Prostaglandin E 2 —Mediated Relaxation of the Ductus Arteriosus

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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 E 2 (PGE 2 ). PGE 2 acts through 3 G protein–coupled receptors (EP 2 , EP 3 , and EP 4 ) 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 PGE 2 . 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 PGE 2 could no longer be demonstrated. EP 2 , EP 3 , and EP 4 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 PGE 2 -induced relaxation in both age groups. Conclusions— Two mechanisms explain the increased sensitivity of the immature ductus to PGE 2 : (1) increased cAMP production because of increased binding of PGE 2 to the individual EP receptors and (2) increased potency of cAMP on protein kinase A–regulated pathways.