Pathophysiology of chronic nitric oxide synthase inhibition-induced fetal growth restriction in the rat.
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.
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Evanston Northwestern Healthcare, Evanston, IL, USA.
Mark G
MG
Neerhof
Sylvia
S
Synowiec
Saira
S
Khan
Larry G
LG
Thaete
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005317:Fetal Growth Retardation / Q000201:enzymology* / Q000503:physiopathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
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