Activation of KCa3.1 by SKA-31 induces arteriolar dilatation and lowers blood pressure in normo- and hypertensive connexin40-deficient mice

Josephine Radtke, Kjestine Schmidt, Heike Wulff, Ralf Köhler, Cor De Wit

Research output: Contribution to journalArticle

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Abstract

Background and Purpose The calcium-activated potassium channel K Ca3.1 is expressed in the vascular endothelium where its activation causes endothelial hyperpolarization and initiates endothelium-derived hyperpolarization (EDH)-dependent dilatation. Here, we investigated whether pharmacological activation of KCa3.1 dilates skeletal muscle arterioles and whether myoendothelial gap junctions formed by connexin40 (Cx40) are required for EDH-type dilatations and pressure depressor responses in vivo. Experimental Approach We performed intravital microscopy in the cremaster muscle microcirculation and blood pressure telemetry in Cx40-deficient mice. Key Results In wild-type mice, the KCa3.1-activator SKA-31 induced pronounced concentration-dependent arteriolar EDH-type dilatations, amounting to ∼40% of maximal dilatation, and enhanced the effects of ACh. These responses were absent in mice devoid of KCa3.1 channels. In contrast, SKA-31-induced dilatations were not attenuated in mice with endothelial cells deficient in Cx40 (Cx40fl/fl:Tie2-Cre). In isolated endothelial cell clusters, SKA-31 induced hyperpolarizations of similar magnitudes (by ∼38 mV) in Cx40fl/fl:Tie2-Cre, ubiquitous Cx40-deficient mice (Cx40 -/-) and controls (Cx40fl/fl), which were reversed by the specific KCa3.1-blocker TRAM-34. In normotensive wild-type and Cx40fl/fl:Tie2-Cre as well as in hypertensive Cx40-/- animals, i.p. injections of SKA-31 (30 and 100 mg·kg-1) decreased arterial pressure by ∼32 mmHg in all genotypes. The depressor response to 100 mg·kg-1 SKA-31 was associated with a decrease in heart rate. Conclusions and Implications We conclude that endothelial hyperpolarization evoked by pharmacological activation of KCa3.1 channels induces EDH-type arteriolar dilatations that are independent of endothelial Cx40 and Cx40-containing myoendothelial gap junctions. As SKA-31 reduced blood pressure in hypertensive Cx40-deficient mice, KCa3.1 activators may be useful drugs for severe treatment-resistant hypertension.

Original languageEnglish (US)
Pages (from-to)293-303
Number of pages11
JournalBritish Journal of Pharmacology
Volume170
Issue number2
DOIs
StatePublished - Sep 2013

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Dilatation
Blood Pressure
Endothelium
Gap Junctions
Endothelial Cells
Pharmacology
Calcium-Activated Potassium Channels
Abdominal Muscles
Telemetry
Vascular Endothelium
Arterioles
Microcirculation
naphtho(1,2-d)thiazol-2-ylamine
Arterial Pressure
Skeletal Muscle
Heart Rate
Genotype
Hypertension
Pressure
Injections

Keywords

  • 2-d]thiazol-2-ylamine)
  • Ca -activated K channel
  • endothelium-derived hyperpolarizing factor
  • gap junction
  • hypertension
  • microcirculation
  • myoendothelial coupling
  • SKA-31 (naphtho[1

ASJC Scopus subject areas

  • Pharmacology

Cite this

Activation of KCa3.1 by SKA-31 induces arteriolar dilatation and lowers blood pressure in normo- and hypertensive connexin40-deficient mice. / Radtke, Josephine; Schmidt, Kjestine; Wulff, Heike; Köhler, Ralf; De Wit, Cor.

In: British Journal of Pharmacology, Vol. 170, No. 2, 09.2013, p. 293-303.

Research output: Contribution to journalArticle

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abstract = "Background and Purpose The calcium-activated potassium channel K Ca3.1 is expressed in the vascular endothelium where its activation causes endothelial hyperpolarization and initiates endothelium-derived hyperpolarization (EDH)-dependent dilatation. Here, we investigated whether pharmacological activation of KCa3.1 dilates skeletal muscle arterioles and whether myoendothelial gap junctions formed by connexin40 (Cx40) are required for EDH-type dilatations and pressure depressor responses in vivo. Experimental Approach We performed intravital microscopy in the cremaster muscle microcirculation and blood pressure telemetry in Cx40-deficient mice. Key Results In wild-type mice, the KCa3.1-activator SKA-31 induced pronounced concentration-dependent arteriolar EDH-type dilatations, amounting to ∼40{\%} of maximal dilatation, and enhanced the effects of ACh. These responses were absent in mice devoid of KCa3.1 channels. In contrast, SKA-31-induced dilatations were not attenuated in mice with endothelial cells deficient in Cx40 (Cx40fl/fl:Tie2-Cre). In isolated endothelial cell clusters, SKA-31 induced hyperpolarizations of similar magnitudes (by ∼38 mV) in Cx40fl/fl:Tie2-Cre, ubiquitous Cx40-deficient mice (Cx40 -/-) and controls (Cx40fl/fl), which were reversed by the specific KCa3.1-blocker TRAM-34. In normotensive wild-type and Cx40fl/fl:Tie2-Cre as well as in hypertensive Cx40-/- animals, i.p. injections of SKA-31 (30 and 100 mg·kg-1) decreased arterial pressure by ∼32 mmHg in all genotypes. The depressor response to 100 mg·kg-1 SKA-31 was associated with a decrease in heart rate. Conclusions and Implications We conclude that endothelial hyperpolarization evoked by pharmacological activation of KCa3.1 channels induces EDH-type arteriolar dilatations that are independent of endothelial Cx40 and Cx40-containing myoendothelial gap junctions. As SKA-31 reduced blood pressure in hypertensive Cx40-deficient mice, KCa3.1 activators may be useful drugs for severe treatment-resistant hypertension.",
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AU - Schmidt, Kjestine

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AU - Köhler, Ralf

AU - De Wit, Cor

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N2 - Background and Purpose The calcium-activated potassium channel K Ca3.1 is expressed in the vascular endothelium where its activation causes endothelial hyperpolarization and initiates endothelium-derived hyperpolarization (EDH)-dependent dilatation. Here, we investigated whether pharmacological activation of KCa3.1 dilates skeletal muscle arterioles and whether myoendothelial gap junctions formed by connexin40 (Cx40) are required for EDH-type dilatations and pressure depressor responses in vivo. Experimental Approach We performed intravital microscopy in the cremaster muscle microcirculation and blood pressure telemetry in Cx40-deficient mice. Key Results In wild-type mice, the KCa3.1-activator SKA-31 induced pronounced concentration-dependent arteriolar EDH-type dilatations, amounting to ∼40% of maximal dilatation, and enhanced the effects of ACh. These responses were absent in mice devoid of KCa3.1 channels. In contrast, SKA-31-induced dilatations were not attenuated in mice with endothelial cells deficient in Cx40 (Cx40fl/fl:Tie2-Cre). In isolated endothelial cell clusters, SKA-31 induced hyperpolarizations of similar magnitudes (by ∼38 mV) in Cx40fl/fl:Tie2-Cre, ubiquitous Cx40-deficient mice (Cx40 -/-) and controls (Cx40fl/fl), which were reversed by the specific KCa3.1-blocker TRAM-34. In normotensive wild-type and Cx40fl/fl:Tie2-Cre as well as in hypertensive Cx40-/- animals, i.p. injections of SKA-31 (30 and 100 mg·kg-1) decreased arterial pressure by ∼32 mmHg in all genotypes. The depressor response to 100 mg·kg-1 SKA-31 was associated with a decrease in heart rate. Conclusions and Implications We conclude that endothelial hyperpolarization evoked by pharmacological activation of KCa3.1 channels induces EDH-type arteriolar dilatations that are independent of endothelial Cx40 and Cx40-containing myoendothelial gap junctions. As SKA-31 reduced blood pressure in hypertensive Cx40-deficient mice, KCa3.1 activators may be useful drugs for severe treatment-resistant hypertension.

AB - Background and Purpose The calcium-activated potassium channel K Ca3.1 is expressed in the vascular endothelium where its activation causes endothelial hyperpolarization and initiates endothelium-derived hyperpolarization (EDH)-dependent dilatation. Here, we investigated whether pharmacological activation of KCa3.1 dilates skeletal muscle arterioles and whether myoendothelial gap junctions formed by connexin40 (Cx40) are required for EDH-type dilatations and pressure depressor responses in vivo. Experimental Approach We performed intravital microscopy in the cremaster muscle microcirculation and blood pressure telemetry in Cx40-deficient mice. Key Results In wild-type mice, the KCa3.1-activator SKA-31 induced pronounced concentration-dependent arteriolar EDH-type dilatations, amounting to ∼40% of maximal dilatation, and enhanced the effects of ACh. These responses were absent in mice devoid of KCa3.1 channels. In contrast, SKA-31-induced dilatations were not attenuated in mice with endothelial cells deficient in Cx40 (Cx40fl/fl:Tie2-Cre). In isolated endothelial cell clusters, SKA-31 induced hyperpolarizations of similar magnitudes (by ∼38 mV) in Cx40fl/fl:Tie2-Cre, ubiquitous Cx40-deficient mice (Cx40 -/-) and controls (Cx40fl/fl), which were reversed by the specific KCa3.1-blocker TRAM-34. In normotensive wild-type and Cx40fl/fl:Tie2-Cre as well as in hypertensive Cx40-/- animals, i.p. injections of SKA-31 (30 and 100 mg·kg-1) decreased arterial pressure by ∼32 mmHg in all genotypes. The depressor response to 100 mg·kg-1 SKA-31 was associated with a decrease in heart rate. Conclusions and Implications We conclude that endothelial hyperpolarization evoked by pharmacological activation of KCa3.1 channels induces EDH-type arteriolar dilatations that are independent of endothelial Cx40 and Cx40-containing myoendothelial gap junctions. As SKA-31 reduced blood pressure in hypertensive Cx40-deficient mice, KCa3.1 activators may be useful drugs for severe treatment-resistant hypertension.

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