Phosphodiesterase 9 Inhibition Combined With Valsartan and With Sacubitril/Valsartan in Experimental Ovine Heart Failure

Abstract

Background LCZ696 (sacubitril/valsartan) antagonizes the renin–angiotensin system while simultaneously augmenting the natriuretic peptides (NPs). Inhibition of phosphodiesterase 9 inhibition (PDE9i), which hydrolyses NP‐generated cGMP may be a more specific means of enhancing NP bioactivity. The objective of the present study was to compare for the first time effects of LCZ696 and PDE9i+valsartan in experimental heart failure (HF) and investigate combination PDE9i+LCZ696. Methods and Results Seven sheep received, on separate days, intravenous boli of (1) LCZ696, (2) PDE9i+valsartan, (3) PDE9i+LCZ696, and (4) vehicle control, during mild HF and severe HF. Compared with control, LCZ696 and PDE9i+LCZ696 induced similar increases in plasma NPs (greater increments in severe HF), whereas PDE9i+valsartan reduced NP levels. Circulating cGMP was elevated following LCZ696 and PDE9i+valsartan, and further increased with combination PDE9i+LCZ696. All active treatments increased plasma renin and angiotensin II (greater increments in severe HF). Plasma aldosterone was unchanged. Plasma endothelin‐1 was elevated by LCZ696 and PDE9i+LCZ696, but not PDE9i+valsartan. Active treatments reduced arterial and left atrial pressure and peripheral resistance and increased cardiac output (more pronounced in severe‐HF). PDE9i+LCZ696 induced greater hemodynamic changes relative to LCZ696 and PDE9i+valsartan. Treatments had minimal renal effect in mild HF. In severe HF, treatments elevated urine cGMP in association with significant increases in creatinine clearance and diuresis and natriuresis, effects especially prominent with PDE9i+LCZ696. Conclusions LCZ696 and PDE9i+valsartan have similar beneficial hemodynamic and renal effects in HF, with combined PDE9i+LCZ696 producing additional improvements. Overall, effects were significantly greater in severe HF. Findings suggest PDE9i might serve as a replacement for neprilysin inhibition or as an adjunct therapy to LCZ696.

Keywords

• cyclic guanosine monophosphate
• heart failure
• natriuretic peptides
• neprilysin
• phosphodiesterase 9