Factors that increase the contractile tone of the ductus arteriosus also regulate its anatomic remodeling

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2001-07, Vol.281 (1), p.291-R301
• Main Authors: Kajino, Hiroki, Chen, Yao-Qi, Seidner, Steven R, Waleh, Nahid, Mauray, Francoise, Roman, Christine, Chemtob, Sylvain, Koch, Cameron J, Clyman, Ronald I
• Format: Article
• Language: English
• Subjects: 6-Ketoprostaglandin F1 alpha - metabolism; Animals; Animals, Newborn; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - metabolism; Ductus Arteriosus - metabolism; Ductus Arteriosus - physiology; Enzyme Inhibitors - pharmacology; Hypoxia - metabolism; Hypoxia - physiopathology; In Vitro Techniques; Indomethacin - pharmacology; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - metabolism; Oxygen - pharmacology; Papio; Sheep
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.2001.281.1.R291

1  Cardiovascular Research Institute and 6  Department of Pediatrics, University of California, San Francisco 94143-0544; 3  SRI International, Menlo Park, California 94025; 2  Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas 78284; 4  Research Center, Hôpital Saint-Justine, Montreal, Quebec H3T 1C5, Canada; and 5  Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 Permanent closure of the full-term newborn ductus arteriosus (DA) occurs only if profound hypoxia develops within the vessel wall during luminal obliteration. We used fetal and newborn baboons and lambs to determine why the immature DA fails to remodel after birth. When preterm newborns were kept in a normoxic range (Pa O 2 : 50-90 mmHg), 86% still had a small patent DA on the sixth day after birth; in addition, the preterm DA wall was only mildly hypoxic and had only minimal remodeling. The postnatal increase in Pa O 2 normally induces isometric contractile responses in rings of DA; however, the excessive inhibitory effects of endogenous prostaglandins and nitric oxide, coupled with a weaker intrinsic DA tone, make the preterm DA appear to have a smaller increment in tension in response to oxygen than the DA near term. We found that oxygen concentrations, beyond the normoxic range, produce an additional increase in tension in the preterm DA that is similar to the contractile response normally seen at term. We predicted that preterm newborns, kept at a higher Pa O 2 , would have increased DA tone and would be more likely to obliterate their lumen. We found that preterm newborns, maintained at a Pa O 2 >200 mmHg, had only a 14% incidence of patent DA. Even though DA constriction was due to elevated Pa O 2 , obliteration of the lumen produced profound hypoxia of the DA wall and the same features of remodeling that were observed at term. DA wall hypoxia appears to be both necessary and sufficient to produce anatomic remodeling in preterm newborns. hypoxia; nitric oxide; prostaglandins; oxygen; newborn