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Am J Physiol Heart Circ Physiol 283: H2534-H2543, 2002. First published August 8, 2002; doi:10.1152/ajpheart.00209.2002
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Vol. 283, Issue 6, H2534-H2543, December 2002

COX-2-derived prostacyclin mediates opioid-induced late phase of preconditioning in isolated rat hearts

Ken Shinmura1, Maiko Nagai1, Kayoko Tamaki1, Masato Tani1, and Roberto Bolli2

1 Department of Internal Medicine, Keio University School of Medicine, Tokyo 160 - 8582, Japan; and 2 Division of Cardiology, University of Louisville and Jewish Hospital Heart and Lung Institute, Louisville, Kentucky 40202

Opioids confer biphasic (early and late) cardioprotection against myocardial infarction by opening mitochondrial ATP-sensitive K+ channels. It is unknown whether cyclooxygenase-2 (COX-2), which mediates ischemia-induced late preconditioning, also mediates opioid-induced cardioprotection. Isolated perfused rat hearts were subjected to 20 min of global ischemia followed by 20 min of reperfusion. BW-373U86 (BW), a delta -opioid receptor agonist, was administered 1, 12, or 24 h before death. Recovery of left ventricular developed pressure (LVDP) after ischemia-reperfusion improved when BW was administered 1 or 24 h before ischemia (control: 57 ± 8, BW 1 h: 75 ± 5, BW 24 h: 85 ± 6%) but not when it was administered 12 h before (60 ± 5%). Levels of 6-keto-PGF1alpha (a stable metabolite of PGI2) in coronary effluent after 20 min of reperfusion were higher with 24-h BW pretreatment than in controls (1,053 ± 92 vs. 724 ± 81 pg/ml), whereas 6-keto-PGF1alpha levels at baseline did not differ. Administration of a selective COX-2 inhibitor, NS-398, abolished the late phase of cardioprotection (recovery of LVDP, 53 ± 8%) and attenuated the increase in PGI2 (706 ± 138 pg/ml) but did not block the early phase of cardioprotection. The selective COX-1 inhibitor SC-560 did not affect either phase of protection. Western immunoblotting revealed upregulation of PGI2 synthase protein 24 h after BW administration without changes in COX-1 and COX-2 protein levels. In conclusion, the late (but not the early) phase of delta -opioid receptor-induced preconditioning is mediated by COX-2. A functional coupling between COX-2 and upregulated PGI2 synthase appears to underlie this cardioprotective phenomenon in the rat.

myocardial ischemia; opioid; prostaglandin; reperfusion injury


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