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Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data

Pediatric Researchvolume 84pages458465 (2018) | Download Citation

Subjects

Abstract

Background

Although studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results.

Methods

We used preterm baboons, mice, and humans (≤276/7 weeks gestation) to examine betamethasone’s effects on ductus gene expression and constriction both in vitro and in vivo.

Results

In mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone’s effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤256/7 weeks gestation, betamethasone’s contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26–27 weeks gestation, betamethasone’s contractile effects were apparent even in the absence of prostaglandin inhibitors.

Conclusions

We speculate that betamethasone’s contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone’s effects vary according to the infant’s developmental age at birth.

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Acknowledgements

Funding

This work was supported by a grant from U.S. Public Health Service NHLBI (HL109199, HL46691, HL56061, HL132805, HL52636 BPD Resource Center, and P51RR13986 Primate Center facility support) and by a gift from the Jamie and Bobby Gates Foundation.

Author information

Affiliations

  1. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    • Elaine L. Shelton
    • , Erin J. Plosa
    • , John T. Benjamin
    • , Christopher W. Hooper
    • , Noah J. Ehinger
    • , Stanley Poole
    • , Naoko Brown
    •  & Jeff Reese
  2. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA

    • Elaine L. Shelton
  3. Biosciences Division, SRI International, Menlo Park, CA, USA

    • Nahid Waleh
  4. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    • Ginger L. Milne
  5. Department of Pediatrics, University of Texas Health Science Center, San Antonio, TX, USA

    • Steven Seidner
    •  & Donald McCurnin
  6. Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN, USA

    • Jeff Reese
  7. Departments of Pediatrics and Cardiovascular Research Center, University of California San Francisco, San Francisco, CA, USA

    • Ronald I. Clyman

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Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Ronald I. Clyman.

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DOI

https://doi.org/10.1038/s41390-018-0006-z