In vivo reopening of the neonatal ductus arteriosus by a prostanoid EP4-receptor agonist in the rat.
Prostaglandin E1 is used to reopen the constricted ductus arteriosus in neonates with ductus-dependent circulation. To clarify possible prostanoid receptor agonists that can reopen the neonatal ductus with fewer side effects, we studied in vivo reopening of the neonatal ductus arteriosus by AE1-329, a prostanoid EP4-receptor agonist, in the rat. Neonatal rats were incubated at 33 degrees C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing. Intraesophageal pressure was measured with a Millar micro-tip transducer. The ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 and 0.08 mm at 0 and 60 min after birth. PGE1 and AE1-329, injected subcutaneously at 60 min after birth, dilated the ductus dose-dependently. Thirty minutes after injection of 10 ng/g of PGE1 and AE1-329, the ductus diameter was 0.52 and 0.65 mm, respectively. The ductus-dilating effect of PGE1 was maximal at 15-30 min, and disappeared at 2 h. The ductus-dilating effect of AE1-329 was prolonged, the ductus was widely open at 6 h, and closed at 12 h after injection of 10 ng/g AE1-329. AE1-259-01 (EP2 agonist) (100 ng/g) did not dilate the neonatal ductus. Respiration was depressed by PGE1, but not by AE1-329. These results indicate the major role of EP4 in the neonatal ductus and that AE1-329, an EP4 agonist, can be used to dilate the neonatal constricted ductus without the side effects shown by EP3, including apnea.
Momma
Kazuo
K
Section of Pediatric Cardiology, Tokyo Women's Medical University, Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan. prmomma@hij.twmu.ac.jp
Toyoshima
Katsuaki
K
Takeuchi
Daiji
D
Imamura
Shinichiro
S
Nakanishi
Toshio
T
D000527:Alprostadil / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004373:Ductus Arteriosus / Q000187:drug effects*; D005260:Female; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058309:Receptors, Prostaglandin E, EP4 Subtype
C545652:Ptger4 protein, rat; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000527:Alprostadil