Openers of SKCa and IKCa channels enhance agonist-evoked endothelial nitric oxide synthesis and arteriolar vasodilation
Openers of SKCa and IKCa channels enhance agonist-evoked endothelial nitric oxide synthesis and arteriolar vasodilation
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DOI：
10.1096/fj.08-120451
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发表时间：
2009-04-01
期刊：
影响因子：
4.8
通讯作者：
Braun, Andrew P.
中科院分区：
文献类型：
--
作者：
Sheng, Jian-zhong;Ella, Srikanth;Braun, Andrew P.
最近的数据使我们假设，开放剂化合物NS309和DCEBIO选择性激活内皮小导和/或中导钙活化钾通道（分别为SKCa和IKCa通道）会增加受刺激的一氧化氮（NO）合成和阻力动脉的血管舒张。实验中，用膜片钳和微荧光法记录了atp引起的单个人内皮细胞膜电位、胞质Ca2+和NO合成的变化。用视频显微镜分析了激动剂诱发的肌原性张力的抑制作用。在离体内皮细胞中，NS309和DCEBIO增强了atp诱导的膜超极化和胞质Ca2+瞬态，以及急性NO合成。在NS309和DCEBIO（10、100和1000 nM）作用下，乙酰胆碱介导的肌原张力抑制（IC50 = 237 nM）左移至IC50值为101、78和43 nM；内皮剥落抑制了这种药物作用。L-NAME减弱了乙酰胆碱诱导的肌原性张力抑制，但不干扰NS309和dcebio引起的血管舒张。总的来说，我们的数据表明，药物诱导的内皮细胞SKCa和IKCa通道活性的增强代表了一种新的细胞机制，可以增加小阻力小动脉的血管舒张，从而突出了这些通道作为与一氧化氮信号受损相关的心血管疾病状态的潜在治疗靶点。-Sheng, j.s., Ella， S, Davis, m.j., Hill, m.a., Braun, a.p.。SKCa和IKCa通道的开启剂增强激动剂诱发的内皮细胞一氧化氮合成和小动脉血管舒张。中华医学杂志，23 （2009）
Recent data have led us to hypothesize that selective activation of endothelial small- and/or intermediate-conductance, calcium-activated potassium channels (SKCa and IKCa channels, respectively) by the opener compounds NS309 and DCEBIO would augment stimulated nitric oxide (NO) synthesis and vasodilation in resistance arteries. Experimentally, ATP-evoked changes in membrane potential, cytosolic Ca2+, and NO synthesis were recorded by patch clamp and microfluorimetry in single human endothelial cells. Agonist-evoked inhibition of myogenic tone in isolated, pressurized arterioles from rat cremaster skeletal muscle was analyzed by video microscopy. NS309 and DCEBIO enhanced ATP-evoked membrane hyperpolarization and cytosolic Ca2+ transients, along with acute NO synthesis in isolated endothelial cells. The acetylcholine-mediated inhibition of myogenic tone (IC50 = 237 nM) was left-shifted in the presence of NS309 and DCEBIO (10, 100, and 1000 nM) to IC50 values of 101, 78, and 43 nM; endothelial denudation inhibited this drug effect. L-NAME attenuated the acetylcholine-induced inhibition of myogenic tone but did not interfere with NS309 and DCEBIO-evoked vasodilation. Collectively, our data demonstrate that drug-induced enhancement of endothelial SKCa and IKCa channel activities represents a novel cellular mechanism to increase vasodilation of small-resistance arterioles, thereby highlighting these channels as potential therapeutic targets in cardiovascular disease states associated with compromised NO signaling.-Sheng, J.S., Ella, S., Davis, M. J., Hill, M. A., Braun, A. P. Openers of SKCa and IKCa channels enhance agonist-evoked endothelial nitric oxide synthesis and arteriolar vasodilation. FASEB J. 23, 1138-1145 (2009)