Cyclooxygenase-1 mediates the final stage of morphine-induced delayed cardioprotection in concert with cyclooxygenase-2.
OBJECTIVE
We sought to investigate the time course of morphine-induced delayed cardioprotection and examine the role of cyclooxygenase (COX) in this cardioprotective effect.


BACKGROUND
Cyclooxygenase-2 has been shown to be essential for the delayed cardioprotection induced by ischemic preconditioning and delta-opioid agonists.


METHODS
Male mice were subjected to 45 min of coronary artery occlusion followed by 120 min of reperfusion. Expressions of COX-2 and COX-1 were assessed by Western blotting, and the myocardial prostaglandin (PG)E2 and 6-keto-PGF(1-alpha) contents were measured using enzyme immunoassays.


RESULTS
A powerful infarct-sparing effect appeared 24 and 48 h after morphine preconditioning and faded after 72 h. After 24 h, the anti-infarct effect was associated with enhanced myocardial levels of COX-2, PGE2, and 6-keto-PGF(1-alpha), and no changes in COX-1 protein levels were found. Cardioprotection and increases in PGE2 and 6-keto-PGF(1-alpha) were completely abolished by the COX-2-selective inhibitor NS-398 and the non-selective COX inhibitor indomethacin, whereas the COX-1-selective inhibitor SC-560 had no effect. After 48 h, up-regulation of myocardial PGE2 and 6-keto-PGF(1-alpha) was also observed, and COX-1 expression was enhanced markedly, but only a slight increase in COX-2 expression was apparent. Cardioprotection and the increases in PGE2 and 6-keto-PGF(1-alpha) 48 h after morphine administration were abrogated only by indomethacin, and not by SC-560 or NS-398.


CONCLUSIONS
Morphine confers delayed cardioprotection via a COX-dependent pathway; COX-2 is essential for the cardioprotection observed in the initial stage (24 h), whereas, in the final stage (48 h), cardioprotection is mediated by COX-1 in concert with COX-2.
Jiang
Xiaojing
X
Department of Anesthesiology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Shi
Enyi
E
Nakajima
Yoshiki
Y
Sato
Shigehito
S
Ohno
Koji
K
Yue
Hui
H
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
D002316:Cardiotonic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011720:Pyrazoles; C115461:SC 560; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015121:6-Ketoprostaglandin F1 alpha; D009020:Morphine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; D015232:Dinoprostone; D007213:Indomethacin