Melatonin and melatonin-derived H2S-containing compounds act as new Kv7.4 activators

Recent evidence suggests an anti-hypertensive effect for the pineal neurohormone melatonin (MT) as it promotes vasorelaxation through concentration-, receptor-, and vessel-dependent mechanisms. Interestingly, Kv7.4 activation results to be a downstream effect of several vasorelaxants that activate the cAMP signalling cascade. Furthermore, positive modulation of Kv7.4 also appears to be the mechanism by which hydrogen sulphide (H2S) mediates vasorelaxation. In fact, the H2S-donor sodium hydrogen sulphide (NaHS) promoted endothelial-independent relaxations of rat aortic rings by facilitating Kv7.4 current activation. Such relaxation was markedly reduced upon co-exposure to Kv7 blocker XE991. In this study, by means of whole-cell patch-clamp technique we aim to investigate the possible direct activation of Kv7.4 currents by MT and the ability of newly-synthesized MT-derived, H2S-containing (MDHS) molecules (herein referred as compound 1, 2, and 3) to activate Kv7.4 currents. The recordings revealed that 10 µM of MT and MDHS compounds increased Kv7.4 currents and shifted leftward the voltage-dependence of Kv7.4 activation. While MT and all MDHS molecules caused a similar leftward shift, the compounds 2 and 3 triggered a larger enhancement of Kv7.4 currents (~70% and ~ 90% current increases, respectively) respect to the compound 1 (~ 40%), melatonin (~ 50%), and NaHS (~ 30%). Moreover, the potentiation of Kv7.4 currents induced by compound 2 and 3 was similar to that triggered by the Kv7 activator retigabine (10 µM), used as a reference compound. In conclusion, melatonin is a new Kv7.4 activator and the compound 2 and 3 show larger functional effects when compared to melatonin.