Effect of Beta 3 Adrenoreceptor Modulation on Patency of the Ductus Arteriosus

Area of Science:

• Pharmacology
• Developmental Biology
• Obstetrics

Background:

• The beta3-adrenoreceptor (β3-AR) is a G-protein coupled receptor with unique regulatory properties and widespread expression.
• β3-AR is found in common neoplasms and its blockade inhibits tumor growth, suggesting potential as an anti-neoplastic drug during pregnancy.
• The role of β3-AR in prenatal development and the fetal effects of its blockade are currently unknown.

Purpose of the Study:

• To investigate the effects of β3-adrenoreceptor blockade on fetal ductus arteriosus (DA) development and function.
• To assess the safety of β3-AR antagonists for fetal use during pregnancy.
• To determine the impact of β3-AR modulation on prenatal morphogenesis and postnatal DA closure.

Main Methods:

• Expression of β3-AR was confirmed in endothelial and smooth muscle cells of the fetal ductus arteriosus (DA).
• Pregnant mice were treated acutely or chronically with the selective β3-AR antagonist SR59230A or with indomethacin.
• Newborn mice were treated with the β3-AR agonist BRL37344 to assess its effect on DA closure.

Main Results:

• SR59230A, at doses effective for cancer treatment (10 and 20 mg/kg), did not cause fetal DA constriction or impair postnatal closure.
• A higher dose of SR59230A (40 mg/kg) induced DA constriction and preterm delivery in mice.
• Postnatal administration of the β3-AR agonist BRL37344 did not affect physiological DA closure.

Conclusions:

• Selective β3-AR blockade at therapeutically relevant doses is safe for fetal ductus arteriosus development and function.
• High doses of β3-AR antagonists may pose risks, including DA constriction and preterm birth.
• β3-AR modulation does not appear to interfere with normal physiological ductus arteriosus closure after birth.