title: COX-2 inhibitor nimesulide protects rat heart against oxidative stress by improving endothelial function and enhancing NO production.
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 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.
authors.affiliation: Department of Physiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Lv
authors.forename: Ying
authors.initials: Y
authors.lastname: Fan
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Chen
authors.forename: Yue-Liang
authors.initials: YL
authors.lastname: Shen
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Wang
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Chen
mesh_terms: D000818:Animals; D003331:Coronary Vessels; D052246:Cyclooxygenase 2 Inhibitors; D004730:Endothelium, Vascular; D045462:Endothelium-Dependent Relaxing Factors; D006321:Heart / Q000187:drug effects*; D006861:Hydrogen Peroxide; D015428:Myocardial Reperfusion Injury; D009206:Myocardium; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin; D013449:Sulfonamides / Q000494:pharmacology*; D014664:Vasodilation; D014665:Vasodilator Agents
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D045462:Endothelium-Dependent Relaxing Factors; D013449:Sulfonamides; D014665:Vasodilator Agents; D009569:Nitric Oxide; D012701:Serotonin; D006861:Hydrogen Peroxide; C012655:nimesulide; D019331:NG-Nitroarginine Methyl Ester