Pathophysiology of Chronic Nitric Oxide Synthase Inhibition-Induced Fetal Growth Restriction in the Rat

Abstract

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.

Thrombomodulin improves maternal and fetal conditions in an experimental pre‐eclampsia rat model

“…24 It has been reported that NOS inhibition from days 14 to 21 of the 22-day gestation period results in decreased uterine and placental perfusion and decreased fetal and placental growth. 25 Because it has been reported that tumor necrosis factor (TNF)-α, which is induced by repeated endotoxin administrations, activates systemic vascular endothelial cells, 26 the experimental PE model was reproduced by a low-dose endotoxin in this study. Sakawi et al 22 administrated endotoxin at 1, 2 and 10 μg/kg and L-NAME at 3 mg/kg as an experimental PE model and successfully reproduced proteinuria and thrombocytopenia, but not hypertension and intrauterine growth restriction (IUGR), whereas L-NAME administration caused hypertension, IUGR and decreased fetal number.…”

Seminal leukocytes are Good Samaritans for spermatozoa

“…This surprising finding could be explained by a possible vasodilator effect of ROS, increasing the uterine blood flow and therefore the birth weight. Actually, nitric oxide is a vasodilator, and chronic nitric oxide synthase inhibition induces fetal growth restriction in the rat (34). Similarly in humans, antioxidant therapy administration in pregnant women at risk of pre-eclampsia resulted in a decrease of mean infant weight, suggesting that ROS have the opposite effect (35).…”

Complex expression changes of the placental endothelin system in early and late onset preeclampsia, fetal growth restriction and gestational diabetes

“…ET-1 may Life Sciences 91 (2012) 710-715 be the key link between the poorly perfused placenta and the impaired maternal vascular function associated with PE by triggering oxidative stress in the human placenta (Fiore et al, 2005). ET-1 has also been implicated in the pathophysiology of FGR in several animal models as well as in humans (Neerhof et al, 2011;Nezar et al, 2009).…”