Author + information
- Received March 6, 2019
- Revision received April 18, 2019
- Accepted May 23, 2019
- Published online August 12, 2019.
- Nicola J.A. Scott, PhDa,∗,
- Miriam T. Rademaker, PhDa,∗∗ (, )@OtagoCHCH,
- Christopher J. Charles, PhDa,b,
- Eric A. Espiner, MDa and
- A. Mark Richards, MD, PhDa,c
- aChristchurch Heart Institute, Department of Medicine, University of Otago-Christchurch, Christchurch, New Zealand
- bCardiovascular Research Institute, Department of Surgery, National University of Singapore, Singapore
- cCardiovascular Research Institute, National University Health Systems, Centre for Translational Medicine, Singapore
- ↵∗Address for correspondence:
Assoc. Prof. Miriam Rademaker, Department of Medicine, University of Otago-Christchurch, P.O. Box 4345, Christchurch, New Zealand.
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.
↵∗ Drs. Scott and Rademaker are joint first authors.
Financial support was provided by grants from the Heart Foundation of New Zealand (#1738) and the Canterbury Medical Research Foundation (2017PRONicolaScott). Dr. Rademaker has a compound transfer agreement with Pfizer for provision of the PF-04749982. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received March 6, 2019.
- Revision received April 18, 2019.
- Accepted May 23, 2019.
- 2019 American College of Cardiology Foundation
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