Katakam Prasad V G, Domoki Ferenc, Snipes James A, Busija Anna R, Jarajapu Yagna P R, Busija David W
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
Am J Physiol Regul Integr Comp Physiol. 2009 Feb;296(2):R289-98. doi: 10.1152/ajpregu.90656.2008. Epub 2008 Nov 12.
Mitochondria affect cerebrovascular tone by activation of mitochondrial ATP-sensitive K+ (K ATP) channels and generation of reactive oxygen species (ROS). Insulin resistance accompanying obesity causes mitochondrial dysfunction, but the consequences on the cerebral circulation have not been fully identified. We evaluated the mitochondrial effects of diazoxide, a putative mitochondrial K ATP channel activator, on cerebral arteries of Zucker obese (ZO) rats with insulin resistance and lean (ZL) controls. Diameter measurements showed diminished diazoxide-induced vasodilation in ZO compared with ZL rats. Maximal relaxation was 38 +/- 3% in ZL vs. 21 +/- 4% in ZO rats (P < 0.05). Iberiotoxin, a Ca2+-activated K+ channel inhibitor, or manganese(III) tetrakis(4-benzoic acid)porphyrin chloride, an SOD mimetic, or endothelial denudation diminished vasodilation to diazoxide, implicating Ca2+-activated K+ channels, ROS, and endothelial factors in vasodilation. Inhibition of nitric oxide synthase (NOS) in ZL rats diminished diazoxide-induced vasodilation in intact arteries, but vasodilation was unaffected in endothelium-denuded arteries. In contrast, NOS inhibition in ZO rats enhanced vasodilation in endothelium-denuded arteries, but intact arteries were unaffected, suggesting that activity of endothelial NOS was abolished, whereas factors derived from nonendothelial NOS promoted vasoconstriction. Fluorescence microscopy showed decreased mitochondrial depolarization, ROS production, and nitric oxide generation in response to diazoxide in ZO arteries. Protein and mRNA measurements revealed increased expression of endothelial NOS and SODs in ZO arteries. Thus, cerebrovascular dilation to mitochondria-derived factors involves integration of endothelial and smooth muscle mechanisms. Furthermore, mitochondria-mediated vasodilation was diminished in ZO rats due to impaired mitochondrial K(ATP) channel activation, diminished mitochondrial ROS generation, increased ROS scavenging, and abnormal NOS activity.
线粒体通过激活线粒体ATP敏感性钾离子（KATP）通道和产生活性氧（ROS）来影响脑血管张力。肥胖伴随的胰岛素抵抗会导致线粒体功能障碍，但对脑循环的影响尚未完全明确。我们评估了二氮嗪（一种假定的线粒体KATP通道激活剂）对具有胰岛素抵抗的 Zucker 肥胖（ZO）大鼠和瘦型（ZL）对照大鼠脑动脉的线粒体效应。直径测量显示，与 ZL 大鼠相比，ZO 大鼠中二氮嗪诱导的血管舒张减弱。ZL 大鼠的最大舒张率为 38±3%，而 ZO 大鼠为 21±4%（P<0.05）。iberiotoxin（一种钙激活钾通道抑制剂）、四（4-苯甲酸）卟啉氯化锰（III）（一种超氧化物歧化酶模拟物）或内皮剥脱会减弱对二氮嗪的血管舒张作用，这表明钙激活钾通道、ROS 和内皮因子参与了血管舒张。在 ZL 大鼠中抑制一氧化氮合酶（NOS）会减弱完整动脉中由二氮嗪诱导的血管舒张，但在内皮剥脱的动脉中血管舒张不受影响。相反，在 ZO 大鼠中抑制 NOS 会增强内皮剥脱动脉中的血管舒张，但完整动脉不受影响，这表明内皮 NOS 的活性被消除，而非内皮 NOS 衍生的因子促进了血管收缩。荧光显微镜显示，ZO 动脉中对二氮嗪的反应中线粒体去极化、ROS 产生和一氧化氮生成减少。蛋白质和 mRNA 测量显示，ZO 动脉中内皮 NOS 和超氧化物歧化酶的表达增加。因此，脑血管对线粒体衍生因子的舒张涉及内皮和平滑肌机制的整合。此外，由于线粒体 K(ATP)通道激活受损、线粒体 ROS 生成减少、ROS 清除增加以及 NOS 活性异常，ZO 大鼠中线粒体介导的血管舒张减弱。
