Published Online
on October 11, 2004

A more recent version of this article appeared on October 19, 2004

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Submitted on March 1, 2004
Accepted on May 20, 2004

Prostaglandin E₂-Mediated Relaxation of the Ductus Arteriosus. Effects of Gestational Age on G Protein-Coupled Receptor Expression, Signaling, and Vasomotor Control

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

From the Cardiovascular Research Institute and Department of Pediatrics (N.W., H.K., C.R., R.I.C.), and the Cancer Center (D.G.), University of California, San Francisco, San Francisco, Calif; the Department of Pediatrics, University of Texas Health Science Center, San Antonio, Tex (S.R.S.); the School of Women’s and Infants’ Health, University of Western Australia, Western Australia (T.J.M.M.); and the Departments of Cardiology, Pediatrics, and Physiology, Université de Montréal, Quebec, Canada (A.M.M., J.-C.F., A.V.-T., S.C.).

^* To whom correspondence should be addressed. E-mail: ric{at}itsa.ucsf.edu.

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 K_ATP 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 G_s, respectively, elicited comparable increases in cAMP in both age groups. K_ATP 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.

Key words: muscle, smooth • receptors • signal transduction • vasodilation • vessels

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