Endogenous natriuretic peptides participate in renal and humoral actions of acute vasopeptidase inhibition in experimental mild heart failure

Mild heart failure is characterized by increases in atrial natriuretic pept ide (ANP) and brain natriuretic peptide (BNP) in the absence of activation of the renin-angiotensin-aldosterone system (RAAS). Vasopeptidase (VP) inhi bitors are novel molecules that coinhibit neutral endopeptidase 24.11, whic h degrades the natriuretic peptides (NPs) and ACE. In a well-characterized canine model of mild heart failure produced by ventricular pacing at 180 bp m for 10 days, we defined the renal and humoral actions of acute VP inhibit ion with omapatrilat (OMA, n=6) and acute ACE inhibition (n=5) alone with f osinoprilat. 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 inhibitio n in association with increases in plasma cGMP, ANP, BNP, urinary cGMP, uri nary ANP excretion, and glomerular filtration rate (P<0.05 for OMA versus A CE inhibition). Plasma renin activity was increased only in the group subje cted to ACE inhibition. Administration of intrarenal HS-142-1 attenuated th e renal properties of OMA in association with a decrease in urinary cGMP ex cretion despite similar increases in plasma ANP and BNP. This study provide s new insight into a unique new pharmacological agent that has beneficial r enal actions in experimental mild heart failure beyond the actions that are observed with ACE inhibition alone and that are linked to the NP system.