Cyclooxygenase-1 Mediates the Final Stage of Morphine-Induced Delayed Cardioprotection in Concert With Cyclooxygenase-2

Abstract

We sought to investigate the time course of morphine-induced delayed cardioprotection and examine the role of cyclooxygenase (COX) in this cardioprotective effect. Cyclooxygenase-2 has been shown to be essential for the delayed cardioprotection induced by ischemic preconditioning and delta-opioid agonists. 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. 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. 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.