title: Prominent role of KCa3.1 in endothelium-derived hyperpolarizing factor-type dilations and conducted responses in the microcirculation in vivo.
abstract: OBJECTIVE
  The activation of endothelial Ca2+-dependent K+-channels, KCa3.1 (IKCa), and KCa2.3 (SKCa) has been proposed to be a prerequisite for endothelial hyperpolarization, which subsequently hyperpolarizes and relaxes smooth muscle [endothelium-derived hyperpolarizing factor (EDHF)-type dilation] and initiates conducted dilations. Although EDHF is the main mediator of acetylcholine (ACh)-induced dilation in the murine skeletal microcirculation, the differential contribution of KCa3.1 and KCa2.3 is not known.
  
  
  RESULTS
  We assessed agonist-induced and conducted dilations as well as endothelial hyperpolarization in the cremaster microcirculation of KCa3.1-deficient (KCa3.1-/-) and wild-type mice (wt) in vivo after blockade of NO and prostaglandins. Compared with wt, resting tone was enhanced by approximately 25% in arterioles of KCa3.1-/- mice. ACh-induced dilations in KCa3.1-/- mice were virtually abolished at low and intermediate concentrations and a remaining dilation at 10 micromol/L ACh was abrogated by blockade of KCa2.3 with UCL1684. Sodium nitroprusside- and adenosine-induced dilations were similar in wt and KCa3.1-/-. Focal application of ACh induced dilations at the local site in both genotypes, which conducted along the vessel. However, the amplitude of the dilation decreased with distance only in KCa3.1-/-. Blockade of KCa2.3 in wt did not affect conducted dilations. A KCa3.1 opener induced a conducting dilation in wt but not in KCa3.1-/-. Membrane potential recordings in vivo demonstrated endothelial hyperpolarization in response to ACh in both genotypes; however, the hyperpolarization was severely impaired in KCa3.1-/- (Delta membrane potential: -3 +/- 1 vs. -14 +/- 2 mV).
  
  
  CONCLUSIONS
  We conclude that KCa3.1 is of major importance for endothelial hyperpolarization and EDHF-type responses in skeletal muscle arterioles, and its deficiency is not compensated by KCa2.3. Sole activation of KCa3.1 is capable of initiating conducted responses, and KCa3.1 may contribute to the propagation of the signal, although its presence is not mandatory.
authors.affiliation: Department of Physiology, Universität zu Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Wölfle
authors.forename: Volker J
authors.initials: VJ
authors.lastname: Schmidt
authors.forename: Joachim
authors.initials: J
authors.lastname: Hoyer
authors.forename: Ralf
authors.initials: R
authors.lastname: Köhler
authors.forename: Cor
authors.initials: C
authors.lastname: de Wit
mesh_terms: D000109:Acetylcholine; D000818:Animals; D001160:Arterioles / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008833:Microcirculation; D018482:Muscle, Skeletal / Q000098:blood supply; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D014664:Vasodilation
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496900:Kcnn3 protein, mouse; C496925:Kcnn4 protein, mouse; D051640:Small-Conductance Calcium-Activated Potassium Channels; D000109:Acetylcholine