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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含量起作用。
This article aims to investigate the role of coronary endothelial endothelium and nitric oxide in the prevention of myocardial oxidative damage by a selective cyclooxygenase 2 (COX-2) inhibitor, nimesulide. Isolated rat heart was perfused with Langendorff, and the cardiac systolic function was observed by H2O2 (140μmol / L). After perfusing the heart with U-46619 and pre-contracting the coronary arteries, the response of coronary arteries to endothelium-dependent relaxing factor 5-HT and endothelium-independent relaxation factor sodium nitroprusside (SNP) was observed. The results showed that: (1) Compared with the blank control group (100%), left ventricular developed pressure (LVDP, (54.8 ± 4.0)%] and maximum rate of change of ventricular pressure ± dp / dtmax, (50.8 ± 3.1)% and (46.2 ± 2.9)%], respectively. Pretreatment with nimesulide (5μmol / L) for 10min before H2O2 perfusion significantly reduced the LVDP and ± dp / dtmax induced by H2O2 [(79.9 ± 2.8)%, (80.3 ± 2.6)% and (81.4 ± 2.6) %, P <0.01]. (2) Compared with the blank control group, 5-HT and SNP induced a significant decrease of endothelium-dependent and endothelium-independent vasodilation after H2O2 perfusion, while nimesulide preconditioning for 10min significantly inhibited endothelium-dependent vascular The decrease of diastolic function [(-22.2 ± 4.2)% vs H2O2 group (-6.0 ± 2.5)%, P <0.01] had no significant effect on the decrease of endothelium-independent vasodilation [(-2.0 ± 1.8)%] vs H2O2 group (-7.0 ± 3.5)%, P> 0.05]. (3) Nitric oxide ynthase (NOS) inhibitor L-NAME partially abolished the improvement effect of nimesulide preconditioning on heart function of H2O2 stress heart [LVDP and ± dp / dtmax were ( 60.2 ± 2.1)%, (63.9 ± 2.4)% and (63.1 ± 2.9)% respectively, P <0.01]. Meanwhile, pretreatment with nimesulide for 10 min increased NO content in H2O2 stress-induced myocardium (2.63 ± 0.40 vs 1.36 ± 0.23 nmol / gprotein, P <0.05), while L-NAME inhibited this effect. (4) Pretreatment with piroxicam, a selective COX-1 inhibitor, failed to inhibit the decrease of LVDP and ± dp / dtmax caused by H2O2, but promoted the increase of left ventricular end diastolic pressure (LVEDP) Rosixikang H2O2-induced endothelium-dependent and endothelial-dependent vasodilation decreased no significant effect. The above results suggest that selective COX-2 inhibitor nimesulide can antagonize oxidative stress injury in isolated rat myocardium, and its mechanism may be through improving endothelium-dependent vasodilation and increasing NO content in myocardium.