Inhibition of phosphodiesterase type 3 dilates the rat ductus arteriosus without inducing intimal thickening.

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  • Additional Information
    • Source:
      Publisher: Japanese Circulation Society Country of Publication: Japan NLM ID: 101137683 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1347-4820 (Electronic) Linking ISSN: 13469843 NLM ISO Abbreviation: Circ J Subsets: MEDLINE
    • Publication Information:
      Original Publication: Kyoto, Japan : Japanese Circulation Society, [2002-
    • Subject Terms:
      Cyclic Nucleotide Phosphodiesterases, Type 3/*biosynthesis ; Ductus Arteriosus/*enzymology ; Ductus Arteriosus/*physiopathology ; Ductus Arteriosus, Patent/*drug therapy ; Ductus Arteriosus, Patent/*enzymology ; Muscle, Smooth, Vascular/*enzymology ; Phosphodiesterase 3 Inhibitors/*pharmacology ; Vasodilation/*drug effects; Alprostadil/metabolism ; Animals ; Animals, Newborn ; Ductus Arteriosus/pathology ; Ductus Arteriosus, Patent/pathology ; Female ; Gene Expression Regulation, Enzymologic/drug effects ; Humans ; Infant, Newborn ; Male ; Muscle, Smooth, Vascular/pathology ; RNA, Messenger/biosynthesis ; Rats, Wistar
    • Abstract:
      Background:  Prostaglandin E(1) (PGE(1)), via cAMP, dilates the ductus arteriosus (DA). For patients with DA-dependent congenital heart disease (CHD), PGE(1) is the sole DA dilator that is used until surgery, but PGE(1) has a short duration of action, and frequently induces apnea. Most importantly, PGE(1) increases hyaluronan (HA) production, leading to intimal thickening (IT) and eventually DA stenosis after long-term use. The purpose of this study was therefore to investigate potential DA dilators, such as phosphodiesterase 3 (PDE3) inhibitors, as alternatives to PGE(1).
      Methods and Results:  Expression of PDE3a and PDE3b mRNAs in rat DA tissue was higher than in the pulmonary artery. I.p. milrinone (10 or 1mg/kg) or olprinone (5 or 0.5mg/kg) induced maximal dilatation of the DA lasting for up to 2h in rat neonates. In contrast, vasodilation induced by PGE(1) (10μg/kg) was diminished within 2h. No respiratory distress was observed with milrinone or olprinone. Most important, milrinone did not induce HA production, cell migration, or proliferation when applied to cultured rat DA smooth muscle cells. Further, high expression of both PDE3a and PDE3b was demonstrated in the human DA tissue of CHD patients.
      Conclusions:  Because PDE3 inhibitors induced longer-lasting vasodilation without causing apnea or HA-mediated IT, they may be good alternatives to PGE(1) for patients with DA-dependent CHD.
    • Accession Number:
      0 (Phosphodiesterase 3 Inhibitors)
      0 (RNA, Messenger)
      EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
      EC 3.1.4.17 (PDE3A protein, human)
      EC 3.1.4.17 (PDE3B protein, human)
      EC 3.1.4.17 (Pde3a protein, rat)
      EC 3.1.4.17 (Pde3b protein, rat)
      F5TD010360 (Alprostadil)
    • Publication Date:
      Date Created: 20120713 Date Completed: 20130214 Latest Revision: 20190819
    • Publication Date:
      20240829
    • Accession Number:
      10.1253/circj.cj-12-0215
    • Accession Number:
      22785618