Jepps, Thomas Andrew3; Bentzen, B H3; Stott, J B2; Povstyan, O V2; Sivaloganathan, K2; Dalby-Brown, W2; Greenwood, I A3
1 Section of Heart and Circulatory Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet2 unknown3 Section of Heart and Circulatory Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, Københavns Universitet
BACKGROUND AND PURPOSE: The KCNQ encoded voltage-gated potassium channel family (Kv7.1-Kv7.5) are established regulators of smooth muscle contractility, where Kv7.4 and Kv7.5 predominate. Various Kv7.2-Kv7.5 channel enhancers have been developed that have been shown to cause a vasorelaxation in both rodent and human blood vessels. Recently, two novel Kv7 channel enhancers have been identified, ML213 and NS15370, that show increased potency, particularly on Kv7.4 channels. The aim of this study was to characterise the effects of these novel enhancers in different rat blood vessels and compare them to Kv7 enhancers (S-1, BMS-204352, retigabine) described previously. We also sought to determine the binding sites of the new Kv7 enhancers. KEY RESULTS: Both 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 EC50 's of 0.74 μM and 0.026 μM, respectively, which were far lower than other Kv7 enhancers tested. Current-clamp experiments revealed both novel enhancers at low concentrations caused significant hyperpolarisation 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, the same binding site for the other Kv7 enhancers tested in this study. CONCLUSIONS AND IMPLICATIONS: In conclusion, this study identifies and characterises ML213 and NS15370 as potent vasorelaxants in different blood vessels, thereby highlighting these new compounds as potential therapeutics for various smooth muscle disorders.
British Journal of Pharmacology, 2014, Vol 171, Issue 19, p. 4413-4424