Genetische Suppression endothelialer KCa3.1 und KCa2.3 unterdrückt die EDHF-vermittelte Vasodilatation und erzeugt Hypertonie
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Philipps-Universität Marburg
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Abstract
Background—It has been proposed
that activation of endothelial SK3 (KCa2.3) and IK1 (KCa3.1)
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. Methods and
Results—Expression and function of endothelial SK3 and IK1 in
IK1//SK3T/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//SK3T/T
(doxycycline) mice abolished endothelial KCa currents and
impaired acetylcholine-induced smooth muscle
hyperpolarization and EDHFmediated 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//SK3T/T mice
partially restored EDHF- and nitric oxide–mediated
vasodilation and lowered elevated blood pressure. The 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 KCa channels may
represent novel therapeutic targets for the treatment of
hypertension.
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Dates
Created: 2009Issued: 2010-08-02Updated: 2011-08-10
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
ion channelhypertensionendotheliumpotassium channel
DFG-subjects
EndothelHypertonieIonenkanalKaliumkanalStickstoffmonoxid
DDC-Numbers
610
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Brähler, Sebastian Paul (142236691): Genetische Suppression endothelialer KCa3.1 und KCa2.3 unterdrückt die EDHF-vermittelte Vasodilatation und erzeugt Hypertonie. : Philipps-Universität Marburg 2010-08-02. DOI: https://doi.org/10.17192/z2010.0398.
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This item has been published with the following license: In Copyright