Selective activation of the prostanoid EP3 receptor reduces myocardial infarct size in rodents

The cardioprotective effects of E-type prostaglandins (EPs) have been attri buted to vasodilatation, inhibition of platelet and neutrophil function (EP , mediated), and an unknown "cytoprotective effect." We have hypothesized t hat selective activation of EP, receptors may cause cardioprotection. The p rostanoid derivative ONO-AE-248 selectively binds to murine EP3 alpha ,rece ptors expressed in Chinese hamster ovary (CHO) cells (K-i, 15 nmol/L) and p revents the rise in cAMP caused by forskolin in CHO cells (IC50 approximate to 1 nmol/L) in which the EP3 alpha receptor had been expressed. In anesth etized rats subjected to regional myocardial ischemia for 25 or 45 minutes and 2 hours of reperfusion, infusion of ONO-AE-248 (5 mu g kg.l min(-1) IV) caused a significant reduction in infarct size, from 60 +/- 3% (n=8) to 36 +/- 6% (n=7) and from 78 +/- 2% (n=11) to 58 +/- 4% (n=9), respectively. T he reduction in infarct size caused by ONO-AE-248 in rats subjected to 25 m inutes of ischemia and reperfusion was abolished by a selective inhibitor o f ATP-sensitive potassium (K-ATP) channels, 5-hydroxydecanoate (n=6), and t he protein kinase C inhibitors staurosporine (n=6) and chelerythrine (n=6), In anesthetized rabbits subjected to coronary artery occlusion for 45 or 6 0 minutes and 2 hours of reperfusion, infusion of ONO-AE-248 (5 mu g(.) kg( -1) min(-1) IV) caused a significant reduction in infarct size, from 61 +/- 2% (n=10) to 36 +/- 4% (n=8) and from 63 +/- 4% (n=7) to 42 +/- 4% (n=7), respectively. The reduction in infarct size caused by ONO-AE-248 in the rab bit was also abolished by 5-hydroxydecanoate, The cardioprotective effect o f ONO-AE-248 in rats or rabbits was not associated with any hemodynamic eff ects. Selective activation of the prostanoid EP, receptor reduces myocardia l infarct size in rodents by a mechanism(s) that may involve the activation of protein kinase C and the opening of K-ATP channels.