Regulation of the ductus arteriosus, an essential fetal vessel connecting the pulmonary artery and aorta, is complex. Failure of this vessel to close after birth may result in a persistent left-to-right shunt through the patent ductus arteriosus (PDA), a condition associated with significant morbidities. Numerous factors contribute to the shift from fetal ductus patency to postnatal closure, requiring precise coordination of molecular cues with biomechanical forces and underlying genetic influences. Despite significant advances, questions remain regarding signaling dynamics and the natural time course of ductus closure, particularly in preterm neonates. This review highlights the contributions of early investigators and more recent clinician scientists to our understanding of the molecular and mechanical factors that mediate ductus patency and closure.
Background: Indomethacin treatment for patent ductus arteriosus (PDA) is associated with acute kidney injury (AKI). Fenoldopam, a dopamine (DA) DA 1-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 (DA 1-like receptor antagonist), phentolamine (αadrenergic receptor antagonist) or indomethacin addressed mechanisms for DA-induced changes. Fenoldopam's effects on postnatal ductus closure were evaluated in vivo. Results: DA 1 receptors were expressed equally in ductus and aorta. High-dose DA induced modest vasoconstriction under newborn O 2 conditions. Phentolamine inhibited DA-induced constriction, while SCH23390 augmented constriction, consistent with a vasodilatory role for DA 1 receptors. Despite this, fenoldopam had little effect on ductus tone nor indomethacin-or O 2induced constriction and did not impair postnatal closure in vivo. Conclusion(s): DA receptors are present in the ductus but have limited physiologic effects. DAinduced ductus vasoconstriction is mediated via α-adrenergic pathways. The absence of DA 1-Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
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Introduction Preterm birth rate continues to rise with over 15 million cases/year and remains the greatest contributor to neonatal morbidities and mortalities. Currently, there are no FDA‐approved tocolytics for the management of preterm labor due to the off‐target side effects and short duration of benefit of current off‐label therapeutics. High‐throughput screening of oxytocin‐induced Ca2+‐mobilization in uterine myometrial cells identified mundulone and mundulone acetate (MA) as hit‐antagonists. The aim of this work was to:1) examine the uterine‐selectivity of mundulone and MA by counterscreening vascular smooth muscle cells (VSMCs)—the major off‐target limiting the use of current tocolytics, 2) determine cytotoxic effects, 3) identify synergistic combinations of mundulone (and MA) with current tocolytics to increase efficacy and/or potency to decrease off‐target side effects and 4) determine the ex vivo tocolytic efficacy and potency on human myometrial tissue and confirm uterine selectivity at the tissue level by evaluating their effect on constriction of fetal ductus arteriosus (DA), a major off target of known tocolytics. Methods Primary human myometrial cells were isolated from tissue collected at the time of cesarean delivery from women at term (≥39 weeks) pregnancy. A phenotypic high‐throughput Ca2+‐ mobilization assay was performed to compare concentration‐response (10‐ point, 3‐fold dilutions) between myometrial and aorta VSMCs (Emax and IC50). The high‐throughput Ca2+‐mobilization assay was adapted for combination screening in 8×8 concentration‐response matrix format. Current tocolytics used for combination included: atosiban, indomethacin and nifedipine. Three models (Bliss independence, HSA and Loewe additivity) were used to determine synergy using Combenefit software. Cytotoxicity of mundulone and MA were determined using WST‐1 cell viability assay using myometrial, hepatic and renal cells. Ex vivo organ bath studies using myometrial tissue and isolated term fetal DA vessels were performed to examine concentration‐response on contractility and vessel diameter, respectively. Results MA was found to display a greater selectivity towards myometrial cells when counter screened against aorta VSMCs. Fold change (FC) in efficacy (Emax) was 13.5 and FC in potency was >4.5 for MA while fold change in potency for mundulone was only >2.3. We found that mundulone displayed synergism with two current tocolytics (atosiban and nifedipine), while MA displayed synergistic efficacy with nifedipine. Mundulone was found to affect the viability of myometrial cells while MA demonstrated a selectivity index of >10 (Ratio of IC50 in cell viability assay to IC50 in Ca2+‐mobilization assay). Both mundulone and MA showed concentration dependent inhibition of uterine contractions, without affecting fetal DA vasoreactivity at the tissue level. Conclusion Based on differences in uterine‐selectivity and tocolytic efficacy between mundulone and MA, this natural product could benefit from medicinal chemistry efforts to study stru...
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