Chronic in utero cyclooxygenase inhibition alters PGE2-regulated ductus arteriosus contractile pathways and prevents postnatal closure.

Reese J, Waleh N, Poole SD, Brown N, Roman C, Clyman RI
Pediatr Res. 2009 66 (2): 155-61

PMID: 19390487 · PMCID: PMC3066019 · DOI:10.1203/PDR.0b013e3181aa07eb

Although prostaglandin E2 (PGE2) vasodilates the ductus arteriosus, tocolysis with cyclooxygenase (COX) inhibitors delays postnatal ductus arteriosus closure. We used fetal mice and sheep to determine whether PGE2 has a role in the development of ductus contractility that is distinct from its function as a vasodilator. Prolonged exposure of fetal ductus to PGE2 in vitro increased the expression of CaL- and K+-channel genes (CaLalpha1c, CaLbeta2, Kir6.1, and Kv1.5, which regulate oxygen-induced constriction) without affecting the genes that regulate Rho-kinase-mediated calcium sensitization. Conversely, chronic exposure to COX inhibitors in utero decreased expression of CaL- and K+-channel genes, without affecting Rho-kinase-associated genes. Chronic COX inhibition in utero decreased the ductus' in vitro contractile response to stimuli that use CaL- and K+-channels (like O2 and K+), whereas the response to stimuli that act through Rho-kinase-mediated pathways (like U46619) was not significantly affected. Phosphodiesterase expression, which decreases the ductus' sensitivity to cAMP- or cGMP-dependent vasodilators, was increased by PGE2 exposure and decreased by COX inhibition, respectively. These studies identify potential downstream effectors of a PGE2-mediated, developmental program, regulating oxygen-induced ductus closure. Alterations in these effectors may explain the increased risk of patent ductus arteriosus (PDA) after in utero COX inhibition.

MeSH Terms (15)

Animals Cyclooxygenase 1 Cyclooxygenase 2 Cyclooxygenase Inhibitors Dinoprostone Ductus Arteriosus Female Gene Expression Regulation, Developmental Humans Isoenzymes Mice Oxygen Pregnancy Sheep Vasoconstriction

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