Key result
Milrinone (10 µM) significantly increased pulmonary vein spontaneous activity by 16.7%, whereas sildenafil reduced it by 25.9%, demonstrating diverse electrophysiological effects of PDE subtypes.
Why the study?
PDE inhibitors are widely used clinically, but their effects on cardiac electrical activity are not well understood.
Do different subtypes of PDE inhibitors (milrinone, rolipram, sildenafil) differentially regulate spontaneous electrical activity and arrhythmogenesis in isolated rabbit pulmonary veins and sinoatrial nodes?
Do different subtypes of PDE inhibitors (milrinone, rolipram, sildenafil) differentially regulate spontaneous electrical activity and arrhythmogenesis in isolated rabbit pulmonary veins and sinoatrial nodes?
Answers are grounded in this paper and cite their sources.
Different PDE inhibitors exert diverse electrophysiological effects on pulmonary vein and sinoatrial node activities, with PDE3 inhibition increasing and PDE5 inhibition reducing arrhythmogenesis, suggesting potential mechanisms for atrial fibrillation susceptibility.
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.
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Lin et al. (2020) studied Atrial fibrillation (experimental model) (n=47). Phosphodiesterase inhibitors (milrinone, rolipram, sildenafil) vs. Baseline (before drug administration) was evaluated on Change in pulmonary vein spontaneous activity (milrinone 10 µM) (p=<0.001). Milrinone (10 µM) significantly increased pulmonary vein spontaneous activity by 16.7%, whereas sildenafil reduced it by 25.9%, demonstrating diverse electrophysiological effects of PDE subtypes.
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