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This Article Full Text Full Text (PDF) All Versions of this Article: 288/5/H2093    most recent 01003.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Shinmura, K. Articles by Bolli, R. Search for Related Content PubMed PubMed Citation Articles by Shinmura, K. Articles by Bolli, R.

Prostacyclin attenuates oxidative damage of myocytes by opening mitochondrial ATP-sensitive K⁺ channels via the EP₃ receptor

¹epartment of Internal Medicine, Keio University School of Medicine, Tokyo; ²Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba; ³Department of Physiology, Tokai University School of Medicine, Isehara, Japan; and ⁴Institute of Molecular Cardiology, University of Louisville, Louisville, Kentucky

Submitted 1 October 2004 ; accepted in final form 14 December 2004

Prostacyclin (PGI₂) and the PGE family alleviate myocardial ischemia-reperfusion injury and limit oxidative damage. The cardioprotective effects of PGI₂ have been traditionally ascribed to activation of IP receptors. Recent advances in prostanoid research have revealed that PGI₂ can bind not only to IP, but also to EP, receptors, suggesting cross talk between PGI₂ and PGEs. The mechanism(s) whereby PGI₂ protects myocytes from oxidative damage and the specific receptors involved remain unknown. Thus fresh isolated adult rat myocytes were exposed to 200 µM H₂O₂ with or without carbaprostacyclin (cPGI₂), IP-selective agonists, and ONO-AE-248 (an EP₃-selective agonist). Cell viability was assessed by trypan blue exclusion after 30 min of H₂O₂ superfusion. cPGI₂ and ONO-AE-248 significantly improved cell survival during H₂O₂ superfusion; IP-selective agonists did not. The protective effect of cPGI₂ and ONO-AE-248 was completely abrogated by pretreatment with 5-hydroxydecanoate or glibenclamide. In the second series of experiments, the mitochondrial ATP-sensitive K⁺ (K_ATP) channel opener diazoxide (Dx) reversibly oxidized flavoproteins in control myocytes. Exposure to prostanoid analogs alone had no effect on flavoprotein fluorescence. A second application of Dx in the presence of cPGI₂ or ONO-AE-248 significantly increased flavoprotein fluorescence compared with Dx alone, but IP-selective agonists did not. This study demonstrates that PGI₂ analogs protect cardiac myocytes from oxidative stress mainly via activation of EP₃. The data also indicate that activation of EP₃ receptors primes the opening of mitochondrial K_ATP channels and that this mechanism is essential for EP₃-dependent protection.

flavoprotein fluorescence; IP receptor; oxidative stress; prostaglandin

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