TY - JOUR
T1 - Prostaglandin E2-mediated relaxation of the ductus arteriosus
T2 - Effects of gestational age on G protein-coupled receptor expression, signaling, and vasomotor control
AU - Waleh, Nahid
AU - Kajino, Hiroki
AU - Marrache, Anne Marilise
AU - Ginzinger, David
AU - Roman, Christine
AU - Seidner, Steven R.
AU - Moss, Timothy J.M.
AU - Fouron, Jean Claude
AU - Vazquez-Tello, Alejandro
AU - Chemtob, Sylvain
AU - Clyman, Ronald I.
PY - 2004/10/19
Y1 - 2004/10/19
N2 - 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.
AB - 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.
KW - Muscle, smooth
KW - Receptors
KW - Signal transduction
KW - Vasodilation
KW - Vessels
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UR - http://www.scopus.com/inward/citedby.url?scp=6444228049&partnerID=8YFLogxK
U2 - 10.1161/01.CIR.0000145159.16637.5D
DO - 10.1161/01.CIR.0000145159.16637.5D
M3 - Article
C2 - 15477420
AN - SCOPUS:6444228049
SN - 0009-7322
VL - 110
SP - 2326
EP - 2332
JO - Circulation
JF - Circulation
IS - 16
ER -