Improvement of endothelium-dependent vasodilations by SKA-31 and SKA-20, activators of small- and intermediate-conductance Ca2+ -activated K+ -channels.
Improvement of endothelium-dependent vasodilations by SKA-31 and SKA-20, activators of small- and intermediate-conductance Ca2+ -activated K+ -channels.
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DOI：
10.1111/j.1748-1716.2010.02240.x
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发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Köhler R
中科院分区：
文献类型：
--
作者：
Hasenau AL;Nielsen G;Morisseau C;Hammock BD;Wulff H;Köhler R
已证实KCa3.1和KCa2.3通道介导的内皮细胞膜超极化可启动内皮衍生超极化因子(EDHF)型血管扩张。此外，KCa3.1/KCa2.3通道的药理增强被认为可以改善EDHF类型的血管扩张。在这里，我们确定了KCa3.1/KCa2.3激活剂SKA-31及其衍生物SKA-20是否改善了KCa3.1−/−和NOS3−/−小鼠的内皮功能障碍。用膜片钳电生理技术测定了野生型(Wt)和Kca3.1−/−小鼠颈动脉内皮细胞的膜电位。用压力肌图法测定CA患者的内皮依赖性血管扩张功能。SKA-31(1微克分子L-1)可激活WT(ΔMP-45 mV)钙通道KCa3.1和KCa2.3通道，并诱发膜超极化。这些反应在KCa3.1−/−(ΔMP-8 mV的CAEC中显著降低。SKA-31(200nmol L~(-1)、500nmol L~(-1))和SKA-20(300nmol L~(-1))显著增强血管收缩功能。在KCa3.1−/−中，血管收缩功能在200nmol L-1SKA-31作用下无明显变化，但在500nmol L-1作用下显著改善。在300nmoL L-1SKA-20作用下，血管舒张性略有增强，但NO合成过程中的血管舒张性无明显变化。SKA-31(500nmol L-1)可使NOS3−/−小鼠受损的内皮依赖性血管扩张增加2倍。在WT和KCa3.1−/−中，t-AUCB(1µmoL L-1)对可溶性环氧化物水解酶的药理抑制并不增加ACh诱导的EDHF或NO介导的血管扩张。KCa3.1/KCa2.3功能的药理增强可改善正常和缺陷小鼠颈动脉内皮依赖性血管扩张。这些发现进一步支持了这样一个概念，即药物激活内皮细胞KCa2.3/KCa3.1可以提供一种新的内皮特异性降压策略。
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. Here 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. 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. SKA-31 (1 µmol L-1) 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 (200 nmol L-1, 500 nmol L-1) and SKA-20 (300 nmol L-1) 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 nmol L-1 SKA-31, but were significantly improved at 500 nmol L-1. EDHF-vasodilations were slightly enhanced at 300 nmol L-1 SKA-20, but vasodilations during NO-synthesis were unchanged. SKA-31 (500 nmol L-1) enhanced the impaired endothelium-dependent vasodilation in NOS3−/− mice 2-fold. Pharmacological inhibition of the soluble epoxide hydrolase by t-AUCB (1 µmol L-1) in contrast did not increase ACh-induced EDHF- or NO-mediated vasodilations in wt and KCa3.1−/−. 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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影响因子：
7.3
作者：
Schmidt, Kjestine;Dubrovska, Galyna;Kohler, Ralf
通讯作者：
Kohler, Ralf
影响因子：
4.8
作者：
Milkau, Malte;Kohler, Ralf;de Wit, Cor
通讯作者：
de Wit, Cor
影响因子：
64.8
作者：
Edwards, G;Dora, KA;Weston, AH
通讯作者：
Weston, AH
影响因子：
37.8
作者：
Feng J;Liu Y;Clements RT;Sodha NR;Khabbaz KR;Senthilnathan V;Nishimura KK;Alper SL;Sellke FW
通讯作者：
Sellke FW
影响因子：
3.6
作者：
Sankaranarayanan, Ananthakrishnan;Raman, Girija;Busch, Christoph;Schultz, Tim;Zimin, Pavel I.;Hoyer, Joachim;Koehler, Ralf;Wulff, Heike
通讯作者：
Wulff, Heike