4羟基2.2.6.6四甲基哌啶对肾性高血压大鼠主动脉重构的影响

Tempol Improved Aortic Remodeling in Renovascular Hypertensive Rats

背景线粒体是活性氧产生的主要来源之一,4羟基2.2.6.6四甲基哌啶(Tempol)可作用于线粒体,清除活性氧。目的探讨Tempol对肾性高血压大鼠主动脉功能和结构的影响以及作用机理。方法两肾一夹的方法建立肾性高血压大鼠模型,术后4周随机分为假手术组(n=8)、高血压组(n=6)及治疗组(n=6),治疗组给予含Tempol 1 mmol/L饮用水。干预8周后观察血压、血管紧张素Ⅱ(AngⅡ)、一氧化氮(NO)、8异前列腺素F_(2α)、胸主动脉NADPH氧化酶亚单位p22 phox mRNA表达的变化;对胸主动脉进行离体血管环实验和HE染色观察其舒张功能和结构的变化。结果1)模型高血压组与假手术组比较,血压、主动脉中膜厚度、中膜厚度/内径显著增加(P均<0.01);AngⅡ、8异前列腺素F_(2α)、NO显著降低(P均<0.01);离体主动脉环对乙酰胆碱(Ach)引起的最大舒张百分数显著下降(P<0.01);主动脉NADPH p22 phox mRNA表达上调。2)治疗组用Tempol治疗8周后与高血压组比较,血压、主动脉中膜厚度、中膜厚度/内径下降;AngⅡ、8异前列腺素F_(2α)显著下降(P均<0.01);NO水平上升(P<0.05);离体主动脉环对Ach引起的最大舒张百分比显著上升(P<0.01);主动脉p22 phox mRNA表达下调;AngⅡ比较没有差异。3)各组间离体主动脉环对硝普钠引起的最大舒张百分比无差异;用L硝基精氨酸甲酯(L-NAME)抑制NO后,各组间离体主动脉环对Ach最大舒张反应无差异。结论Tempol可以明显降低肾性高血压大鼠中氧化应激水平,改善NO代谢,降低血压,其降压机制与其改善NO代谢有关,Tempol还可下调主动脉p22 phox mRNA表达改善主动脉内皮依赖性的舒张功能。

Background Mitoehondria are the primary sites for ROS production within cells, Tempol（4-Hydroxy2,2,6,6, tetramethyl piperidine） is a classic compounds targeting ROS scavengers in mitoehondria. Objective To investigate the effects of Tempol on aortic function and remodeling in renovaseular hypertensive rats. Methods The 2 kindey 1 clip hypertensive model was established in 24 male Wista rats and randomized to untreated hypertensive rats （n=6） or treated with Tempol （1 retool/L） in drinking water （n=6） for 8 weeks. BP blood plasma angiotensin Ⅱ （ Ang Ⅱ ）, nitric oxide（ NO）, 8-iso-PGF2, level were determined. Isometric tension change of aortic rings were recorded; RT-PCR were used to measure the expression of NADPH p22 phox mRNA of aorta. Results Hypertensive rats had highter BP, Ang Ⅱ , 8-iso-PGF2,, media wall, media wall/lumen （W/L） （P〈0. 01）; lower NO （P〈0. 01）when compared with control rats. The expression of NADPH p22 phox mRNA in aorta in hypertensive rats was significantly higher while endothelium dependent vasodilatation reduced in hypertensive rats （P〈 0. 01）. Tempol treatment reduced BP, 8-iso-PGF2,, media wall, W/L（P〈0. 01）; and increased NO endothelium dependent vasodilatation with no changes in Ang Ⅱ. Conclusion Tempol reduces BP, media wall, media W/L, adjustment NO and attenuates oxidative stress wihout influence on Ang Ⅱ. Increases in NO and decreases in oxidatants may be involved in to the effect of Tempol on the functional and structural remodeling of aorta in renovaseular hypertensive rats.