title: Regulation of phosphodiesterase 3 in the pulmonary arteries during the perinatal period in sheep.
abstract: The role of cAMP in the pulmonary vasculature during the transition from intrauterine to extrauterine life is poorly understood. We hypothesized that cAMP levels are regulated by alterations in phosphodiesterase 3 (PDE3), which hydrolyzes cAMP. PDE3 protein expression and hydrolytic activity were increased in the resistance pulmonary arteries (PA) from spontaneously breathing 1-d-old (1dSB) lambs relative to equivalent-gestation fetuses. This was accompanied by a decrease in steady-state cAMP. Ventilation with 21% O2 and 100% O2 for 24 h disrupted the normal transition, whereas ventilation with 100% O2 + inhaled NO (iNO) for 24 h restored both PDE3 activity and cAMP to 1dSB levels. Consistent with these findings, relaxation to milrinone, a PDE3 inhibitor, was greater in the PA isolated from 1dSB and 100% O2 + iNO lambs, relative to fetal, 21% O2, and 100% O2 lambs. In conclusion, PDE3 expression and activity in the PA dramatically increase after birth, with a concomitant decrease in steady-state cAMP. Ventilation with either 21% O2 or 100% O2 blunts this PDE3 increase, whereas iNO restores PDE3 activity to levels equivalent to 1dSB lambs. The vasodilatory effects of milrinone were most pronounced in vessels from lambs with the highest PDE3 activity, i.e., 1dSB and 100% O2 + iNO lambs. Thus, milrinone may be most beneficial when used in conjunction with iNO.
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Chen
authors.forename: Satyan
authors.initials: S
authors.lastname: Lakshminrusimha
authors.forename: Lyubov
authors.initials: L
authors.lastname: Czech
authors.forename: Beezly S
authors.initials: BS
authors.lastname: Groh
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Gugino
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: Farrow
authors.forename: Robin H
authors.initials: RH
authors.lastname: Steinhorn
mesh_terms: D000280:Administration, Inhalation; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D000242:Cyclic AMP / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D007118:Immunoassay; D007150:Immunohistochemistry; D020105:Milrinone / Q000494:pharmacology*; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology; D010100:Oxygen / Q000008:administration & dosage / Q000494:pharmacology; D058987:Phosphodiesterase 3 Inhibitors; D011651:Pulmonary Artery / Q000201:enzymology*; D012121:Respiration, Artificial / Q000379:methods*; D012756:Sheep
chemical_list: D058987:Phosphodiesterase 3 Inhibitors; D009569:Nitric Oxide; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D020105:Milrinone; D010100:Oxygen
references.citation: J Crit Care. 2006 Jun;21(2):217-22
references.pmid: 16769471
references.citation: N Engl J Med. 1997 Feb 27;336(9):597-604
references.pmid: 9036320
references.citation: Am J Physiol. 1999 Nov;277(5):H1849-56
references.pmid: 10564139
references.citation: Circ Res. 2008 Feb 1;102(2):226-33
references.pmid: 17991881
references.citation: Physiol Rev. 1995 Oct;75(4):725-48
references.pmid: 7480160
references.citation: Aust Vet J. 1967 Feb;43(2):63-4
references.pmid: 6067585
references.citation: Am J Physiol. 1993 Oct;265(4 Pt 2):H1056-63
references.pmid: 8238393
references.citation: Pediatr Crit Care Med. 2004 May;5(3):234-9
references.pmid: 15115560
references.citation: Annu Rev Physiol. 1995;57:115-34
references.pmid: 7778860
references.citation: J Appl Physiol (1985). 1998 Jan;84(1):13-8
references.pmid: 9451612
references.citation: Biochem Pharmacol. 2002 May 1;63(9):1763-72
references.pmid: 12007579
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Am J Physiol. 1993 Jun;264(6 Pt 2):H2162-7
references.pmid: 8322947
references.citation: Br J Pharmacol. 1998 Dec;125(7):1501-10
references.pmid: 9884079
references.citation: Biol Neonate. 2006;89(1):1-5
references.pmid: 16155380
references.citation: Br J Pharmacol. 2002 Dec;137(8):1187-94
references.pmid: 12466227
references.citation: N Engl J Med. 1997 Feb 27;336(9):605-10
references.pmid: 9032045
references.citation: Pediatrics. 2000 Jan;105(1 Pt 1):14-20
references.pmid: 10617698
references.citation: Am J Physiol Lung Cell Mol Physiol. 2001 Jun;280(6):L1359-69
references.pmid: 11350817
references.citation: Am J Respir Crit Care Med. 2006 Dec 15;174(12):1370-7
references.pmid: 17008638
references.citation: Semin Perinatol. 2005 Feb;29(1):8-14
references.pmid: 15921147
references.citation: Pediatr Crit Care Med. 2009 Jan;10(1):106-12
references.pmid: 19057444
references.citation: Curr Top Med Chem. 2007;7(4):421-36
references.pmid: 17305583
references.citation: Anesthesiology. 2007 Jan;106(1):124-31
references.pmid: 17197854
references.citation: Pediatr Res. 2007 Sep;62(3):313-8
references.pmid: 17622960
references.citation: Crit Care Med. 2000 Mar;28(3):795-9
references.pmid: 10752832
references.citation: J Pharmacol Exp Ther. 1997 Nov;283(2):619-24
references.pmid: 9353377