Combined Inhibition of Phosphodiesterase-5 and-9 in Experimental Heart Failure

BACKGROUND Intracellular second messenger cyclic guanosine monophosphate (cGMP) mediates bioactivity of the natriuretic peptides and nitric oxide, and is key to circulatory homeostasis and protection against cardiovascular disease. Inhibition of cGMP-degrading phosphodiesterases (PDEs) PDE5 and PDE9 are emerging as pharmacological targets in heart failure (HF). OBJECTIVES The present study investigated dual enhancement of cGMP in experimental HF by combining inhibition of PDE-5 (P5 -I) and PDE-9 (P9 -I). METHODS Eight sheep with pacing-induced HF received on separate days intravenous P5 -I (sildenafil), P9 -I (PF-04749982), P5-I thorn P9-I, and vehicle control, in counterbalanced order. RESULTS Compared with control, separate P5 -I and P9 -I significantly increased circulating cGMP concentrations in association with reductions in mean arterial pressure (MAP), left atrial pressure (LAP), and pulmonary arterial pressure (PAP), with effects of P5 -I on cGMP, MAP, and PAP greater than those of P9 -I. Only P5 -I decreased pulmonary vascular resistance. Combination P5-I thorn P9-I further reduced MAP, LAP, and PAP relative to inhibition of either phosphodiesterase alone. P9 -I and, especially, P5 -I elevated urinary cGMP levels relative to control. However, whereas inhibition of either enzyme increased urine creatinine excretion and clearance, only P9 -I induced a significant diuresis and natriuresis. Combined P5-I thorn P9-I further elevated urine cGMP with concomitant increases in urine volume, sodium and creatinine excretion, and clearance similar to P9 -I alone, despite the greater MAP reductions induced by combination treatment. CONCLUSIONS Combined P5-I thorn P9-I amalgamated the superior renal effects of P9 -I and pulmonary effects of P5-1, while concurrently further reducing cardiac preload and afterload. These findings support combination P5-I thorn P9-I as a therapeutic strategy in HF. (c) 2024 by the American College of Cardiology Foundation.