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Updated: Jun 5, 2026
Fetal Echocardiography and Pulsed-wave Doppler Ultrasound in a Rabbit Model of Intrauterine Growth Restriction
Published on: June 29, 2013
Pathophysiology of chronic nitric oxide synthase inhibition-induced fetal growth restriction in the rat
Mark G Neerhof1, Sylvia Synowiec, Saira Khan
1Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Evanston Northwestern Healthcare, Evanston, IL, USA.
Objective:
To evaluate the pathophysiology of chronic nitric oxide synthase (NOS) inhibition-induced fetal growth restriction (FGR) in the rat.
Methods:
Timed-pregnant rats received L-NAME (2.5 mg/kg/h) with or without endothelin (ET-1) receptor A (ETA) antagonist from day 14 to 21 of gestation. In separate groups, ETA antagonist and/or L-NAME were discontinued on day 18. On day 21 fetal and placental weights, and maternal and fetal plasma nitrate/nitrite (NOx) were determined.
Results:
L-NAME led to FGR, and decreased maternal and fetal NOx. Maternal NOx was further decreased when ETA antagonist was co-administered with L-NAME. ETA antagonism along with L-NAME did not impact fetal growth. Discontinuation of L‐NAME on day 18 resulted in normal fetal and placental growth at day 21 and an increase of maternal NOx. Simultaneous cessation of both NOS inhibition and ETA antagonism on day 18 produced FGR at day 21, whereas continuation of ETA antagonism after discontinuation of L-NAME resulted in normal fetal growth.
Conclusions:
NOS inhibition in the pregnant rat leads to decreased maternal and fetal nitric oxide (NO) production and FGR. The effects of NOS inhibition on fetal growth are reversible, and are mediated at least in part by ET-1. With chronic NOS inhibition, ETA antagonism improves but does not normalize fetal growth, and may allow increased access of L-NAME to the fetal compartment. Continued access of L-NAME to the fetal compartment may limit the effect on fetal growth of any therapeutic intervention in this model of FGR.
Insights
Chronic nitric oxide synthase (NOS) inhibition causes fetal growth restriction (FGR) in rats, which is reversible and partly mediated by endothelin-1 (ET-1). ETA antagonism improves but doesn't normalize FGR, potentially increasing L-NAME exposure to fetuses.
Area of Science:
- Reproductive biology
- Developmental toxicology
- Pharmacology
Background:
- Nitric oxide synthase (NOS) inhibition is a known cause of fetal growth restriction (FGR).
- The role of endothelin-1 (ET-1) in NOS inhibition-induced FGR is not fully understood.
- Understanding the pathophysiology of FGR is crucial for developing effective interventions.
Purpose of the Study:
- To investigate the pathophysiology of chronic NOS inhibition-induced FGR in a rat model.
- To evaluate the role of endothelin type A (ETA) receptors in this process.
- To assess the reversibility of FGR following cessation of NOS inhibition and ETA antagonism.
Main Methods:
- Timed-pregnant rats were treated with L-NAME (a NOS inhibitor) with or without an ETA antagonist from day 14 to 21 of gestation.
- In some groups, L-NAME and/or the ETA antagonist were discontinued on day 18.
- Fetal and placental weights, and maternal and fetal plasma nitrate/nitrite (NOx) levels were measured on day 21.
Main Results:
- L-NAME administration induced FGR and decreased maternal and fetal NOx levels.
- Co-administration of an ETA antagonist with L-NAME did not alter fetal growth but further reduced maternal NOx.
- Discontinuation of L-NAME on day 18 normalized fetal and placental growth and increased maternal NOx, indicating reversibility.
Conclusions:
- Chronic NOS inhibition in pregnant rats reduces nitric oxide (NO) production, leading to FGR.
- The FGR induced by NOS inhibition is reversible and involves ET-1 signaling.
- ETA antagonism partially improves FGR but does not fully normalize it and may affect L-NAME's placental transfer, potentially limiting therapeutic efficacy.
