in plasma
ANP and BNP. This study provides new insight into a unique new pharmacological agent that has beneficial renal actions in experimental mild
heart failure beyond the actions that are observed with ACE inhibition alone and that are linked to the NP system.