title: Improvement of endothelium-dependent vasodilations by SKA-31 and SKA-20, activators of small- and intermediate-conductance Ca2+ -activated K+ -channels.
abstract: OBJECTIVE
  Endothelial membrane hyperpolarization mediated by KCa3.1 and KCa2.3 channels has been demonstrated to initiate endothelium-derived hyperpolarizing factor (EDHF)-type vasodilations. Moreover, pharmacological potentiation of KCa3.1/KCa2.3 channels has been suggested to improve EDHF-type vasodilations. Herein, we determined whether the KCa3.1/KCa2.3 activator SKA-31 and its derivative SKA-20 improve endothelial dysfunction in KCa3.1-/- and NOS3-/- mice.
  
  
  METHODS
  Membrane potentials were measured using patch-clamp electrophysiology on carotid artery (CA) endothelial cells (CAEC) from wild-type (wt) and KCa3.1-/- mice. Endothelium-dependent vasodilations were determined by pressure myography in CA.
  
  
  RESULTS
  SKA-31 (1 μm) activated KCa3.1 and KCa2.3 channels and induced membrane hyperpolarization in CAEC of wt (ΔMP -45 mV). These responses were significantly reduced in CAEC of KCa3.1-/- (ΔMP -8 mV). SKA-31 (200 nm, 500 nm) and SKA-20 (300 nm) significantly enhanced EDHF vasodilations in wt. SKA-20 also improved vasodilations during NO synthesis. In KCa3.1-/-, the defective EDHF vasodilations were unchanged at 200 nm SKA-31, but were significantly improved at 500 nm. EDHF vasodilations were slightly enhanced at 300 nm SKA-20, but vasodilations during NO synthesis were unchanged. SKA-31 (500 nm) enhanced the impaired endothelium-dependent vasodilation in NOS3-/- mice twofold. Pharmacological inhibition of the soluble epoxide hydrolase by t-AUCB (1 μm) in contrast did not increase ACh-induced EDHF- or NO-mediated vasodilations in wt and KCa3.1-/-.
  
  
  CONCLUSIONS
  Normal and defective endothelium-dependent vasodilations in murine carotid arteries can be improved by pharmacological enhancement of KCa3.1/KCa2.3 functions. These findings further support the concept that pharmacological activation of endothelial KCa2.3/KCa3.1 could offer a novel endothelium-specific antihypertensive strategy.
authors.affiliation: Faculty of Medicine, Philipps University, Marburg, Germany.
authors.forename: A-L
authors.initials: AL
authors.lastname: Hasenau
authors.forename: G
authors.initials: G
authors.lastname: Nielsen
authors.forename: C
authors.initials: C
authors.lastname: Morisseau
authors.forename: B D
authors.initials: BD
authors.lastname: Hammock
authors.forename: H
authors.initials: H
authors.lastname: Wulff
authors.forename: R
authors.initials: R
authors.lastname: Köhler
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
chemical_list: D052160:Benzothiazoles; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; C535212:naphtho(1,2-d)thiazol-2-ylamine