RvD1 and LXA4 inhibitory effects on cardiac voltage-gated potassium channels

Aims The resolution of inflammation is modulated by specialized pro-resolving lipid mediators (SPMs), which can be modified in some cardiovascular diseases. Among them, RvD1 and LXA 4 prevent atrial fibrillation (AF) remodeling in the atria and cardiac hypertrophy, respectively in animal models. However, little is known about their electrophysiological effects on cardiac voltage-gated (VG) ion channels. Methods and results We used the patch-clamp technique in heterologous systems and cardiomyocytes to assess the acute effect of RvD1, and LXA 4 , on VG potassium currents. In silico simulations were used to predict the effect of current modulation on the atrial and ventricular action potentials (AP). RvD1 and LXA 4 reduced I Ks (channel K V 7.1/KCNE1) in COS-7 cells and guinea-pig cardiomyocytes without modifying its voltage dependence; RvD1 was more potent than LXA 4 . In heterologous systems, RvD1 was also tested on I Kur (channel K V 1.5), I to (channel K V 4.3/KChIP2), I Kr (channel K V 11.1), and I K1 (channel K ir 2.1) with the largest inhibitory effect on I Ks and I Kr . In simulations RvD1 prolonged repolarization significantly in both atrial and ventricular myocytes. Conclusion The results provide a comprehensive evaluation of RvD1 and LXA 4 on cardiac human potassium channels, at pathophysiological relevant concentrations, being RvD1 more potent than LXA 4 . The predicted effects on the action potential suggest that, along with their antiinflammatory action, RvD1 may reverse AF-induced electrical remodeling in the atria by direct modulation of K + currents. The same action might instead contribute to ventricular functional remodeling; however, direct evidence for this is missing.