Key result
PDE9 inhibition lowers pressures and boosts diuresis in experimental heart failure by increasing plasma cGMP.
Why the study?
PDE9 reduces natriuretic peptide signaling and may contribute to HF pathophysiology, but the integrated hemodynamic, endocrine, and renal effects of PDE9 inhibition had not been investigated.
Does phosphodiesterase-9 inhibition improve hemodynamic, hormonal, and renal parameters in an experimental sheep model of heart failure?
Does phosphodiesterase-9 inhibition improve hemodynamic, hormonal, and renal parameters in an experimental sheep model of heart failure?
Phosphodiesterase-9 inhibition demonstrates beneficial hemodynamic and renal effects in an experimental model of heart failure, suggesting a potential novel therapeutic target.
PDE9 inhibition improves hemodynamics in experimental HF models; leaves open translation to clinical outcomes and patient safety.
BACKGROUND: Phosphodiesterase-9 (PDE9) reduces natriuretic peptide (NP) signaling and may be involved in the pathophysiology of heart failure (HF). OBJECTIVES: This study investigated for the first time the integrated hemodynamic, endocrine, and renal effects of phosphodiesterase-9 inhibition (PDE9-I). METHODS: A total of 8 normal sheep and 8 sheep with pacing-induced HF received incremental intravenous boluses of PDE9-I (30, 100, and 300 mg PF-04749982 at 1-h intervals). RESULTS: PDE9-I dose-dependently increased plasma cyclic guanosine monophosphate (cGMP) in normal sheep (p < 0.05) while concurrently reducing circulating atrial natriuretic peptide levels (p < 0.01). Similar trends were evident in HF, resulting in significant elevations in the cGMP/NP ratio in both states (p < 0.001 and p < 0.05, respectively). PDE9-I also produced progressive falls in arterial pressure (HF: p < 0.001), atrial pressure (Normal: p < 0.001; HF: p < 0.001), and peripheral resistance (HF: p < 0.001), and transiently increased cardiac output at the top dose (Normal: p < 0.05; HF: p < 0.001). Inhibition of PDE9 had a negligible effect on circulating hormones at the lower doses, but post-high dose, acutely increased renin activity (Normal: p < 0.001; HF: p < 0.05), vasopressin (Normal: p < 0.001; HF: p < 0.01), and cyclic adenosine monophosphate (HF: p < 0.001). Plasma aldosterone increased briefly after high-dose PDE9-I in normal sheep, and fell following the top dose in HF. PDE9-I dose-dependently increased urinary cGMP in both states (both p < 0.001). In HF, this was associated with increases in urine volume (p < 0.01), sodium excretion (p < 0.01), and creatinine clearance (p < 0.001). CONCLUSIONS: PDE9-I improves NP efficacy in conjunction with beneficial hemodynamic and renal effects in experimental HF. These results support a role for PDE9 in HF pathophysiology and suggest its inhibition may constitute a novel therapeutic approach to this disease.
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Scott et al. (2019) studied Heart failure (n=16). Phosphodiesterase-9 inhibition (PF-04749982) was evaluated on Hemodynamic, endocrine, and renal effects (including plasma cGMP, arterial pressure, and urine volume). In experimental heart failure, PDE9 inhibition dose-dependently increased plasma cGMP, reduced arterial and atrial pressures, and increased urine volume and sodium excretion.
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