title: Impaired endothelium-derived hyperpolarizing factor-mediated dilations and increased blood pressure in mice deficient of the intermediate-conductance Ca2+-activated K+ channel.
abstract: The endothelium plays a key role in the control of vascular tone and alteration in endothelial cell function contributes to several cardiovascular disease states. Endothelium-dependent dilation is mediated by NO, prostacyclin, and an endothelium-derived hyperpolarizing factor (EDHF). EDHF signaling is thought to be initiated by activation of endothelial Ca(2+)-activated K(+) channels (K(Ca)), leading to hyperpolarization of the endothelium and subsequently to hyperpolarization and relaxation of vascular smooth muscle. In the present study, we tested the functional role of the endothelial intermediate-conductance K(Ca) (IK(Ca)/K(Ca)3.1) in endothelial hyperpolarization, in EDHF-mediated dilation, and in the control of arterial pressure by targeted deletion of K(Ca)3.1. K(Ca)3.1-deficient mice (K(Ca)3.1(-/-)) were generated by conventional gene-targeting strategies. Endothelial K(Ca) currents and EDHF-mediated dilations were characterized by patch-clamp analysis, myography and intravital microscopy. Disruption of the K(Ca)3.1 gene abolished endothelial K(Ca)3.1 currents and significantly diminished overall current through K(Ca) channels. As a consequence, endothelial and smooth muscle hyperpolarization in response to acetylcholine was reduced in K(Ca)3.1(-/-) mice. Acetylcholine-induced dilations were impaired in the carotid artery and in resistance vessels because of a substantial reduction of EDHF-mediated dilation in K(Ca)3.1(-/-) mice. Moreover, the loss of K(Ca)3.1 led to a significant increase in arterial blood pressure and to mild left ventricular hypertrophy. These results indicate that the endothelial K(Ca)3.1 is a fundamental determinant of endothelial hyperpolarization and EDHF signaling and, thereby, a crucial determinant in the control of vascular tone and overall circulatory regulation.
authors.affiliation: Department of Internal Medicine-Nephrology, Philipps-University, Marburg, Germany.
authors.forename: Han
authors.initials: H
authors.lastname: Si
authors.forename: Willm-Thomas
authors.initials: WT
authors.lastname: Heyken
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Wölfle
authors.forename: Marcin
authors.initials: M
authors.lastname: Tysiac
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schubert
authors.forename: Ivica
authors.initials: I
authors.lastname: Grgic
authors.forename: Larisa
authors.initials: L
authors.lastname: Vilianovich
authors.forename: Günter
authors.initials: G
authors.lastname: Giebing
authors.forename: Tanja
authors.initials: T
authors.lastname: Maier
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gross
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
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: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001685:Biological Factors / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology*; D002339:Carotid Arteries / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D004594:Electrophysiology; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D014655:Vascular Resistance; D014664:Vasodilation / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001685:Biological Factors; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D000109:Acetylcholine