Mechanism of Diazoxide-mediated Cardioprotection
作者单位：Division of PharmacologyCollege of PharmacyOhio State University Columbus OHU.S.A. Division of PharmacologyCollege of PharmacyOhio State University Columbus OHU.S.A.
会议名称：《第十五届国际药理学大会》
会议日期：2006年
学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学]
关 键 词：preconditioning diazoxide PKC
摘 要：正 Ischemic preconditioning （IPC） can be mimicked by K+ channel openers such as diazoxide. Diazoxide has multiple ATP-sensitive K+ channel （KATP）-indepen-dent actions, and the mechanism underlying diazoxidemediated cardioprotection remains inconclusive. Giving that the KATP pore-forming subunit Kir6.2-knock-out mice have shown no cardioprotection of IPC, we tested the hypothesis that diazoxide protects the heart by promoting import of Kir6.2-containing KATP into mitochondria from cytosol where they are synthesized. The effect of diazoxide on mitochondrial localization of Kir6.2 was examined in KATP deficient COS-7 cells transfected with HA tagged Kir6.2 and SUR2A by laser confocal microscopy. We found that the percentage of cells showing mitochondrial localization of Kir6.2 was significantly higher in diazoxide （100 micro M）-treated group than that in control group （68.0% vs. 11.0%）. The effect was almost completely prevented by the KATP channel inhibitors 5-hydroxydecanoate or glibenclamide, or a selective protein kinase C （PKC） inhibitor chelerythrine. We conclude that diazoxide increases Kir6.2-containing KATP channels in mitochondria by activation of PKC.