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 PGI 2 can bind not only to IP, but also to EP, receptors, suggesting cross talk between PGI2 and PGEs. The mechanism(s) whereby PGI 2 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 EP 3-selective agonist). Cell viability was assessed by trypan blue exclusion after 30 min of H2O2 superfusion. cPGI 2 and ONO-AE-248 significantly improved cell survival during H 2O2 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+ (KATP) 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 PGI 2 analogs protect cardiac myocytes from oxidative stress mainly via activation of EP3. The data also indicate that activation of EP 3 receptors primes the opening of mitochondrial KATP channels and that this mechanism is essential for EP3-dependent protection.
|ジャーナル||American Journal of Physiology - Heart and Circulatory Physiology|
|出版ステータス||Published - 2005 5|
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)