Phosphodiesterase 3 (PDE3) (PDE3)

Phosphodiesterase 3 (PDE3) is a family of enzymes, primarily comprising the isoforms PDE3A and PDE3B, that regulate intracellular signaling by catalyzing the hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) [5, 10]. PDE3 is expressed in various tissues, including airway smooth muscle, cardiac myocytes, vascular smooth muscle, and platelets, where it modulates critical physiological processes such as muscle contraction and platelet aggregation [5, 9, 17]. In the lungs, PDE3 inhibition increases cAMP levels, leading to the relaxation of airway smooth muscle and subsequent bronchodilation [1, 2, 3]. In the heart, PDE3 regulates contractility and is a target for inotropic agents used in acute heart failure [5, 7, 15]. Ensifentrine is a first-in-class, inhaled dual inhibitor of PDE3 and PDE4 that was recently approved for the maintenance treatment of chronic obstructive pulmonary disease (COPD) [8, 11, 12]. By inhibiting PDE3, ensifentrine provides potent bronchodilatory effects, while its inhibition of PDE4 contributes anti-inflammatory activity and improves mucociliary clearance [1, 2, 6]. This dual mechanism distinguishes it from traditional COPD therapies that typically target only one pathway [13, 14]. While systemic PDE3 inhibitors are often limited by cardiovascular side effects like arrhythmias and hypotension, the inhaled delivery of ensifentrine minimizes systemic exposure and focuses its therapeutic effects on the respiratory tract [4, 11, 17].

Other names

cGMP-inhibited phosphodiesteraseCyclic nucleotide phosphodiesterase 3PDE3APDE3B

Inhibition of PDE3 prevents the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), leading to increased intracellular levels of these second messengers. In the lungs, this promotes airway smooth muscle relaxation (bronchodilation). In the heart, it increases contractility (positive inotropy). In platelets, it inhibits aggregation.