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

Abstract

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.

• Authors: Ken Shinmura, Maiko Nagai, Kayoko Tamaki, Masato Tani, Roberto Bolli
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 283 Issue 6 Pg. H2534-43 (Dec 2002) ISSN: 0363-6135 [Print] United States
• PMID: 12388283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzamides
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Isoenzymes
• Membrane Proteins
• Narcotics
• Nitrobenzenes
• Piperazines
• Pyrazoles
• Receptors, Opioid, delta
• SC 560
• Sulfonamides
• N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
• BW 373U86
• 6-Ketoprostaglandin F1 alpha
• Epoprostenol
• Cyclooxygenase 1
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Ptgs1 protein, rat

Topics

• 6-Ketoprostaglandin F1 alpha (analysis, biosynthesis)
• Animals
• Benzamides (pharmacology)
• Cyclooxygenase 1
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (pharmacology)
• Dose-Response Relationship, Drug
• Epoprostenol (metabolism)
• Heart (drug effects, physiology)
• In Vitro Techniques
• Ischemic Preconditioning, Myocardial
• Isoenzymes (metabolism)
• Male
• Membrane Proteins
• Myocardial Reperfusion
• Myocardium (metabolism)
• Narcotics (pharmacology)
• Nitrobenzenes (pharmacology)
• Piperazines (pharmacology)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Pyrazoles (pharmacology)
• Rats
• Rats, Inbred F344
• Receptors, Opioid, delta (agonists)
• Sulfonamides (pharmacology)
• Ventricular Function, Left (drug effects, physiology)