# Pharmacologic Contributors to Patent Ductus Arteriosus

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $720,055

## Abstract

Project Summary
Vascular adaptation after birth is dependent on closure of the ductus arteriosus (DA), a fetal vascular shunt
connecting the pulmonary artery and aorta. Failure of DA closure results in persistent patency of the DA (PDA),
a common disorder associated with increased morbidity and mortality in the most vulnerable infants. Current
pharmacological treatments for PDA are limited and only focus on a single therapeutic pathway –
cyclooxygenase-mediated prostaglandin (PG) synthesis. However, recent data reveal complex networks of
genes and druggable pathways involved in the vasodilatory-to-vasoconstrictive shift that drives postnatal DA
closure. Efforts to identify new DA-selective vasoconstrictors overlook the possibility that ongoing vasodilatory
stimuli perpetuate DA relaxation and inhibit its closure. Because critically ill preterm newborns are exposed to
multiple medications during the time that DA closure takes place, we postulate that pharmacologic agents used
in the neonatal ICU prevent DA closure and contribute to PDA.
The DA of prematurely-born infants is developmentally primed to respond to vasodilatory signals. Our prior
studies using mouse models and human data show that drugs frequently used in preterm infants have
unexpected vasodilatory effects on the DA, including specific antibiotics, antacids, and diuretics. These data
suggest that drug-induced DA relaxation is a modifiable contributor to PDA, but this has not been systematically
evaluated. We therefore hypothesize that drugs commonly used in the NICU have an adverse effect on
closure of the premature DA and that specific drug combinations act synergistically to impair postnatal
DA closure. Mouse and human tissues will be used to test this hypothesis in three Aims: 1) Determine whether
drugs in the neonatal pharmacopeia prevent the initial phase of DA closure - smooth muscle constriction - that
leads to physiologic closure of the DA lumen; 2) Determine whether drugs in the neonatal pharmacopeia impair
the second phase of DA closure - fibromuscular remodeling - that leads to permanent sealing of the constricted
DA; 3) Identify drug combinations that interact to adversely affect either phase of DA closure. Drug effects will
be examined using primary (in vitro) high throughput screening (HTS) of preterm mouse DA smooth muscle
cells. A series of secondary screening assays will prioritize single- and synergistic combinations of hits based
on potency/efficacy, DA-selectivity, and toxicity for further study of their ex vivo and in vivo vasoactive effects on
the DA. A novel ex vivo mouse DA-reopening assay will be used to screen for drugs of interest. The effect of hit
DA-vasodilatory compounds will be examined on ex vivo human neonatal DA segments and in a large national
database of preterm infants. These studies have high translational potential and will definitively identify which
drugs or drug combinations pose increased risks for PDA in preterm infants, providing an innova...

## Key facts

- **NIH application ID:** 10444540
- **Project number:** 1R01HL164327-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** John Jeffrey Reese
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $720,055
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444540

## Citation

> US National Institutes of Health, RePORTER application 10444540, Pharmacologic Contributors to Patent Ductus Arteriosus (1R01HL164327-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10444540. Licensed CC0.

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