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Phosphodiesterase (PDE)3-5 are expressed in cardiac tissue and play critical roles in the pathogenesis of heart failure and atrial fibrillation. PDE inhibitors are widely used in the clinic, but their effects on the electrical activity of the heart are not well understood. The aim of the present study was to examine the effects of various PDE inhibitors on spontaneous cardiac activity and compare those effects between sinoatrial nodes (SANs) and pulmonary veins (PVs). Conventional microelectrodes were used to record action potentials in isolated rabbit SAN and PV tissue preparations, before and after administration of different concentrations (0.1, 1 and 10 µM) of milrinone (PDE3 inhibitor), rolipram (PDE4 inhibitor) and sildenafil (PDE5 inhibitor), with or without the application of isoproterenol (cAMP and PKA activator), KT5823 (PKG inhibitor) or H89 (PKA inhibitor). Milrinone (1 and 10 µM) increased the spontaneous activity in PVs by 10.6±4.9 and 16.7±5.3% and in SANs by 9.3±4.3 and 20.7±4.6%, respectively. In addition, milrinone (1 and 10 µM) induced the occurrence of triggered activity (0/8 vs. 5/8; P<0.005) in PVs. Rolipram increased PV spontaneous activity by 7.5±1.3-9.5±4.0%, although this was not significant, and did not alter SAN spontaneous activity. Sildenafil reduced spontaneous activity in PVs to a greater extent than that seen in SANs. Both KT5823 and H89 suppressed milrinone-increased PV spontaneous activity. In the presence of isoproterenol, milrinone did not alter isoproterenol-induced PV arrhythmogenesis, suggesting that the effects of PDE3 are mediated by the protein kinase G and protein kinase A signaling pathways. In conclusion, inhibitors of different PDE subtypes exert diverse electrophysiological effects on PV and SAN activities., (Copyright © 2020, Spandidos Publications.)

Atrial fibrillation (AF) is associated with mitochondrial dysfunction. Sinoatrial node (SAN) dysfunction increases arrhythmogenesis of pulmonary veins (PVs), which is the most important trigger of AF; however, it is not clear whether mitochondrial dysfunction differentially regulates electrical activity of SANs and PVs. In the present study, conventional microelectrodes were used to record the action potentials (APs) in isolated rabbit PVs, SANs, left atrium (LA) and right atrium (RA) before and after application of trifluorocarbonylcyanide phenylhydrazone (FCCP; a mitochondrial uncoupling agent) at 10, 100 and 300 nM. FCCP application at 100 and 300 nM decreased spontaneous rates in PVs and in SANs at 10, 100 and 300 nM. FCCP shortened the 20, 50 and 90% AP durations in the LA, and shortened only the 20% AP duration in the RA. FCCP caused a greater rate reduction in SANs than in PVs; however, in the presence of coenzyme-Q 10 (10 µM), FCCP reduced the beating rate in PVs and SANs to a similar extent. In SAN-PV preparations with intact electrical connections, FCCP (100 nM) application shifted the SAN-PV electrical conduction into PV-SAN conduction in 5 (62.5%) of 8 preparations. In conclusion, mitochondrial dysfunction modulates PV and SAN electrical activities, which may contribute to atrial arrhythmogenesis.