Cyclic nucleotide phosphodiesterase 3, 4, and 5 (PDE3/4/5)

Phosphodiesterases 3, 4, and 5 (PDE3, PDE4, PDE5) are distinct families of enzymes that catalyze the hydrolysis of cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP), thereby regulating intracellular signaling (Francis et al., 2011 [PMID: 21505021]). PDE3 is found in the heart, vascular smooth muscle, and platelets, where it modulates contractility and aggregation; PDE4 is the predominant PDE in inflammatory cells and airway smooth muscle; and PDE5 is primarily expressed in the corpus cavernosum and pulmonary vasculature (Bender & Beavo, 2006 [PMID: 16740784]). Inhibition of these enzymes leads to the accumulation of cyclic nucleotides, resulting in diverse therapeutic effects such as vasodilation, bronchodilation, and suppression of inflammatory mediators (Soderling & Beavo, 2000 [PMID: 10769175]). Drugs targeting these enzymes include milrinone (PDE3) for heart failure, roflumilast (PDE4) for COPD, and sildenafil (PDE5) for erectile dysfunction and pulmonary hypertension (StatPearls, 2023). Dual inhibitors like ensifentrine (PDE3/4) have also been developed to combine bronchodilatory and anti-inflammatory properties for respiratory diseases (O'Donnell, 2024 [PMID: 38934844]). However, the clinical utility of these inhibitors can be constrained by side effects such as nausea, headaches, and cardiovascular risks (Torphy, 1998 [PMID: 9597155]).

Other names

PDE3PDE4PDE5Phosphodiesterase 3Phosphodiesterase 4Phosphodiesterase 5cAMP-specific 3',5'-cyclic phosphodiesterasecGMP-specific 3',5'-cyclic phosphodiesterase

Inhibition of the catalytic activity of phosphodiesterase enzymes (PDE3, PDE4, and/or PDE5), which prevents the hydrolysis of the second messengers cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). This leads to increased intracellular concentrations of these nucleotides, resulting in downstream effects such as smooth muscle relaxation, suppression of inflammatory cytokine release, and increased myocardial contractility (Francis et al., 2011 [PMID: 21505021]; StatPearls, 2023).