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(Circulation. 1999;100:1751-1756.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Developmental Changes in Prostaglandin E₂ Receptor Subtypes in Porcine Ductus Arteriosus

Possible Contribution in Altered Responsiveness to Prostaglandin E₂

Mousumi Bhattacharya, PhD; Pierre Asselin, PhD; Pierre Hardy, MD; Anne-Marie Guerguerian, MD; Hitoshi Shichi, PhD; Xin Hou, MD, PhD; Daya R. Varma, MD, PhD; Asmàa Bouayad, MSc; Jean-Claude Fouron, MD; Ronald I. Clyman, MD; Sylvain Chemtob, MD, PhD

From the Departments of Pharmacology and Therapeutics, McGill University (M.B., D.R.V., S.C.), and the Departments of Pediatrics and Pharmacology, Université de Montréal (P.A., P.H., A.-M.G., X.H., A.B., J.-C.F., S.C.), Montréal, Quebec, Canada; the Department of Ophthalmology, Wayne State University, Detroit, Mich (H.S.); and the Department of Pediatrics, University of California at San Francisco (R.I.C.).

Correspondence to Sylvain Chemtob, MD, PhD, FRCP(C), Research Center, Ste-Justine Hospital, 3175 Côte Ste-Catherine, Montréal, Québec, Canada, H3T 1C5. E-mail chemtobs{at}ere.umontreal.ca

Background—Prostaglandin E₂ (PGE₂) is important in ductus arteriosus (DA) patency, but the types of functional PGE₂ receptors (EP) in the developing DA are not known. We postulated that age-dependent alterations in EP and/or their subtypes may possibly contribute to the reduced responsiveness of the newborn DA to PGE₂.

Methods and Results—We determined PGE₂ receptor subtypes by competition binding and immunoblot studies on the DA of fetal (75% and 90% gestation) and newborn (<45 minutes old) pigs. We studied the effects of EP receptor stimulation on cAMP signaling in vitro and on term newborn (<3 hours old) DA patency in vivo. Fetal pig DA expressed EP₂, EP₃, and EP₄ receptors equivalently, but not EP₁. In neonatal DA, EP₁, EP₃, and EP₄ were undetectable, whereas EP₂ density was similar in fetus and newborn. Prostaglandin-induced changes in cAMP mirrored binding data. 16,16-Dimethyl PGE₂ and 11-deoxy PGE₁ (EP₂/EP₃/EP₄ agonist) produced more cAMP in fetus than newborn, but butaprost (selective EP₂ agonist) caused similar cAMP increases in both; EP₃ and EP₄ ligands (M&B28767 and AH23848B, respectively) affected cAMP production only in fetus. After birth, administration of butaprost alone was as effective as 11-deoxy PGE₁ and 16,16-dimethyl PGE₂ in dilating DA in vivo.

Conclusions—The data reveal fewer PGE₂ receptors in the DA of the newborn than in that of the fetus; this may contribute to the decreased responsiveness of the DA to PGE₂ in newborn. Because EP₂ receptors seem to mediate the effects of PGE₂ on the newborn DA, one may propose that a selective EP₂ agonist may be preferred as a pharmacological agent to maintain DA patency in infants with certain congenital heart diseases.

Key Words: ductus arteriosus • receptors • prostaglandins • pediatrics

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