title: Vasorelaxant effects of novel Kv 7.4 channel enhancers ML213 and NS15370.
abstract: OBJECTIVE
  The KCNQ-encoded voltage-gated potassium channel family (Kv 7.1-Kv 7.5) are established regulators of smooth muscle contractility, where Kv 7.4 and Kv 7.5 predominate. Various Kv 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 Kv 7 channel enhancers have been identified, ML213 and NS15370, that show increased potency, particularly on Kv 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 Kv 7 enhancers (S-1, BMS204352, retigabine) described previously. We also sought to determine the binding sites of the new Kv 7 enhancers.
  
  
  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 that were far lower than other Kv 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 Kv 7 enhancers tested in this study.
  
  
  CONCLUSIONS
  This 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.
authors.affiliation: Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: T A
authors.initials: TA
authors.lastname: Jepps
authors.forename: B H
authors.initials: BH
authors.lastname: Bentzen
authors.forename: J B
authors.initials: JB
authors.lastname: Stott
authors.forename: O V
authors.initials: OV
authors.lastname: Povstyan
authors.forename: K
authors.initials: K
authors.lastname: Sivaloganathan
authors.forename: W
authors.initials: W
authors.lastname: Dalby-Brown
authors.forename: I A
authors.initials: IA
authors.lastname: Greenwood
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D044482:Benzeneacetamides / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000502:physiology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D032342:Muscle Cells / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D017208:Rats, Wistar; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C584425:2-(3,5-difluorophenyl)-N-(6-((4-fluorophenyl)methylamino)-2-morpholino-3-pyridyl)acetamide; D000631:Aminopyridines; D000813:Anilides; D044482:Benzeneacetamides; D001643:Bridged Bicyclo Compounds; D051656:KCNQ Potassium Channels; C000591918:N-mesitybicyclo(2.2.1)heptane-2-carboxamide; D020033:Protein Isoforms; D014665:Vasodilator Agents