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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

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Citing This Article：

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).