Abstract 3018: A Dual Inhibitor of Neprilysin and Ligand of the Natriuretic Peptide Receptor C Augments the Endogenous Natriuretic Peptide System and Has Favorable Cardiorenal Actions in Experimental Heart Failure
Background: Heart failure (HF) is a common disease syndrome associated with vasoconstriction, increased cardiac filling pressures, salt and water retention, and neurohumoral activation. Secretion of the natriuretic peptides (NP) ANP and BNP by the heart in conditions of cardiac overload can be considered an endogenous compensatory mechanism. However, NP actions are frequently blunted in HF, which may in part be due to enzymatic degradation and clearance of ANP and BNP. The peptidase neprilysin (NEP 24.11) has been implicated in the metabolism of both ANP and BNP, while the NP C receptor (NPR-C) functions as a clearance receptor. The compound (S)-Thiorphan-Gly-Arg-Ile-Asp-Arg-Ile-NH2 is simultaneously a neprilysin inhibitor (IC50: 10 nM) and a NPR-C ligand (IC50: 500 nM) and can therefore be considered a dual NP clearance inhibitor (NP-C-I). We hypothesized that this NP-C-I would augment the NPs in experimental HF and improve cardiorenal function.
Methods: HF was induced by tachypacing in 6 canines. On day 11 of pacing, cardiorenal function was assessed in an acute study under anesthesia in 30-minute clearances at baseline, with two subsequent intravenous doses of NP-C-I (30 and 100 μg/kg/min), and post-infusion. Values provided are mean±SEM for baseline vs. 100 μg/kg/min.
Results: The dual NP-C-I significantly increased plasma ANP (203±50 vs. 691±131 pg/mL), BNP (57±9 vs. 157±35 pg/mL), and their second messenger cGMP (23±4 vs. 75±11 pmol/mL), and the same was true for their urinary excretion. This was associated with a reduction in mean arterial pressure (124±6 vs. 109±5 mmHg) and right atrial pressure (10±1 vs. 8±1 mmHg). Renal blood flow increased (132±31 vs. 170±30 mL/min) while renal vascular resistance decreased. Urine flow and urinary sodium excretion increased (3±1 vs. 31±6 μEq/min), as did glomerular filtration rate (26±4 vs. 49±7 mL/min). Despite the hypotensive actions, plasma renin activity and angiotensin II levels decreased, whereas aldosterone remained unchanged.
Conclusion: The dual neprilysin inhibitor and NPR-C ligand (S)-Thiorphan-Gly-Arg-Ile-Asp-Arg-Ile-NH2 augments the endogenous NP system, unloads the heart, enhances renal function, and suppresses some neurohormones. These promising findings warrant further studies.