Effects of phosphodiesterase‐1 inhibitor on pulmonary vein electrophysiology and arrhythmogenesis

Introduction Phosphodiesterase (PDE) isoform inhibitors have mechanical and electrical effects on the heart. Inhibition of PDE‐1 enzymes is a novel strategy for treating heart failure. However, the electrophysiological effects of PDE‐1 inhibition on the heart remain unclear. This study explored the effects of PDE‐1 inhibition using ITI‐214 on electrical activity in the pulmonary vein (PV), the most common trigger of atrial fibrillation, and investigated the underlying ionic mechanisms. Methods Conventional microelectrodes or whole‐cell patch clamps were employed to study the effects of ITI‐214 (0.1‐10 μM) on PV electrical activity, mechanical responses and ionic currents in isolated rabbit PV tissue specimens and isolated single PV cardiomyocytes. Results ITI‐214 at 1 μM and 10 μM (but not 0.1 μM) significantly reduced PV spontaneous beating rate (10 ± 2% and 10 ± 3%, respectively) and PV diastolic tension (11 ± 3% and 17 ± 3%, respectively). ITI‐24 (1 μM) significantly reduced late sodium current (INa‐Late), L‐type calcium current (ICa‐L) and the reverse mode of the sodium‐calcium exchanger (NCX), but it did not affect peak sodium currents. Conclusions ITI‐214 reduces PV spontaneous activity and PV diastolic tension by reducing INa‐Late, ICa‐L and NCX current. Considering its therapeutic potential in heart failure, targeting PDE‐1 inhibition may provide a novel strategy for managing atrial arrhythmogenesis.