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

本文旨在研究冠状动脉内皮和NO在选择性环加氧酶2（cyclooxygenase2,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（140Bmol／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（sodiumnitroprusside,SNP）的反应。结果显示：（1）与空白对照组（100％）相比,H202灌流20min后,左心室发展压[left ventriculardevelo pedpressure,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μdp/dtmax下降[（79．9±2．8）％,（80．3±2．6）％和（81．4±2．6）％,P〈0．0l]。（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〈0．0l],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）％vsH202组（-7．0±3．5）％,P〉0．05]。（3）一氧化氮合酶（nitric oxide synthase,NOS）抑制剂L-NAME能够部分取消尼美舒利预处理对H20,应激心脏心功能指标的改善作用ILVDP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H202应激心肌NO含量增加[（2．63±0．40）vs（1．36±0．23）nmol／gprotein,P〈0．051,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H202引起的LVDP和±dp/dtmax下降,但促进左心室舒张末压（1eftventricular end diastolicpressure,LVEDP）升高;吡罗昔康对H202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含量起作用。

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

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 mumol/L of H2O2, 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: (1) In hearts exposed to H2O2 for 20 min, the left ventricular developed pressure [LVDP, (54.8 +/- 4.0)%] and maximal rate of rise/fall of ventricular pressure [+/-dp/dt(max), (50.8 +/- 3.1)% and (46.2 +/- 2.9) %] were reduced compared with that in the control group (100%). After pretreatment with nimesulide (5 mumol/L) for 10 min before H2O2 perfusion, LVDP and +/-dp/dt(max) 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 H2O2-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 H2O2-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 10 min increased the NO production in H2O2-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 COX-1 inhibitor piroxicam had no effect on LVDP and +/-dp/dt(max) in isolated hearts exposed to H2O2, but the left ventricular end diastolic pressure (LVEDP) was much higher than that in the group treated with H2O2 alone. Piroxicam did not influence the coronary resistance in H2O2-treated rat hearts. These data suggest that the COX-2 inhibitor nimesulide improves myocardial function in rat hearts suffering from oxidative stress, and this may be through an improvement in endothelium-dependent arterial relaxation and an enhancement of NO production in rat heart.