Role of dopamine and selective dopamine receptor agonists on mouse ductus arteriosus tone and responsiveness

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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Fig. 1: Dopamine receptors are expressed and functional in the isolated ductus.
Fig. 2: Fenoldopam has minimal effect on ductus tone.
Fig. 3: Fenoldopam does not impair oxygen-induced constriction of the ductus arteriosus.
Fig. 4: Fenoldopam has no effect on indomethacin-induced constriction of the ductus arteriosus.
Fig. 5: Fenoldopam exposure does not prevent postnatal closure of the ductus.

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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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Correspondence to Jeffrey L. Segar.

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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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