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 (ET_A) antagonist from day 14 to 21 of gestation. In separate groups, ET_A antagonist and/or L-NAME were discontinued on day 18. On day 21 fetal and placental weights, and maternal and fetal plasma nitrate/nitrite (NO_x) were determined. Results. L-NAME led to FGR, and decreased maternal and fetal NO_x. Maternal NO_x was further decreased when ET_A antagonist was co-administered with L-NAME. ET_A 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 NO_x. Simultaneous cessation of both NOS inhibition and ET_A antagonism on day 18 produced FGR at day 21, whereas continuation of ET_A 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, ET_A 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.

• Endothelin antagonism
• Fetal growth restriction
• Nitric oxide synthase inhibition
• Rat

ACKNOWLEDGMENT

This work was supported by National Institutes of Health grant HD046968.

Declaration of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.