Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension
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Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension. / Brähler, Sebastian; Kaistha, Anuradha; Schmidt, Volker J; Wölfle, Stephanie E; Busch, Christoph; Kaistha, Brajesh P; Kacik, Michael; Hasenau, Anna-Lena; Grgic, Ivica; Si, Han; Bond, Chris T; Adelman, John P; Wulff, Heike; de Wit, Cor; Hoyer, Joachim; Köhler, Ralf.
I: Circulation, Bind 119, Nr. 17, 05.05.2009, s. 2323-32.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension
AU - Brähler, Sebastian
AU - Kaistha, Anuradha
AU - Schmidt, Volker J
AU - Wölfle, Stephanie E
AU - Busch, Christoph
AU - Kaistha, Brajesh P
AU - Kacik, Michael
AU - Hasenau, Anna-Lena
AU - Grgic, Ivica
AU - Si, Han
AU - Bond, Chris T
AU - Adelman, John P
AU - Wulff, Heike
AU - de Wit, Cor
AU - Hoyer, Joachim
AU - Köhler, Ralf
PY - 2009/5/5
Y1 - 2009/5/5
N2 - 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.METHODS AND 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.
AB - 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.METHODS AND 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.
KW - Animals
KW - Biological Factors/metabolism
KW - Blood Pressure/physiology
KW - Calcium/metabolism
KW - Hypertension/etiology
KW - Membrane Potentials
KW - Mice
KW - Mice, Knockout
KW - Muscle, Smooth, Vascular/physiopathology
KW - Myocytes, Smooth Muscle/physiology
KW - Shaw Potassium Channels/deficiency
KW - Small-Conductance Calcium-Activated Potassium Channels/deficiency
KW - Vasodilation
U2 - 10.1161/CIRCULATIONAHA.108.846634
DO - 10.1161/CIRCULATIONAHA.108.846634
M3 - Journal article
C2 - 19380617
VL - 119
SP - 2323
EP - 2332
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 17
ER -
ID: 329569581