Glutamate Promotes Contraction of the Rat Ductus Arteriosus

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  • Fujita Shujiro
    Cardiovascular Research Institute, Yokohama City University Department of Pediatrics, Graduate School of Medicine, Yokohama City University
  • Yokoyama Utako
    Cardiovascular Research Institute, Yokohama City University
  • Ishiwata Ryo
    Cardiovascular Research Institute, Yokohama City University
  • Aoki Rika
    Cardiovascular Research Institute, Yokohama City University Department of Pediatrics, Graduate School of Medicine, Yokohama City University
  • Nagao Kenji
    Institute for Innovation, Ajinomoto Co, Inc
  • Masukawa Daiki
    Department of Molecular Pharmacology and Neurobiology, Yokohama City University
  • Umemura Masanari
    Cardiovascular Research Institute, Yokohama City University
  • Fujita Takayuki
    Cardiovascular Research Institute, Yokohama City University
  • Iwasaki Shiho
    Department of Pediatrics, Graduate School of Medicine, Yokohama City University
  • Nishimaki Shigeru
    Department of Pediatrics, Graduate School of Medicine, Yokohama City University
  • Seki Kazuo
    Department of Pediatrics, Graduate School of Medicine, Yokohama City University
  • Ito Shuichi
    Department of Pediatrics, Graduate School of Medicine, Yokohama City University
  • Goshima Yoshio
    Department of Molecular Pharmacology and Neurobiology, Yokohama City University
  • Asou Toshihide
    Department of Cardiovascular Surgery, Kanagawa Children’s Medical Center
  • Masuda Munetaka
    Department of Surgery, Yokohama City University
  • Ishikawa Yoshihiro
    Cardiovascular Research Institute, Yokohama City University

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<p>Background:Extremely preterm infants frequently have patent ductus arteriosus (PDA). Recent recommendations include immediately beginning amino acid supplementation in extremely preterm infants. However, the effect of amino acids on closure of the ductus arteriosus (DA) remains unknown.</p><p>Methods and Results:Aminogram results in human neonates at day 2 revealed that the plasma glutamate concentration was significantly lower in extremely preterm infants (<28 weeks’ gestation) with PDA than in those without PDA and relatively mature preterm infants (28–29 weeks gestation). To investigate the effect of glutamate on DA closure, glutamate receptor expression in fetal rats was examined and it was found that the glutamate inotropic receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type subunit 1 (GluR1), mRNA was highly expressed in the DA compared to the aorta on gestational day 19 (preterm) and gestational day 21 (term). GluR1 proteins were co-localized with tyrosine hydroxylase-positive autonomic nerve terminals in the rat and human DA. Intraperitoneal administration of glutamate increased noradrenaline production in the rat DA. A whole-body freezing method demonstrated that glutamate administration induced DA contraction in both preterm (gestational day 20) and term rat fetuses. Glutamate-induced DA contraction was attenuated by the calcium-sensitive GluR receptor antagonist, NASPM, or the adrenergic receptor α1 blocker, prazosin.</p><p>Conclusions:These data suggest that glutamate induces DA contraction through GluR-mediated noradrenaline production. Supplementation of glutamate might help to prevent PDA in extremely preterm infants. (Circ J 2016; 80: 2388–2396)</p>

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  • Circulation Journal

    Circulation Journal 80 (11), 2388-2396, 2016

    一般社団法人 日本循環器学会

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