COX-2-derived prostacyclin mediates opioid-induced late phase of preconditioning in isolated rat hearts.
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-PGF(1alpha) (a stable metabolite of PGI(2)) 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-PGF(1alpha) 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 PGI(2) (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 PGI(2) 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 PGI(2) synthase appears to underlie this cardioprotective phenomenon in the rat.
Shinmura
Ken
K
Department of Internal Medicine, Keio University School of Medicine, Tokyo 160 - 8582, Japan. shimmura@sc.itc.keio.ac.jp
Nagai
Maiko
M
Tamaki
Kayoko
K
Tani
Masato
M
Bolli
Roberto
R
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis / Q000096:biosynthesis; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000378:metabolism*; D006321:Heart / Q000187:drug effects* / Q000502:physiology*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism; D009294:Narcotics / Q000494:pharmacology*; D009578:Nitrobenzenes / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017465:Receptors, Opioid, delta / Q000819:agonists; D013449:Sulfonamides / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D001549:Benzamides; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D009294:Narcotics; D009578:Nitrobenzenes; D010879:Piperazines; D011720:Pyrazoles; D017465:Receptors, Opioid, delta; C115461:SC 560; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C083877:BW 373U86; D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat