Improvement of endothelium-dependent vasodilations by SKA-31 and SKA-20, activators of small- and intermediate-conductance Ca 2+-activated K +-channels

A. L. Hasenau, G. Nielsen, C. Morisseau, B. D. Hammock, Heike Wulff, R. Köhler

Research output: Contribution to journalArticle

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Abstract

Aim: Endothelial membrane hyperpolarization mediated by KCa3.1 and KCa2.3 channels has been demonstrated to initiate endothelium-derived hyperpolarizing factor (EDHF)-type vasodilations. Moreover, pharmacological potentiation of KCa3.1/KCa2.3 channels has been suggested to improve EDHF-type vasodilations. Herein, we determined whether the KCa3.1/KCa2.3 activator SKA-31 and its derivative SKA-20 improve endothelial dysfunction in KCa3.1-/- and NOS3-/- mice. Methods: Membrane potentials were measured using patch-clamp electrophysiology on carotid artery (CA) endothelial cells (CAEC) from wild-type (wt) and KCa3.1-/- mice. Endothelium-dependent vasodilations were determined by pressure myography in CA. Results: SKA-31 (1μm) activated KCa3.1 and KCa2.3 channels and induced membrane hyperpolarization in CAEC of wt (ΔMP -45mV). These responses were significantly reduced in CAEC of KCa3.1-/- (ΔMP -8mV). SKA-31 (200nm, 500nm) and SKA-20 (300nm) significantly enhanced EDHF vasodilations in wt. SKA-20 also improved vasodilations during NO synthesis. In KCa3.1-/-, the defective EDHF vasodilations were unchanged at 200nm SKA-31, but were significantly improved at 500nm. EDHF vasodilations were slightly enhanced at 300nm SKA-20, but vasodilations during NO synthesis were unchanged. SKA-31 (500nm) enhanced the impaired endothelium-dependent vasodilation in NOS3-/- mice twofold. Pharmacological inhibition of the soluble epoxide hydrolase by t-AUCB (1μm) in contrast did not increase ACh-induced EDHF- or NO-mediated vasodilations in wt and KCa3.1-/- Conclusion: Normal and defective endothelium-dependent vasodilations in murine carotid arteries can be improved by pharmacological enhancement of KCa3.1/KCa2.3 functions. These findings further support the concept that pharmacological activation of endothelial KCa2.3/KCa3.1 could offer a novel endothelium-specific antihypertensive strategy.

Original languageEnglish (US)
Pages (from-to)117-126
Number of pages10
JournalActa Physiologica
Volume203
Issue number1
DOIs
StatePublished - Sep 2011

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Vasodilation
Endothelium
Carotid Arteries
Endothelial Cells
Pharmacology
naphtho(1,2-d)thiazol-2-ylamine
Myography
Epoxide Hydrolases
Electrophysiology
Ion Channels
Membrane Potentials
Antihypertensive Agents
Pressure
Membranes

Keywords

  • Endothelial dysfunction
  • Endothelium-derived hyperpolarizing factor
  • KCa2.3
  • KCa3.1
  • Nitric oxide
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Physiology

Cite this

Improvement of endothelium-dependent vasodilations by SKA-31 and SKA-20, activators of small- and intermediate-conductance Ca 2+-activated K +-channels. / Hasenau, A. L.; Nielsen, G.; Morisseau, C.; Hammock, B. D.; Wulff, Heike; Köhler, R.

In: Acta Physiologica, Vol. 203, No. 1, 09.2011, p. 117-126.

Research output: Contribution to journalArticle

Hasenau, A. L. ; Nielsen, G. ; Morisseau, C. ; Hammock, B. D. ; Wulff, Heike ; Köhler, R. / Improvement of endothelium-dependent vasodilations by SKA-31 and SKA-20, activators of small- and intermediate-conductance Ca 2+-activated K +-channels. In: Acta Physiologica. 2011 ; Vol. 203, No. 1. pp. 117-126.
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abstract = "Aim: Endothelial membrane hyperpolarization mediated by KCa3.1 and KCa2.3 channels has been demonstrated to initiate endothelium-derived hyperpolarizing factor (EDHF)-type vasodilations. Moreover, pharmacological potentiation of KCa3.1/KCa2.3 channels has been suggested to improve EDHF-type vasodilations. Herein, we determined whether the KCa3.1/KCa2.3 activator SKA-31 and its derivative SKA-20 improve endothelial dysfunction in KCa3.1-/- and NOS3-/- mice. Methods: Membrane potentials were measured using patch-clamp electrophysiology on carotid artery (CA) endothelial cells (CAEC) from wild-type (wt) and KCa3.1-/- mice. Endothelium-dependent vasodilations were determined by pressure myography in CA. Results: SKA-31 (1μm) activated KCa3.1 and KCa2.3 channels and induced membrane hyperpolarization in CAEC of wt (ΔMP -45mV). These responses were significantly reduced in CAEC of KCa3.1-/- (ΔMP -8mV). SKA-31 (200nm, 500nm) and SKA-20 (300nm) significantly enhanced EDHF vasodilations in wt. SKA-20 also improved vasodilations during NO synthesis. In KCa3.1-/-, the defective EDHF vasodilations were unchanged at 200nm SKA-31, but were significantly improved at 500nm. EDHF vasodilations were slightly enhanced at 300nm SKA-20, but vasodilations during NO synthesis were unchanged. SKA-31 (500nm) enhanced the impaired endothelium-dependent vasodilation in NOS3-/- mice twofold. Pharmacological inhibition of the soluble epoxide hydrolase by t-AUCB (1μm) in contrast did not increase ACh-induced EDHF- or NO-mediated vasodilations in wt and KCa3.1-/- Conclusion: Normal and defective endothelium-dependent vasodilations in murine carotid arteries can be improved by pharmacological enhancement of KCa3.1/KCa2.3 functions. These findings further support the concept that pharmacological activation of endothelial KCa2.3/KCa3.1 could offer a novel endothelium-specific antihypertensive strategy.",
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AU - Nielsen, G.

AU - Morisseau, C.

AU - Hammock, B. D.

AU - Wulff, Heike

AU - Köhler, R.

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N2 - Aim: Endothelial membrane hyperpolarization mediated by KCa3.1 and KCa2.3 channels has been demonstrated to initiate endothelium-derived hyperpolarizing factor (EDHF)-type vasodilations. Moreover, pharmacological potentiation of KCa3.1/KCa2.3 channels has been suggested to improve EDHF-type vasodilations. Herein, we determined whether the KCa3.1/KCa2.3 activator SKA-31 and its derivative SKA-20 improve endothelial dysfunction in KCa3.1-/- and NOS3-/- mice. Methods: Membrane potentials were measured using patch-clamp electrophysiology on carotid artery (CA) endothelial cells (CAEC) from wild-type (wt) and KCa3.1-/- mice. Endothelium-dependent vasodilations were determined by pressure myography in CA. Results: SKA-31 (1μm) activated KCa3.1 and KCa2.3 channels and induced membrane hyperpolarization in CAEC of wt (ΔMP -45mV). These responses were significantly reduced in CAEC of KCa3.1-/- (ΔMP -8mV). SKA-31 (200nm, 500nm) and SKA-20 (300nm) significantly enhanced EDHF vasodilations in wt. SKA-20 also improved vasodilations during NO synthesis. In KCa3.1-/-, the defective EDHF vasodilations were unchanged at 200nm SKA-31, but were significantly improved at 500nm. EDHF vasodilations were slightly enhanced at 300nm SKA-20, but vasodilations during NO synthesis were unchanged. SKA-31 (500nm) enhanced the impaired endothelium-dependent vasodilation in NOS3-/- mice twofold. Pharmacological inhibition of the soluble epoxide hydrolase by t-AUCB (1μm) in contrast did not increase ACh-induced EDHF- or NO-mediated vasodilations in wt and KCa3.1-/- Conclusion: Normal and defective endothelium-dependent vasodilations in murine carotid arteries can be improved by pharmacological enhancement of KCa3.1/KCa2.3 functions. These findings further support the concept that pharmacological activation of endothelial KCa2.3/KCa3.1 could offer a novel endothelium-specific antihypertensive strategy.

AB - Aim: Endothelial membrane hyperpolarization mediated by KCa3.1 and KCa2.3 channels has been demonstrated to initiate endothelium-derived hyperpolarizing factor (EDHF)-type vasodilations. Moreover, pharmacological potentiation of KCa3.1/KCa2.3 channels has been suggested to improve EDHF-type vasodilations. Herein, we determined whether the KCa3.1/KCa2.3 activator SKA-31 and its derivative SKA-20 improve endothelial dysfunction in KCa3.1-/- and NOS3-/- mice. Methods: Membrane potentials were measured using patch-clamp electrophysiology on carotid artery (CA) endothelial cells (CAEC) from wild-type (wt) and KCa3.1-/- mice. Endothelium-dependent vasodilations were determined by pressure myography in CA. Results: SKA-31 (1μm) activated KCa3.1 and KCa2.3 channels and induced membrane hyperpolarization in CAEC of wt (ΔMP -45mV). These responses were significantly reduced in CAEC of KCa3.1-/- (ΔMP -8mV). SKA-31 (200nm, 500nm) and SKA-20 (300nm) significantly enhanced EDHF vasodilations in wt. SKA-20 also improved vasodilations during NO synthesis. In KCa3.1-/-, the defective EDHF vasodilations were unchanged at 200nm SKA-31, but were significantly improved at 500nm. EDHF vasodilations were slightly enhanced at 300nm SKA-20, but vasodilations during NO synthesis were unchanged. SKA-31 (500nm) enhanced the impaired endothelium-dependent vasodilation in NOS3-/- mice twofold. Pharmacological inhibition of the soluble epoxide hydrolase by t-AUCB (1μm) in contrast did not increase ACh-induced EDHF- or NO-mediated vasodilations in wt and KCa3.1-/- Conclusion: Normal and defective endothelium-dependent vasodilations in murine carotid arteries can be improved by pharmacological enhancement of KCa3.1/KCa2.3 functions. These findings further support the concept that pharmacological activation of endothelial KCa2.3/KCa3.1 could offer a novel endothelium-specific antihypertensive strategy.

KW - Endothelial dysfunction

KW - Endothelium-derived hyperpolarizing factor

KW - KCa2.3

KW - KCa3.1

KW - Nitric oxide

KW - Soluble epoxide hydrolase

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