Prostaglandin E2-mediated relaxation of the ductus arteriosus: Effects of gestational age on G protein-coupled receptor expression, signaling, and vasomotor control

Nahid Waleh, Hiroki Kajino, Anne Marilise Marrache, David Ginzinger, Christine Roman, Steven R. Seidner, Timothy J.M. Moss, Jean Claude Fouron, Alejandro Vazquez-Tello, Sylvain Chemtob, Ronald I. Clyman

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Background - In the preterm newborn, a patent ductus arteriosus is in large part a result of the increased sensitivity of the immature ductus to prostaglandin E2 (PGE2). PGE2 acts through 3 G protein-coupled receptors (EP2, EP3, and EP4) that activate both adenyl cyclase and KATP channels. We explored these pathways to identify the mechanisms responsible for the increased sensitivity of the immature ductus to PGE2. Methods and Results - We measured EP receptor content (mRNA and protein), receptor binding, cAMP production, and isometric tension in rings of ductus taken from immature (65% gestation) and mature (95% gestation) sheep and baboon fetuses. Ductus relaxation and cAMP generation were augmented in response to selective EP receptor agonists in the immature ductus. 8-Br-cAMP, a stable cAMP analogue, produced greater relaxation in the immature ductus. In the presence of a selective protein kinase A inhibitor, Rp-8-CPT cAMPS, the developmental differences in sensitivity to PGE2 could no longer be demonstrated. EP2, EP3, and EP4 receptor densities were higher in immature ductus, despite similar receptor mRNA and protein contents at the 2 gestational ages. In contrast, forskolin and NaF, direct activators of adenyl cyclase and Gs, respectively, elicited comparable increases in cAMP in both age groups. KATP channel inhibition also had similar effects on PGE2-induced relaxation in both age groups. Conclusions - Two mechanisms explain the increased sensitivity of the immature ductus to PGE2: (1) increased cAMP production because of increased binding of PGE2 to the individual EP receptors and (2) increased potency of cAMP on protein kinase A-regulated pathways.

Original languageEnglish (US)
Pages (from-to)2326-2332
Number of pages7
JournalCirculation
Volume110
Issue number16
DOIs
StatePublished - Oct 19 2004

Keywords

  • Muscle, smooth
  • Receptors
  • Signal transduction
  • Vasodilation
  • Vessels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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