ah-23848 and 8-bromoadenosine

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.. 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.. 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.

Topics: 16,16-Dimethylprostaglandin E2; 8-Bromo Cyclic Adenosine Monophosphate; Adenosine; Adenylyl Cyclases; Alprostadil; Animals; Biphenyl Compounds; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dinoprostone; Ductus Arteriosus; Enzyme Activation; Female; Gestational Age; Glyburide; Indomethacin; Isometric Contraction; NG-Nitroarginine Methyl Ester; Nitroprusside; Papio; Potassium Channels; Pregnancy; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Sheep; Signal Transduction; Sodium Fluoride; Thionucleotides; Vasomotor System