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

Xiaojing Jiang, MD^_*, Enyi Shi, MD, PhD, Yoshiki Nakajima, MD, PhD^_*, Shigehito Sato, MD^_*,_*, Koji Ohno, PhD and Hui Yue, MD^_*

^_* Department of Anesthesiology, Hamamatsu University School of Medicine, Hamamatsu, Japan
First Department of Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan
Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Manuscript received December 15, 2004; revised manuscript received January 21, 2005, accepted February 1, 2005.

^_* Reprint requests and correspondence: Dr. Shigehito Sato, Department of Anesthesiology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, #431-3192, Japan. (Email: ssato{at}hama-med.ac.jp).

OBJECTIVES: 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.

Abbreviations and Acronyms   COX = cyclooxygenase   IN = indomethacin   M = morphine   NS = NS-398   PG = prostaglandin   SC = SC-560

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