title: Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension.
abstract: BACKGROUND
  It has been proposed that activation of endothelial SK3 (K(Ca)2.3) and IK1 (K(Ca)3.1) K+ channels plays a role in the arteriolar dilation attributed to an endothelium-derived hyperpolarizing factor (EDHF). However, our understanding of the precise function of SK3 and IK1 in the EDHF dilator response and in blood pressure control remains incomplete. To clarify the roles of SK3 and IK1 channels in the EDHF dilator response and their contribution to blood pressure control in vivo, we generated mice deficient for both channels.
  
  
  RESULTS
  Expression and function of endothelial SK3 and IK1 in IK1(-/-)/SK3(T/T) mice was characterized by patch-clamp, membrane potential measurements, pressure myography, and intravital microscopy. Blood pressure was measured in conscious mice by telemetry. Combined IK1/SK3 deficiency in IK1(-/-)/SK3(T/T) (+doxycycline) mice abolished endothelial K(Ca) currents and impaired acetylcholine-induced smooth muscle hyperpolarization and EDHF-mediated dilation in conduit arteries and in resistance arterioles in vivo. IK1 deficiency had a severe impact on acetylcholine-induced EDHF-mediated vasodilation, whereas SK3 deficiency impaired NO-mediated dilation to acetylcholine and to shear stress stimulation. As a consequence, SK3/IK1-deficient mice exhibited an elevated arterial blood pressure, which was most prominent during physical activity. Overexpression of SK3 in IK1(-/-)/SK3(T/T) mice partially restored EDHF- and nitric oxide-mediated vasodilation and lowered elevated blood pressure. The IK1-opener SKA-31 enhanced EDHF-mediated vasodilation and lowered blood pressure in SK3-deficient IK1(+/+)/SK3(T/T) (+doxycycline) mice to normotensive levels.
  
  
  CONCLUSIONS
  Our study demonstrates that endothelial SK3 and IK1 channels have distinct stimulus-dependent functions, are major players in the EDHF pathway, and significantly contribute to arterial blood pressure regulation. Endothelial K(Ca) channels may represent novel therapeutic targets for the treatment of hypertension.
authors.affiliation: Department of Internal Medicine/Nephrology, Philipps University, Marburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brähler
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kaistha
authors.forename: Volker J
authors.initials: VJ
authors.lastname: Schmidt
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Wölfle
authors.forename: Christoph
authors.initials: C
authors.lastname: Busch
authors.forename: Brajesh P
authors.initials: BP
authors.lastname: Kaistha
authors.forename: Michael
authors.initials: M
authors.lastname: Kacik
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Hasenau
authors.forename: Ivica
authors.initials: I
authors.lastname: Grgic
authors.forename: Han
authors.initials: H
authors.lastname: Si
authors.forename: Chris T
authors.initials: CT
authors.lastname: Bond
authors.forename: John P
authors.initials: JP
authors.lastname: Adelman
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Cor
authors.initials: C
authors.lastname: de Wit
authors.forename: Joachim
authors.initials: J
authors.lastname: Hoyer
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000378:metabolism / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D006973:Hypertension / Q000209:etiology*; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D051670:Shaw Potassium Channels / Q000172:deficiency; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000172:deficiency; D014664:Vasodilation
chemical_list: D001685:Biological Factors; C496900:Kcnn3 protein, mouse; D051670:Shaw Potassium Channels; D051640:Small-Conductance Calcium-Activated Potassium Channels; C067410:endothelium-dependent hyperpolarization factor; D002118:Calcium