title: COX-2 mediates morphine-induced delayed cardioprotection via an iNOS-dependent mechanism.
abstract: Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) have been shown to be mediators of cardioprotection induced by ischemic preconditioning and opioids. However, it is not known whether COX-2 is involved in morphine-induced cardioprotection accompanied with iNOS. Therefore, we investigated the role of COX-2 in morphine-induced cardioprotection and the effect of iNOS on COX-2. Myocardial ischemia was induced by a 45-min coronary artery occlusion in mice. Infarct size (IS) as a percentage of the area at risk (AAR) was determined by triphenyltetrazolium chloride staining. The COX-2-selective inhibitor NS-398 was used to investigate the role of COX-2. Expression of COX-2 was assessed by Western blotting, and the myocardial prostaglandin (PG)E2 and 6-keto-PGF(1alpha) contents were measured using enzyme immunoassays. The iNOS-selective inhibitor SMT and iNOS gene-knockout mice were used to investigate the effect of iNOS on COX-2. IS/AAR was reduced significantly 1 and 24 h after morphine preconditioning. The infarct-sparing effect 24 h after morphine administration, but not the cardioprotection 1 h later, was completely abolished by NS-398. Marked enhancement of myocardial COX-2 expression was measured 24 h after morphine preconditioning associated with up-regulation of myocardial contents of PGE2 and 6-keto-PGF(1alpha). Neither the level of COX-2 nor the contents of PGE2 and 6-keto-PGF(1alpha) were enhanced 1 h later. Administration of SMT and targeted abrogation of iNOS gene blocked the enhancement of myocardial PGE2 and 6-keto-PGF(1alpha) 24 h after morphine administration but did not inhibit the up-regulation of COX-2 expression. We concluded that COX-2 mediates morphine-induced delayed cardioprotection via an iNOS-dependent pathway.
authors.affiliation: Department of Anesthesiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, #431-3192, Japan.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Jiang
authors.forename: Enyi
authors.initials: E
authors.lastname: Shi
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Shigehito
authors.initials: S
authors.lastname: Sato
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects; D019157:Ischemic Preconditioning, Myocardial; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D002316:Cardiotonic Agents; D052246:Cyclooxygenase 2 Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D007550:Isothiuronium; D015121:6-Ketoprostaglandin F1 alpha; D009020:Morphine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C027744:S-methylisothiopseudouronium; D015232:Dinoprostone