Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension

Sebastian Brähler, Anuradha Kaistha, Volker J Schmidt, Stephanie E Wölfle, Christoph Busch, Brajesh P Kaistha, Michael Kacik, Anna-Lena Hasenau, Ivica Grgic, Han Si, Chris T Bond, John P Adelman, Heike Wulff, Cor de Wit, Joachim Hoyer, Ralf Köhler

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.
OriginalsprogEngelsk
TidsskriftCirculation
Vol/bind119
Udgave nummer17
Sider (fra-til)2323-32
Antal sider9
ISSN0009-7322
DOI
StatusUdgivet - 2009

Fingeraftryk

Endothelium
Vasodilation
Acetylcholine
Dilatation
Doxycycline
Arterial Pressure
Myography
Smooth Muscle
Nitric Oxide

Citer dette

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. / Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension. I: Circulation. 2009 ; Bind 119, Nr. 17. s. 2323-32.
@article{792db7f0b95d11deab49000ea68e967b,
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. 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.",
author = "Sebastian Br{\"a}hler and Anuradha Kaistha and Schmidt, {Volker J} and W{\"o}lfle, {Stephanie E} and Christoph Busch and Kaistha, {Brajesh P} and Michael Kacik and Anna-Lena Hasenau and Ivica Grgic and Han Si and Bond, {Chris T} and Adelman, {John P} and Heike Wulff and {de Wit}, Cor and Joachim Hoyer and Ralf K{\"o}hler",
year = "2009",
doi = "10.1161/CIRCULATIONAHA.108.846634",
language = "English",
volume = "119",
pages = "2323--32",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams & Wilkins",
number = "17",

}

Brähler, S, Kaistha, A, Schmidt, VJ, Wölfle, SE, Busch, C, Kaistha, BP, Kacik, M, Hasenau, A-L, Grgic, I, Si, H, Bond, CT, Adelman, JP, Wulff, H, de Wit, C, Hoyer, J & Köhler, R 2009, 'Genetic deficit of SK3 and IK1 channels disrupts the endothelium-derived hyperpolarizing factor vasodilator pathway and causes hypertension', Circulation, bind 119, nr. 17, s. 2323-32. https://doi.org/10.1161/CIRCULATIONAHA.108.846634

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, 2009, s. 2323-32.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

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

Y1 - 2009

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.

U2 - 10.1161/CIRCULATIONAHA.108.846634

DO - 10.1161/CIRCULATIONAHA.108.846634

M3 - Journal article

VL - 119

SP - 2323

EP - 2332

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 17

ER -