This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zacharowski, K. Articles by Thiemermann, C. Search for Related Content PubMed PubMed Citation Articles by Zacharowski, K. Articles by Thiemermann, C. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Attack Related Collections Cell signalling/signal transduction Ischemic biology - basic studies Receptor pharmacology Other Vascular biology

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2141-2147.)
© 1999 American Heart Association, Inc.

Vascular Biology

Selective Activation of the Prostanoid EP₃ Receptor Reduces Myocardial Infarct Size in Rodents

Kai Zacharowski; Antje Olbrich; Julie Piper; Gerd Hafner; Kigen Kondo; Christoph Thiemermann

From the William Harvey Research Institute (K.Z., A.O., J.P., C.T.), St Bartholomew's and the Royal London School of Medicine and Dentistry, London, UK; Klinische Chemie (G.H.), Gutenberg-Universitat, Mainz, Germany; and the Minase Research Institute (K.K.), ONO Pharmaceuticals Co Ltd, Osaka, Japan.

Correspondence to Prof C. Thiemermann, The William Harvey Research Institute, Charterhouse Square, London EC1 M 6BQ, UK. E-mail C.Thiemermann{at}mds.qmw.ac.uk

Abstract—The cardioprotective effects of E-type prostaglandins (EPs) have been attributed to vasodilatation, inhibition of platelet and neutrophil function (EP₂ mediated), and an unknown "cytoprotective effect." We have hypothesized that selective activation of EP₃ receptors may cause cardioprotection. The prostanoid derivative ONO-AE-248 selectively binds to murine EP₃ 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 (IC₅₀ 1 nmol/L) in which the EP₃ 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 µg · 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 µg · 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 EP₃ 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.

Key Words: E-type prostaglandin–receptor agonist • myocardial injury • rodents • protein kinase C • ATP-sensitive potassium channels

This article has been cited by other articles:

				Y. Shoji, M. Takahashi, N. Takasuka, N. Niho, T. Kitamura, H. Sato, T. Maruyama, Y. Sugimoto, S. Narumiya, T. Sugimura, et al. Prostaglandin E receptor EP3 deficiency modifies tumor outcome in mouse two-stage skin carcinogenesis Carcinogenesis, December 1, 2005; 26(12): 2116 - 2122. [Abstract] [Full Text] [PDF]

				M. Martin, J. Meyer-Kirchrath, G. Kaber, C. Jacoby, U. Flogel, J. Schrader, U. Ruther, K. Schror, and T. Hohlfeld Cardiospecific Overexpression of the Prostaglandin EP3 Receptor Attenuates Ischemia-Induced Myocardial Injury Circulation, July 19, 2005; 112(3): 400 - 406. [Abstract] [Full Text] [PDF]

				K. Shinmura, K. Tamaki, T. Sato, H. Ishida, and R. Bolli Prostacyclin attenuates oxidative damage of myocytes by opening mitochondrial ATP-sensitive K+ channels via the EP3 receptor Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2093 - H2101. [Abstract] [Full Text] [PDF]

				A. Hobbs, P. Foster, C. Prescott, R. Scotland, and A. Ahluwalia Natriuretic Peptide Receptor-C Regulates Coronary Blood Flow and Prevents Myocardial Ischemia/Reperfusion Injury: Novel Cardioprotective Role for Endothelium-Derived C-Type Natriuretic Peptide Circulation, September 7, 2004; 110(10): 1231 - 1235. [Abstract] [Full Text] [PDF]

				C.-Y. Xiao, K.-i. Yuhki, A. Hara, T. Fujino, S. Kuriyama, T. Yamada, K. Takayama, O. Takahata, H. Karibe, T. Taniguchi, et al. Prostaglandin E2 Protects the Heart From Ischemia-Reperfusion Injury via Its Receptor Subtype EP4 Circulation, May 25, 2004; 109(20): 2462 - 2468. [Abstract] [Full Text] [PDF]

				M. Loubani, A. Hassouna, and M. Galinanes Delayed preconditioning of the human myocardium: signal transduction and clinical implications Cardiovasc Res, February 15, 2004; 61(3): 600 - 609. [Abstract] [Full Text] [PDF]

				K.-J. Bar, G. Natura, A. Telleria-Diaz, P. Teschner, R. Vogel, E. Vasquez, H.-G. Schaible, and A. Ebersberger Changes in the Effect of Spinal Prostaglandin E2 during Inflammation: Prostaglandin E (EP1-EP4) Receptors in Spinal Nociceptive Processing of Input from the Normal or Inflamed Knee Joint J. Neurosci., January 21, 2004; 24(3): 642 - 651. [Abstract] [Full Text] [PDF]

				L. Calabresi, G. Rossoni, M. Gomaraschi, F. Sisto, F. Berti, and G. Franceschini High-Density Lipoproteins Protect Isolated Rat Hearts From Ischemia-Reperfusion Injury by Reducing Cardiac Tumor Necrosis Factor-{alpha} Content and Enhancing Prostaglandin Release Circ. Res., February 21, 2003; 92(3): 330 - 337. [Abstract] [Full Text] [PDF]

				R. Bolli, K. Shinmura, X.-L. Tang, E. Kodani, Y.-T. Xuan, Y. Guo, and B. Dawn Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning Cardiovasc Res, August 15, 2002; 55(3): 506 - 519. [Abstract] [Full Text] [PDF]

				J. Liu, T. Akahoshi, S. Jiang, R. Namai, H. Kitasato, H. Endo, T. Kameya, and H. Kondo Induction of neutrophil death resembling neither apoptosis nor necrosis by ONO-AE-248, a selective agonist for PGE2 receptor subtype 3 J. Leukoc. Biol., August 1, 2000; 68(2): 187 - 193. [Abstract] [Full Text]

				S. L Borgland, M. Connor, R. M Ryan, H. J Ball, and M. J Christie Prostaglandin E2 inhibits calcium current in two sub-populations of acutely isolated mouse trigeminal sensory neurons J. Physiol., March 1, 2002; 539(2): 433 - 444. [Abstract] [Full Text] [PDF]