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1 Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: shimmura{at}sc.itc.keio.ac.jp.
Prostacyclin and the PGE family (PGEs) 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, however, have revealed that PGI2 can bind not only to the IP but also to the EP receptors, suggesting a crosstalk 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, IP selective agonists, and ONO-AE-248 (EP3 selective agonist). Cell viability was assessed by trypan blue exclusion after 30 min of H2O2 superfusion. Carbaprostacyclin and ONO-AE-248 significantly improved cell survival during H2O2 superfusion; in contrast, IP selective agonists did not. The protective effect of carbaprostacyclin and ONO-AE-248 was completely abrogated by pretreatment with 5-hydroxydecanoate or glibenclamide. In the second series of experiments, the mitochondrial KATP channel opener, diazoxide, reversibly oxidized flavoproteins in control myocytes. Exposure to prostanoid analogs in itself had no effect on flavoprotein fluorescence. A second application of diazoxide in the presence of carbaprostacyclin or ONO-AE-248 significantly increased flavoprotein fluorescence compared with diazoxide alone but IP selective agonists did not. In conclusion, 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 KATP channels, and that this mechanism is essential for EP3-dependent protection.
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