Genetic deficit of SK3 and IK1 channels disrupts the endothelium-deerived 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

Research output: Contribution to journalArticle

164 Citations (Scopus)

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/SK3 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 (+doxycycline) mice abolished endothelial KCa 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 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 (+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 KCa channels may represent novel therapeutic targets for the treatment of hypertension.

Original languageEnglish (US)
Pages (from-to)2323-2332
Number of pages10
JournalCirculation
Volume119
Issue number17
DOIs
StatePublished - May 5 2009

Fingerprint

Vasodilator Agents
Endothelium
Hypertension
Blood Pressure
Vasodilation
Acetylcholine
Dilatation
Doxycycline
Arterial Pressure
Myography
Telemetry
Arterioles
Membrane Potentials
Smooth Muscle
Nitric Oxide
Arteries
Pressure

Keywords

  • Blood pressure
  • Endothelium-derived factors
  • Ion channels
  • KCa3.1 protein, mouse

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Brähler, S., Kaistha, A., Schmidt, V. J., Wölfle, S. E., Busch, C., Kaistha, B. P., ... Köhler, R. (2009). Genetic deficit of SK3 and IK1 channels disrupts the endothelium-deerived hyperpolarizing factor vasodilator pathway and causes hypertension. Circulation, 119(17), 2323-2332. https://doi.org/10.1161/CIRCULATIONAHA.108.846634

Genetic deficit of SK3 and IK1 channels disrupts the endothelium-deerived 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.

In: Circulation, Vol. 119, No. 17, 05.05.2009, p. 2323-2332.

Research output: Contribution to journalArticle

Brähler, S, Kaistha, A, Schmidt, VJ, Wölfle, SE, Busch, C, Kaistha, BP, Kacik, M, Hasenau, AL, 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-deerived hyperpolarizing factor vasodilator pathway and causes hypertension', Circulation, vol. 119, no. 17, pp. 2323-2332. https://doi.org/10.1161/CIRCULATIONAHA.108.846634
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-deerived hyperpolarizing factor vasodilator pathway and causes hypertension. In: Circulation. 2009 ; Vol. 119, No. 17. pp. 2323-2332.
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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

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N2 - 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/SK3 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 (+doxycycline) mice abolished endothelial KCa 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 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 (+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 KCa channels may represent novel therapeutic targets for the treatment of hypertension.

AB - 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/SK3 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 (+doxycycline) mice abolished endothelial KCa 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 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 (+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 KCa channels may represent novel therapeutic targets for the treatment of hypertension.

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