Augmentation of Natriuretic Peptide Bioactivity via Combined Inhibition of Neprilysin and Phosphodiesterase-9 in Heart Failure

Abstract

Background: The natriuretic peptides (NPs) are potent natriuretic/diuretic and vasodilatory factors, and augmentation of their levels or signaling via inhibition of the enzymes neprilysin (NEP) and phosphodiesterase 9 (PDE9), respectively, has beneficial actions in heart failure (HF).

Objectives: The authors investigated dual enhancement of NP bioactivity by combining PDE9 inhibition and NEP inhibition in HF using an ovine model.

Methods: Eight sheep with pacing-induced HF received on 4 separate days intravenous PDE9 inhibition (PF-04749982), NEP inhibition (SCH-32615), PDE9 inhibition + NEP inhibition (PI+NI), and vehicle control treatment.

Results: Compared with the control treatment, NEP inhibition significantly increased plasma NP concentrations with a corresponding rise in second messenger cyclic guanosine monophosphate (cGMP), whereas PDE9 inhibition increased circulating cGMP with a negligible effect on NP levels. Combined PI+NI elevated plasma NPs to an extent comparable to that seen with NEP inhibition alone but further increased cGMP, resulting in a rise in the cGMP-to-NP ratio. All active treatments reduced mean arterial pressure, left atrial pressure, pulmonary arterial pressure, and peripheral resistance, with combined PI+NI further reducing mean arterial pressure and left atrial pressure relative to either inhibitor separately. Active treatments increased urine volume and sodium, potassium and creatinine excretion, and creatinine clearance, in association with rises in urine cGMP levels. PI+NI induced a significantly greater natriuresis and increase in urinary cGMP relative to either inhibitor singly.

Conclusions: The present study demonstrates for the first time that combined PI+NI has additional beneficial hemodynamic and renal effects when compared with either PDE9 inhibition or NEP inhibition alone. The superior efficacy of this 2-pronged augmentation of NP bioactivity supports PI+NI as a potential therapeutic strategy for HF.

Keywords: cyclic guanosine monophosphate; heart failure; natriuretic peptides; neprilysin; phosphodiesterase 9.