Abstract 105 Cardiology: Signaling Mechanisms and Cardiovascular Function Platform, Sunday, 5/2

Prostaglandin E2 (PGE2) is important for ductus arteriosus (DA) tone; but the type(s) of functional PGE2 receptors (EP) in the developing DA are not known. We tested the postulate that fewer and/or specific changes in EP subtypes in the DA of the newborn compared with that of the fetus may provide at least a partial explanation for the reduced responsiveness to PGE2 of the newborn DA. We determined PGE2 receptor subtypes by competition binding and immunoblot studies on DA of fetal (∼75% and 90% gestation) and newborn (<45 min old) pigs and we studied effects of EP receptor stimulation on cAMP signaling in vitro, and on term newborn (<3 h old) DA patency in vivo. Fetal pig DA expressed equivalently EP2, EP3 and EP4 receptors, but not EP1. In neonatal DA, EP1, EP3 and EP4 were undetectable, whereas EP2 density was similar in fetus and newborn. Prostaglandin-induced changes in cAMP mirrored binding data. 16,16-Dimethyl PGE2 (which stimulates all EP receptors) and 11-deoxy PGE1 (EP2/EP3/EP4 agonist) produced more cAMP in fetus than newborn, but butaprost (selective EP2 agonist) caused similar cAMP increases in both; EP3 and EP4 ligands (M&B28767 and AH23848B respectively) affected cAMP production only in fetus. After birth, administration of only butaprost was as effective as 11-deoxy PGE1 and 16,16 dimethyl PGE2 in dilating DA in vivo. Data reveal fewer PGE2 receptors coupled to relaxation in the DA of the newborn than in that of the fetus; this may contribute to the decreased responsiveness of the DA to PGE2 in newborn. Since EP2 receptors seem to mediate effects of PGE2 on the newborn DA, one may propose that a selective EP2 agonist may be preferred as a pharmacologic agent to maintain DA patency in infants with certain congenital heart disease.

Funded by Medical Research Council of Canada and Heart & Stroke Foundation of Quebec.