Endothelin and the regulation of uteroplacental perfusion in nitric oxide synthase inhibition-induced fetal growth restriction.
The vasoactive mediators nitric oxide and endothelin are both produced in and active in the uterine and placental vasculature. Inhibition of nitric oxide synthase (NOS) results in fetal growth restriction. Endothelin (ET-1) is upregulated in the setting of NOS inhibition. Our purpose was to determine the impact of ET-1 on uterine and placental perfusion in the pregnant rat treated with a NOS inhibitor. Timed-pregnant Sprague-Dawley rats were treated with L-NAME (2.5 mg/kg/h), with and without A-127722 (10 mg/kg/day), or their respective vehicles, for 1, 4, or 7 days beginning on day 14 of gestation. Blood flow to various organs was determined by microsphere infusion. Maternal and fetal plasma nitrate/nitrite (NOx) was determined by fluorometric assay. Uterine and placental perfusion was significantly decreased by NOS inhibition and was restored to normal by ETA antagonism at 1 and 4 days of infusion but not at 7 days. Maternal plasma NOx, but not fetal plasma NOx, was significantly decreased by NOS inhibition alone. ETA antagonism in combination with NOS inhibition significantly lowered fetal plasma NOx. These results indicate that ET-1 is an important regulator of uterine and placental perfusion in the NOS inhibition model of fetal growth restriction. Our results also suggest that maternal administration of L-NAME does not result in significant transport of L-NAME across the placenta, but that addition of an ETA antagonist results in increased placental perfusion, allowing L-NAME greater access to the fetal compartment.
Thaete
L G
LG
Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. l-thaete@northwestern.edu
Kushner
D M
DM
Dewey
E R
ER
Neerhof
M G
MG
D000818:Animals; D000077868:Atrasentan; D001783:Blood Flow Velocity / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005317:Fetal Growth Retardation / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D005865:Gestational Age; D008863:Microspheres; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000097:blood; D010920:Placenta / Q000098:blood supply* / Q000187:drug effects; D011247:Pregnancy / Q000097:blood; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D014599:Uterus / Q000098:blood supply* / Q000187:drug effects
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D011759:Pyrrolidines; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester; D000077868:Atrasentan