Abstract
Background
Indomethacin treatment for patent ductus arteriosus (PDA) is associated with acute kidney injury (AKI). Fenoldopam, a dopamine (DA) DA1-like receptor agonist dilates the renal vasculature and may preserve renal function during indomethacin treatment. However, limited information exists on DA receptor-mediated signaling in the ductus and fenoldopam may prevent ductus closure given its vasodilatory nature.
Methods
DA receptor expression in CD-1 mouse vessels was analyzed by qPCR and immunohistochemistry. Concentration−response curves were established using pressure myography. Pretreatment with SCH23390 (DA1-like receptor antagonist), phentolamine (α -adrenergic receptor antagonist) or indomethacin addressed mechanisms for DA-induced changes. Fenoldopam’s effects on postnatal ductus closure were evaluated in vivo.
Results
DA1 receptors were expressed equally in ductus and aorta. High-dose DA induced modest vasoconstriction under newborn O2 conditions. Phentolamine inhibited DA-induced constriction, while SCH23390 augmented constriction, consistent with a vasodilatory role for DA1 receptors. Despite this, fenoldopam had little effect on ductus tone nor indomethacin- or O2-induced constriction and did not impair postnatal closure in vivo.
Conclusion(s)
DA receptors are present in the ductus but have limited physiologic effects. DA-induced ductus vasoconstriction is mediated via α-adrenergic pathways. The absence of DA1-mediated impairment of ductus closure supports the study of potential role for fenoldopam during PDA treatment.
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Acknowledgements
This study was supported in part by NIH grants HL132805 (E.L.S.), HL109199 (J.R.), HL128386 (J.R., E.L.S.), and DK113073 (J.L.S.).
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S.L.C., M.H., N.B., R.L.S., M.T.Y., C.D.B., E.L.S., J.R., and J.L.S. made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; E.L.S., J.R., and J.L.S. participated in drafting and critical revisions for important intellectual content; J.R. and J.L.S. had final approval of the version to be published.
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Crockett, S.L., Harris, M., Boatwright, N. et al. Role of dopamine and selective dopamine receptor agonists on mouse ductus arteriosus tone and responsiveness. Pediatr Res 87, 991–997 (2020). https://doi.org/10.1038/s41390-019-0716-x
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DOI: https://doi.org/10.1038/s41390-019-0716-x
