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 language | English (US) |
|---|---|
| Pages (from-to) | 117-126 |
| Number of pages | 10 |
| Journal | Acta Physiologica |
| Volume | 203 |
| Issue number | 1 |
| DOIs | |
| State | Published - Sep 2011 |
Fingerprint
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 journal › Article
}
TY - JOUR
T1 - Improvement of endothelium-dependent vasodilations by SKA-31 and SKA-20, activators of small- and intermediate-conductance Ca 2+-activated K +-channels
AU - Hasenau, A. L.
AU - Nielsen, G.
AU - Morisseau, C.
AU - Hammock, B. D.
AU - Wulff, Heike
AU - Köhler, R.
PY - 2011/9
Y1 - 2011/9
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
UR - http://www.scopus.com/inward/record.url?scp=80051669926&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80051669926&partnerID=8YFLogxK
U2 - 10.1111/j.1748-1716.2010.02240.x
DO - 10.1111/j.1748-1716.2010.02240.x
M3 - Article
C2 - 21362152
AN - SCOPUS:80051669926
VL - 203
SP - 117
EP - 126
JO - Acta Physiologica Scandinavica
JF - Acta Physiologica Scandinavica
SN - 0370-839X
IS - 1
ER -