Impact of endothelin A receptor antagonist selectivity in chronic nitric oxide synthase inhibition-induced fetal growth restriction in the rat.
OBJECTIVE
Endothelin receptor A (ETA) antagonism improves fetal and placental growth and placental perfusion on days 1 and 4, but not day 7 of a 7-day infusion of a nitric oxide synthase (NOS) inhibitor. Our purpose was to evaluate the significance of the degree of ETA antagonist selectivity on uteroplacental perfusion and fetal growth on day 7 of chronic NOS inhibition.


METHODS
Timed-pregnant rats were treated with the NOS inhibitor nitro-L-arginine methyl ester (L-NAME, 2.5 mg/kg/h) with and without one of the following ETA antagonists or their respective vehicles for 7 days beginning on day 14 of gestation: A-127722 (2,000-fold selective for ETA over ETB), FR139317 (8,000-fold ETA-selective), or ABT-546 (28,000-fold ETA-selective). Uterine and placental perfusion, as well as fetal and placental weight, was evaluated at the 7th day of treatment (gestation day 21).


RESULTS
L-NAME administration resulted in a significant reduction in uterine and placental perfusion as well as fetal and placental growth. In the setting of NOS inhibition, ETA antagonism did not improve uterine or placental perfusion or fetal growth after 7 days of infusion irrespective of the degree of selectivity of the antagonist used.


CONCLUSIONS
ETA antagonism, irrespective of the degree of receptor selectivity, does not improve fetal growth or uteroplacental perfusion on day 7 of chronic NOS inhibition.
Neerhof
Mark G
MG
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, North Shore University Health System, Evanston, Illinois 60201, USA. mneerhof@ enh.org
Synowiec
Sylvia
S
Khan
Saira
S
Thaete
Larry G
LG
D000704:Analysis of Variance; D000818:Animals; D065128:Endothelin Receptor Antagonists; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000378:metabolism; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D065128:Endothelin Receptor Antagonists; D017466:Receptors, Endothelin; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester