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The effects of volatile anesthetics on recombinant adenosine triphosphate-sensitive potassium channels

挥发性麻醉药对重组三磷酸腺苷敏感钾通道的影响

基本信息

批准号：
17591636
负责人：
TANAKA Katsuya
金额：
$ 2.24万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591636/
关键词：
Volatile anesthetics Isoflurane Vascular smooth muscle cells KATP channels pancreatic β cells patch clamp configurations 血菅内皮細胞

项目摘要

Background ; Recent evidence indicates that vascular adenosine triphosphate-sensitive potassium (K_<ATP>) channels in vascular smooth muscle cells are critical in the regulation of vascular tonus under both physiological and pathophysiological conditions. Studies of the interaction of volatile anesthetics with vascular K_<ATP> channels have been limited. In the present study, we investigated the molecular mechanism of isoflurane's action on vascular K_<ATP> channels.Methods ; Electrophysiologic experiments were performed using cell-attached and inside-out patch-clamp techniques to monitor native vascular K_<ATP> channels, and recombinant K_<ATP> channels comprised of inwardly rectifying potassium, channel subunits (Kir6. 1) and the sulfonylurea receptor (SUR2B). Isometric tension experiments were performed in rat thoracic aortic rings without endothelium.Results ; Application of isoflurane (0.5mM) to the bath solution during cell-attached recordings induced a significant increase in K_ … More <ATP> channel activity, which was greatly reduced by pretreatment with a selective inhibitor protein kinase A (PKA), Rp-cAMPS (100 μM). In inside-out patches, isoflurane failed to activate K_<ATP> channels. Isoflurane significantly activated wild type recombinant SUR2B/Kir6.1 in cell-attached patches. Isoflurane-induced activation of wild-type channels was diminished in the PKA-insensitive mutant SUR2B-T633A/Kir6.1, SUR2B-S1465A/Kir6. 1, and SUR2B/Kir6.1-S385A. In addition, we demonstrated that isoflurane-induced PKA activation was associated with isoflurane-induced decreases in isometric tension in the rat aorta.Conclusion ; Our results indicated that isoflurane activates K_<ATP> channels via PKA activation. PKA-dependent vasodilation induced by isoflurane also was observed in isometric tension experiments. Analysis of expressed vascular type K_<ATP>, channels suggested that PKA-mediated phosphorylation of both Kir6.1 and SUR2B subunits plays a pivotal role in isoflurane-induced vascular K_<ATP>, channel activation. Less

研究背景：近年来的研究表明，血管平滑肌细胞三磷酸腺苷敏感性钾通道（adenosinetriphosphate-sensitivekotassium，<ATP>K_2）在生理和病理生理条件下对血管紧张性的调节起着重要作用。目前对吸入麻醉药与血管钾通道相互作用的研究<ATP>还很有限。本研究探讨了异氟醚对血管钾通道作用的分子机制<ATP>。采用细胞贴附和由内向外膜片钳技术对天然血管钾<ATP>通道和<ATP>由内向整流钾通道亚基（Kir 6. 1)磺酰脲受体（SUR 2B）。结果：在细胞贴壁记录过程中，在浴槽液中加入异氟醚（0.5mM），可使离体大鼠胸主动脉环的K_（max）显著增加，而在离体大鼠胸主动脉环的K_（max）则显著增加。 ...更多信息 <ATP>通道活性，用选择性抑制剂蛋白激酶A（PKA）Rp-cAMPS（100 μM）预处理后大大降低。在由内向外的膜片上，异氟醚不能激活钾<ATP>通道。异氟烷显著激活细胞贴附贴片中的野生型重组SUR 2B/Kir6.1。在PKA不敏感突变体SUR 2B-T633 A/Kir6.1、SUR 2B-S1465 A/Kir 6中，异氟烷诱导的野生型通道激活减弱。1和SUR 2B/Kir6.1-S385 A。此外，我们证明，异氟醚诱导的PKA激活与异氟醚诱导的大鼠主动脉等长收缩张力的降低有关。结论：我们的研究结果表明，异氟醚通过PKA激活激活K_<ATP>通道。在等长张力实验中也观察到异氟烷诱导的PKA依赖性血管舒张。对表达的血管型K_1通道的分析<ATP>表明，PKA介导的Kir6.1和SUR 2B亚基的磷酸化在异氟醚诱导的血管K_1通道激活中起关键作用<ATP>。少