Selective activation of the prostanoid EP(3) receptor reduces myocardial infarct size in rodents.
The cardioprotective effects of E-type prostaglandins (EPs) have been attributed to vasodilatation, inhibition of platelet and neutrophil function (EP(2) mediated), and an unknown "cytoprotective effect." We have hypothesized that selective activation of EP(3) receptors may cause cardioprotection. The prostanoid derivative ONO-AE-248 selectively binds to murine EP(3alpha) receptors expressed in Chinese hamster ovary (CHO) cells (K(i), 15 nmol/L) and prevents the rise in cAMP caused by forskolin in CHO cells (IC(50) approximately 1 nmol/L) in which the EP(3alpha) receptor had been expressed. In anesthetized rats subjected to regional myocardial ischemia for 25 or 45 minutes and 2 hours of reperfusion, infusion of ONO-AE-248 (5 microg kg(-1). 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. The reduction in infarct size caused by ONO-AE-248 in rats subjected to 25 minutes of ischemia and reperfusion was abolished by a selective inhibitor of ATP-sensitive potassium (K(ATP)) channels, 5-hydroxydecanoate (n=6), and the protein kinase C inhibitors staurosporine (n=6) and chelerythrine (n=6). In anesthetized rabbits subjected to coronary artery occlusion for 45 or 60 minutes and 2 hours of reperfusion, infusion of ONO-AE-248 (5 microg. 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 rabbit was also abolished by 5-hydroxydecanoate. The cardioprotective effect of ONO-AE-248 in rats or rabbits was not associated with any hemodynamic effects. Selective activation of the prostanoid EP(3) receptor reduces myocardial infarct size in rodents by a mechanism(s) that may involve the activation of protein kinase C and the opening of K(ATP) channels.
Zacharowski
K
K
William Harvey Research Institute, St Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK.
Olbrich
A
A
Piper
J
J
Hafner
G
G
Kondo
K
K
Thiemermann
C
C
D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology*; D017202:Myocardial Ischemia / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011982:Receptors, Prostaglandin / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014162:Transfection; D020107:Troponin T / Q000037:antagonists & inhibitors / Q000378:metabolism
C121546:ONO AE 248; C545648:Ptger3 protein, mouse; C545651:Ptger4 protein, mouse; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020107:Troponin T; D005576:Colforsin; D000242:Cyclic AMP; D015232:Dinoprostone