Vasorelaxant effects of novel Kv7.4 channel enhancers ML213 and NS15370

Background and PurposeThe KCNQ-encoded voltage-gated potassium channel family (K(v)7.1-K(v)7.5) are established regulators of smooth muscle contractility, where K(v)7.4 and K(v)7.5 predominate. Various K(v)7.2-7.5 channel enhancers have been developed that have been shown to cause a vasorelaxation in both rodent and human blood vessels. Recently, two novel K(v)7 channel enhancers have been identified, ML213 and NS15370, that show increased potency, particularly on K(v)7.4 channels. The aim of this study was to characterize the effects of these novel enhancers in different rat blood vessels and compare them with K(v)7 enhancers (S-1, BMS204352, retigabine) described previously. We also sought to determine the binding sites of the new K(v)7 enhancers. Key ResultsBoth ML213 and NS15370 relaxed segments of rat thoracic aorta, renal artery and mesenteric artery in a concentration-dependent manner. In the mesenteric artery ML213 and NS15370 displayed EC(50)s that were far lower than other K(v)7 enhancers tested. Current-clamp experiments revealed that both novel enhancers, at low concentrations, caused significant hyperpolarization in mesenteric artery smooth muscle cells. In addition, we determined that the stimulatory effect of these enhancers relied on a tryptophan residue located in the S5 domain, which is the same binding site for the other K(v)7 enhancers tested in this study. Conclusions and ImplicationsThis study has identified and characterized ML213 and NS15370 as potent vasorelaxants in different blood vessels, thereby highlighting these new compounds as potential therapeutics for various smooth muscle disorders.