Prostaglandin E2 receptor subtype EP-2 is not involved in the induction of non-pregnant guinea pig uterine contractions associated with terminal pregnancy.
Prostaglandin E2 (PGE2) exerts its biological effects through 4 different receptor subtypes, EP-1, EP-2, EP-3, and EP-4. Recently we have demonstrated the importance of the prostaglandin E2 receptor subtype EP-2 in the healing of bone defects and fractures. This discovery led to the identification of CP-533,536, an EP-2 selective agonist, a promising therapeutic alternative for the enhancement of bone healing and the treatment of fractures (J Bone Miner Res 18 (2003) 2033). PGE2 has a myriad of effects throughout the body including the induction of uterine contractions, which results in termination of pregnancies. Our objective in this study was to determine the role of the EP-2 receptor and specifically that of CP-533,536, an EP-2 specific agonist, to induce uterine contractions and terminate pregnancy in guinea pigs, an animal model of human pregnancy. Preliminary experiments confirmed earlier reports that the guinea pig uterus was more sensitive than that of the rat. The guinea pig uterus contains the four PGE2 receptor subtypes, and ex vivo treatment of the uterus with PGE2 as expected causes profound uterine contractions. However, using receptor selective prostaglandin agonists including CP-533,536 we showed that the EP-1 and 3 receptors not the EP-2 receptor is responsible for the induction of uterine contractions of PGE2. Further, CP-533,536 did not antagonize the ability of PGE2 to induce uterine contractions in this model.
Lebel
Wes
W
Pfizer Global Research and Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA.
Riccardi
Keith
K
Grasser
W A
WA
Terry
Ketti
K
Thompson
David
D
Paralkar
V M
VM
D000818:Animals; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D016595:Misoprostol / Q000494:pharmacology; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013997:Time Factors; D014590:Uterine Contraction / Q000187:drug effects / Q000502:physiology*; D014599:Uterus / Q000187:drug effects / Q000502:physiology*
C092396:17-phenyltrinorprostaglandin E2; C475539:CP533536; C545644:PTGER2 protein, human; C545646:Ptger2 protein, rat; D011725:Pyridines; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D016595:Misoprostol; D015232:Dinoprostone