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

The resolution of inflammation is modulated by specialized pro-resolving lipid mediators (SPMs), which can be modified in some cardiovascular diseases. Among these SPMs, RvD1 and LXA4 prevent atrial fibrillation (AF) remodeling and cardiac hypertrophy, respectively in animal models. However, little is known about their electrophysiological effects on cardiac voltage-gated (VG) ion channels. We used the patch-clamp technique in heterologous systems and cardiomyocytes to assess the acute effects of RvD1, and LXA4, 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 (5 nM) reduced IKs (channel KV7.1/KCNE1) in COS-7 cells and guinea-pig cardiomyocytes by 50.3 ± 7.3 % and 29.9 ± 5.4 % at + 40 mV, respectively, without modifying its voltage dependence. RvD1 was more potent than LXA4. In heterologous systems, RvD1 was also tested on IKur (channel KV1.5), Ito (channel KV4.3/KChIP2), IKr (channel KV11.1), and IK1 (channel Kir2.1) with the largest inhibitory effect on IKs and IKr. In in silico simulations RvD1 prolonged repolarization significantly in both atrial and ventricular myocytes. All these results provide a comprehensive evaluation of RvD1 and LXA4 on cardiac human potassium channels, at pathophysiologically relevant concentrations, being RvD1 more potent than LXA4. The predicted effects on the AP suggest that, along with their antiinflammatory action, RvD1 may reverse AF-induced electrical remodeling in the atria by their modulation of K+ currents. The same action might instead contribute to ventricular functional remodeling; however, direct evidence for this is missing.