title: Aminoglycoside-mediated relaxation of the ductus arteriosus in sepsis-associated PDA.
abstract: Sepsis is strongly associated with patency of the ductus arteriosus (PDA) in critically ill newborns. Inflammation and the aminoglycoside antibiotics used to treat neonatal sepsis cause smooth muscle relaxation, but their contribution to PDA is unknown. We examined whether: 1) lipopolysaccharide (LPS) or inflammatory cytokines cause relaxation of the ex vivo mouse DA; 2) the aminoglycosides gentamicin, tobramycin, or amikacin causes DA relaxation; and 3) newborn infants treated with aminoglycosides have an increased risk of symptomatic PDA (sPDA). Changes in fetal mouse DA tone were measured by pressure myography in response to LPS, TNF-α, IFN-γ, macrophage-inflammatory protein 2, IL-15, IL-13, CXC chemokine ligand 12, or three aminoglycosides. A clinical database of inborn patients of all gestations was analyzed for association between sPDA and aminoglycoside treatment. Contrary to expectation, neither LPS nor any of the inflammatory mediators caused DA relaxation. However, each of the aminoglycosides caused concentration-dependent vasodilation in term and preterm mouse DAs. Pretreatment with indomethacin and N-(G)-nitro-L-arginine methyl ester did not prevent gentamicin-induced DA relaxation. Gentamicin-exposed DAs developed less oxygen-induced constriction than unexposed DAs. Among 488,349 infants who met the study criteria, 40,472 (8.3%) had sPDA. Confounder-adjusted odds of sPDA were higher in gentamicin-exposed infants, <25 wk and >32 wk. Together, these findings suggest that factors other than inflammation contribute to PDA. Aminoglycoside-induced vasorelaxation and inhibition of oxygen-induced DA constriction support the paradox that antibiotic treatment of sepsis may contribute to DA relaxation. This association was also found in newborn infants, suggesting that antibiotic selection may be an important consideration in efforts to reduce sepsis-associated PDA.
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee;
authors.forename: Megan M
authors.initials: MM
authors.lastname: Vucovich
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee;
authors.forename: Robert B
authors.initials: RB
authors.lastname: Cotton
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee;
authors.forename: Elaine L
authors.initials: EL
authors.lastname: Shelton
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee;
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Goettel
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee;
authors.forename: Noah J
authors.initials: NJ
authors.lastname: Ehinger
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee;
authors.forename: Stanley D
authors.initials: SD
authors.lastname: Poole
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee;
authors.forename: Naoko
authors.initials: N
authors.lastname: Brown
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee;
authors.forename: James L
authors.initials: JL
authors.lastname: Wynn
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee;
authors.forename: Bibhash C
authors.initials: BC
authors.lastname: Paria
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: James C
authors.initials: JC
authors.lastname: Slaughter
authors.affiliation: Pediatrix Medical Group, Sunrise, Florida; and.
authors.forename: Reese H
authors.initials: RH
authors.lastname: Clark
authors.affiliation: Department of Pediatrics, Wake Forest University School of Medicine, Winston Salem, North Carolina.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Rojas
authors.affiliation: Department of Pediatrics, Vanderbilt University School of Medicine and the Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; jeff.reese@vanderbilt.edu.
authors.forename: Jeff
authors.initials: J
authors.lastname: Reese
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000494:pharmacology; D004373:Ductus Arteriosus / Q000187:drug effects* / Q000503:physiopathology; D004374:Ductus Arteriosus, Patent / Q000209:etiology / Q000503:physiopathology*; D005839:Gentamicins / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018805:Sepsis / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014664:Vasodilation
chemical_list: D054377:Chemokine CXCL12; D005839:Gentamicins; D007378:Interleukins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin
keywords: aminoglycoside; cytokine; ductus arteriosus; endotoxin; gentamicin; human; lipopolysaccharide; mouse