辛伐他汀对内皮依赖性血管舒张及内源性一氧化氮合酶抑制剂的影响。

Effect of simvastatin on endothelium-dependent vaso-relaxation and endogenous nitric oxide synthase inhibitor.

作者信息

Jiang Jun-lin, Jiang De-jian, Tang Yu-hai, Li Nian-sheng, Deng Han-wu, Li Yuan-jian

机构信息

Department of Pharmacology, School of Pharmaceutic Sciences, Central South University, Changsha 410078, China.

出版信息

Acta Pharmacol Sin. 2004 Jul;25(7):893-901.

PMID:15210062

Abstract

AIM

To investigate the effect of simvastatin on endothelium-dependent vasorelaxation and endogenous nitric oxide synthesis inhibitor asymmetric dimethylarginine (ADMA) in rats and cultured ECV304 cells.

METHODS

Endothelial injury was induced by a single injection of low density lipoprotein (LDL) (4 mg/kg, 48 h) in rats or incubation with LDL (300 mg/L) or oxidative-modified LDL (100 mg/L) in cultured ECV304 cells, and vasodilator responses to acetylcholine (ACh) in the aortic rings and the level of ADMA, nitrite/nitrate (NO) and tumor necrosis factor-alpha (TNF-alpha) in the serum or cultured medium were determined. And the adhesion of the monocytes to endothelial cells and the activity of dimethylarginine dimethylaminohydrolase (DDAH) in the cultured ECV304 cells were measured.

RESULTS

A single injection of LDL decreased endothelium-dependent relaxation to ACh, markedly increased the serum level of endogenous ADMA and TNF-alpha, and reduced serum level of NO. Pretreatment with simvastatin (30 or 60 mg/kg) markedly attenuated inhibition of vasodilator responses to ACh, the increased level of TNF-alpha and the decreased level of NO by LDL, but no effect on serum concentration of endogenous ADMA. In cultured ECV304 cells, LDL or ox-LDL markedly increased the level of ADMA and TNF-alpha and potentiated the adhesion of monocytes to endothelial cells, concomitantly with a significantly decrease in the activity of DDAH and serum level of NO. Pretreatment with simvastatin (0.1, 0.5, or 2.5 micromol/L) markedly decreased the level of TNF-alpha and the adhesion of monocytes to endothelial cells, but did not affect the concentration of endogenous ADMA and the activity of DDAH.

CONCLUSION

Simvastatin protect the vascular endothelium against the damages induced by LDL or ox-LDL in rats or cultured ECV304 cells, and the beneficial effects of simvastatin may be related to the reduction of inflammatory cytokine TNF-alpha level.

摘要

目的

研究辛伐他汀对大鼠及培养的ECV304细胞中内皮依赖性血管舒张及内源性一氧化氮合成抑制剂不对称二甲基精氨酸（ADMA）的影响。

方法

通过单次注射低密度脂蛋白（LDL）（4mg/kg，48小时）诱导大鼠内皮损伤，或在培养的ECV304细胞中与LDL（300mg/L）或氧化修饰的LDL（100mg/L）孵育，测定主动脉环对乙酰胆碱（ACh）的血管舒张反应以及血清或培养基中ADMA、亚硝酸盐/硝酸盐（NO）和肿瘤坏死因子-α（TNF-α）的水平。并检测培养的ECV304细胞中单核细胞与内皮细胞的黏附以及二甲基精氨酸二甲胺水解酶（DDAH）的活性。

结果

单次注射LDL降低了对ACh的内皮依赖性舒张，显著提高了内源性ADMA和TNF-α的血清水平，并降低了NO的血清水平。辛伐他汀（30或60mg/kg）预处理显著减弱了LDL对ACh血管舒张反应的抑制、TNF-α水平的升高和NO水平的降低，但对内源性ADMA的血清浓度无影响。在培养的ECV304细胞中，LDL或氧化型LDL显著提高了ADMA和TNF-α的水平，并增强了单核细胞与内皮细胞的黏附，同时DDAH活性和NO血清水平显著降低。辛伐他汀（0.1、0.5或2.5μmol/L）预处理显著降低了TNF-α水平和单核细胞与内皮细胞的黏附，但不影响内源性ADMA的浓度和DDAH的活性。