过刊浏览

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

吕萍萍, 范莹, 陈文良, 沈岳良, 朱立, 王琳琳, 陈莹莹

浙江大学医学院生理学系.浙江,杭州 310058

摘要

该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H_(2)O_(2)(140#mu#mol/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,H_(2)O_(2)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/dt_(max),(50.8±3.1)%和(46.2±2.9)%]明显降低。H_(2)O_(2)灌流前尼美舒利(5#mu#mol//L)预处理10min,能够显著抑制H_(2)O_(2)引起的LVDP和±dp/dt_(max)下降[(79.9±2.8)%,(80.3±2.6)%和(81.4±2.6)%,{sl P}<0.01]。(2)与空白对照组相比,H_(2)O_(2)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)%vs H_(2)O_(2)组(-6.0±2.5)%, {sl 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)%vs H_(2)O_(2)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H_(2)O_(2)应激心脏心功能指标的改善作用[LVDP和±dp/dt_(max)分别为(60.2±2.1)%,(63.9±2.4)%和(63.1±2.9)%, {sl P}<0.01] 。同时尼美舒利预处理10 min能使H_(2)O_(2)应激心肌NO含量增加[(2.63±0.40)vs(1.36±0.23)nmol/gprotein, {sl 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H_(2)O_(2)引起的LVDP和±dp/dt_(max)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H_(2)O_(2)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。

关键词： 氧化应激; 环加氧酶-2; 心肌; 血管阻力; 一氧化氮合酶

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

Lu Pingping, Fan Ying, Chen Wenliang, Shen Yueliang, Zhu Li, Wang Linlin, Chen Yingying

Department of Physiology, Zhejiang University School of Medicine.Hangzhou 310058,Zhejiang

Abstract

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 #mu#mol/L of H_(2)O_(2), 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 H_(2)O_(2) 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 #mu#mol/L) for 10 min before H_(2)O_(2)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 H_(2)O_(2)-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 H_(2)O_(2)-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 H_(2)O_(2)-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-1inhibitor piroxicam had no effect on LVDP and ±dp/dt_(max) in isolated hearts exposed to H_(2)O_(2), but the left ventricular end diastolic pressure (LVEDP) was much higher than that in the group treated with H_(2)O_(2) alone. Piroxicam did not influence the coronary resistance in H_(2)O_(2)-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.

Key words: oxidative stress;cyclooxygenase 2;Myocardium;vascular resistance;nitric oxide synthase

收稿日期：　　录用日期：

通讯作者：　　E-mail:

引用本文：

吕萍萍, 范莹, 陈文良, 沈岳良, 朱立, 王琳琳, 陈莹莹. 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[J]. 生理学报 2007; 59 (5): 674-680.

Lu Pingping, Fan Ying, Chen Wenliang, Shen Yueliang, Zhu Li, Wang Linlin, Chen Yingying. COX--2 inhibitor nimesulide protects rat heart against oxidative stress by improving endothelial function and enhancing NO production. Acta Physiol Sin 2007; 59 (5): 674-680 (in Chinese with English abstract).