Effects of phosphodiesterase-1 inhibitor on pulmonary vein electrophysiology and arrhythmogenesis.

Abstract

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.

• Authors: Dony Yugo, Yao-Chang Chen, Yung-Kuo Lin, Chih Min Liu, Jen Hung Huang, Shih-Ann Chen, Yi-Jen Chen
• Journal: European journal of clinical investigation (Eur J Clin Invest) Vol. 51 Issue 9 Pg. e13585 (Sep 2021) ISSN: 1365-2362 [Electronic] England
• PMID: 34002387 (Publication Type: Journal Article)
• Copyright: © 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

Chemical References

• Heterocyclic Compounds, 4 or More Rings
• ITI-214
• Phosphodiesterase Inhibitors
• Cyclic Nucleotide Phosphodiesterases, Type 1
• Calcium

Topics

• Action Potentials (drug effects)
• Animals
• Calcium (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 1 (antagonists & inhibitors)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Myocytes, Cardiac (drug effects)
• Patch-Clamp Techniques
• Phosphodiesterase Inhibitors (pharmacology)
• Pulmonary Veins (cytology, drug effects)
• Rabbits