环加氧酶-2抑制剂尼美舒利通过改善内皮功能和增加NO含量对抗大鼠心肌氧化应激损伤(英文)  

COX-2 inhibitor nimesulide protects rat heart against oxidative stress by improving endothelial function and enhancing NO production

作　　者：吕萍萍[1] 范莹[1] 陈文良[1] 沈岳良[1] 朱立[1] 王琳琳[1] 陈莹莹[1] 

机构地区：[1]浙江大学医学院生理学系,杭州310058

出　　处：《生理学报》2007年第5期674-680,共7页Acta Physiologica Sinica

基　　金：This work was supported by the National Natural Science Foundation of China (No. 30400094);the Scientific Research Foundation ofEducation Ministry of China for the Returned Overseas Chinese Scholars (No. 419100-G50619).

摘　　要：本文旨在研究冠状动脉内皮和NO在选择性环加氧酶2(cyclooxygenase 2,COX-2)抑制剂尼美舒利(nimesulide)对抗心肌氧化损伤中的作用。离体大鼠心脏行Langendorff灌流,给予H2O2(140μmol/L)观察心脏收缩功能。用U-46619灌流心脏,使冠状动脉预收缩后,观察冠状动脉对内皮依赖性舒张因子5-HT和内皮非依赖性舒张因子硝普钠(sodium nitroprusside,SNP)的反应。结果显示:(1)与空白对照组(100%)相比,H2O2灌流20min后,左心室发展压[left ventricular developed pressure,LVDP,(54.8±4.0)%],和心室内压最大变化速率[±dp/dtmax,(50.8±3.1)%和(46.2±2.9)%]明显降低。H2O2灌流前尼美舒利(5μmol//L)预处理10min,能够显著抑制H2O2引起的LVDP和±dp/dtmax下降[(79.9±2.8)%,(80.3±2.6)%和(81.4±2.6)%,P<0.01]。(2)与空白对照组相比,H2O2灌流后,5-HT和SNP引起内皮依赖性和内皮非依赖性血管舒张功能均明显下降;而尼美舒利预处理10min能明显对抗内皮依赖性血管舒张功能的下降[(-22.2±4.2)%vsH2O2组(-6.0±2.5)%,P<0.01],但对其内皮非依赖性血管舒张功能的下降没有明显作用[(-2.0±1.8)%vsH2O2组(-7.0±3.5)%,P>0.05]。(3)一氧化氮合酶(nitric oxides ynthase,NOS)抑制剂L-NAME能够部分取消尼美舒利预处理对H2O2应激心脏心功能指标的改善作用[LVDP和±dp/dtmax分别为(60.2±2.1)%,(63.9±2.4)%和(63.1±2.9)%,P<0.01]。同时尼美舒利预处理10min能使H2O2应激心肌NO含量增加[(2.63±0.40)vs(1.36±0.23)nmol/gprotein,P<0.05],而L-NAME抑制此作用。(4)选择性COX-1抑制剂吡罗昔康(piroxicam)预处理不能抑制H2O2引起的LVDP和±dp/dtmax下降,但促进左心室舒张末压(left ventricular end diastolic pressure,LVEDP)升高;吡罗昔康对H2O2引起的内皮依赖性和内皮非依赖性血管舒张功能下降无显著作用。以上结果提示,选择性COX-2抑制剂尼美舒利能够对抗大鼠离体心肌氧化应激损伤,其机制可能是通过改善内皮依赖性血管舒张功能和增加心肌NO�Since a cyclooxygenase 2 （COX-2） inhibitor can reduce infarct size and improve contractility in ischemic myocardium, the aim of the present study was to explore whether COX-2 inhibitor nimesulide could protect myocardial function against oxidative stress injury in rat hearts, and to investigate the underlying mechanisms. The isolated rat hearts perfused by Langendorff method were exposed to 140 μmol/L of H202, and the cardiac contractility was measured. Then, the responses of coronary arteries, precontracted with U-46619, to the endothelium-dependent vasodilator serotonin （5-HT） and the endothelium-independent vasodilator sodium nitroprusside （SNP） were evaluated. The results were as follows： （l） In hearts exposed to H202 for 20 min, the left ventricular developed pressure [LVDP, （54.8±4.0）%] and maximal rate of rise/fall of ventricular pressure [±dp/dtmax （50.8±3.1）% and （46.2±2.9）%] were reduced compared with that in the control group （100%）. After pretreatment with nimesulide （5 μmol/L） for l0 min before H202 perfusion, LVDP and ±dp/dtmax were enhanced to （79.9±2.8）%, （80.3±2.6）% and （81.4±2.6）%, respectively （P〈0.01）, and this was partially abolished by the nitric oxide synthase （NOS） inhibitor L-NAME [（60.2±2.1）%, （63.9±2.4）% and （63.1±2.9）%, respectively, P〈0.01]. （2） The vasodilatation induced by 5-HT and SNP in H202-treated group was significantly less than that in the control group. Pretreatment with nimesulide for 10 min antagonized the decrease of endothelium-dependent vasodilatation in H202-treated group [（-22.2±4.2）% vs （-6.0±2.5）%, P〈0.01], but had no effect on the decline of endothelium-independent vasodilatation [（-2.0±1.8）% vs （-7.0±3.5）%, P〉0.05]. （3） Pretreatment with nimesulide for l0 min increased the NO production in H202-treated hearts [（2.63±0.40） vs （1.36±0.23） nmol/g protein, P〈0.05], and this was inhibited by L-NAME. （4） Pretreatment with the selective C

关 键 词：氧化应激 环加氧酶-2 心肌 血管阻力 一氧化氮合酶 

分 类 号：R541[医药卫生—心血管疾病]