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Improvement of endothelium‐dependent vasodilations by SKA‐31 and SKA‐20, activators of small‐ and intermediate‐conductance Ca 2+ ‐activated K + ‐channels
Author(s) -
Hasenau A.L.,
Nielsen G.,
Morisseau C.,
Hammock B. D.,
Wulff H.,
Köhler R.
Publication year - 2011
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/j.1748-1716.2010.02240.x
Subject(s) - conductance , endothelium , chemistry , cardiology , medicine , physics , condensed matter physics
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 (1 μ m ) activated KCa3.1 and KCa2.3 channels and induced membrane hyperpolarization in CAEC of wt (ΔMP −45 mV). These responses were significantly reduced in CAEC of KCa3.1−/− (ΔMP −8 mV). SKA‐31 (200 n m , 500 n m ) and SKA‐20 (300 n m ) significantly enhanced EDHF vasodilations in wt. SKA‐20 also improved vasodilations during NO synthesis. In KCa3.1−/−, the defective EDHF vasodilations were unchanged at 200 n m SKA‐31, but were significantly improved at 500 n m . EDHF vasodilations were slightly enhanced at 300 n m SKA‐20, but vasodilations during NO synthesis were unchanged. SKA‐31 (500 n m ) enhanced the impaired endothelium‐dependent vasodilation in NOS3−/− mice twofold. Pharmacological inhibition of the soluble epoxide hydrolase by t‐ AUCB (1 μ m ) 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.