Inhibition of Succinate Dehydrogenase by Diazoxide Is Independent of the ATP-Sensitive Potassium Channel Subunit Sulfonylurea Type 1 Receptor
Inhibition of Succinate Dehydrogenase by Diazoxide Is Independent of the ATP-Sensitive Potassium Channel Subunit Sulfonylurea Type 1 Receptor
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DOI：
10.1016/j.jamcollsurg.2013.01.048
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发表时间：
2013-06-01
影响因子：
5.2
通讯作者：
Lawton, Jennifer S.
中科院分区：
文献类型：
--
作者：
Anastacio, Melissa M.;Kanter, Evelyn M.;Lawton, Jennifer S.
背景：二氮嗪通过一种未知的机制在应激过程中维持心肌细胞的体积和收缩力。作用机制可能涉及未确定的（基因型未知）线粒体ATP敏感性钾通道，并依赖于ATP敏感性钾通道亚单位磺酰脲1型受体（SUR 1）。ATP敏感性钾通道开放剂已被证明能抑制琥珀酸脱氢酶（SDH），并且在SUR内含子中发现了一部分SDH的基因。二氮嗪可能通过抑制SDH来保护心脏，SDH可以形成ATP敏感性钾通道的一部分或共享其遗传物质。本研究探讨了二氮嗪抑制SDH的作用及其与SUR 1亚基的关系。研究设计：从野生型和SUR 1基因敲除小鼠中分离线粒体。琥珀酸脱氢酶活性通过20分钟的2，6-二氯靛酚还原的分光光度分析测量为吸光度随时间的相对变化。用琥珀酸盐（20 mM）、琥珀酸盐+1%二甲亚砜、琥珀酸盐+丙二酸盐（8 mM）处理线粒体结果：丙二酸和二氮嗪均抑制野生型小鼠和缺乏SUR 1亚单位小鼠线粒体中的SDH活性结论：DZX抑制SDH的能力即使在SUR 1基因缺失后仍然存在。因此，酶复合物SDH不依赖于SUR 1基因。DZX对SDH的抑制在DZX提供的心脏保护中起作用;然而，这种作用不依赖于ATP敏感性钾通道亚基SUR 1。（J Am科尔外科杂志2013; 216：1144-1149。(C)2013年美国外科医生学会）
BACKGROUND: Diazoxide maintains myocyte volume and contractility during stress via an unknown mechanism. The mechanism of action may involve an undefined (genotype unknown) mitochondrial ATP-sensitive potassium channel and is dependent on the ATP-sensitive potassium channel subunit sulfonylurea type 1 receptor (SUR1). The ATP-sensitive potassium channel openers have been shown to inhibit succinate dehydrogenase (SDH) and a gene for a portion of SDH has been found in the SUR intron. Diazoxide may be cardioprotective via inhibition of SDH, which can form part of an ATP-sensitive potassium channel or share its genetic material. This study investigated the role of inhibition of SDH by diazoxide and its relationship to the SUR1 subunit.STUDY DESIGN: Mitochondria were isolated from wild-type and SUR1 knockout mice. Succinate dehydrogenase activity was measured by spectrophotometric analysis of 2,6-dichloroindophenol reduction for 20 minutes as the relative change in absorbance over time. Mitochondria were treated with succinate (20 mM), succinate + 1% dimethylsulfoxide, succinate + malonate (8 mM) (competitive inhibitor of SDH), or succinate + diazoxide (100 mM).RESULTS: Both malonate and diazoxide inhibit SDH activity in mitochondria of wild-type mice and in mice lacking the SUR1 subunit (p < 0.05 vs control).CONCLUSIONS: The ability of DZX to inhibit SDH persists even after deletion of the SUR1 gene. Therefore, the enzyme complex SDH is not dependent on the SUR1 gene. The inhibition of SDH by DZX can play a role in the cardioprotection afforded by DZX; however, this role is independent of the ATP-sensitive potassium channel subunit SUR1. (J Am Coll Surg 2013; 216: 1144-1149. (C) 2013 by the American College of Surgeons)