Inhibition of nitric oxide synthetase at mid-gestation in rats is associated with increases in arterial pressure, serum tumor necrosis factor-alpha, and placental apoptosis.
BACKGROUND
Reduced uteroplacental perfusion and maternal cardiovascular dysfunction have been considered to be the main pathophysiological features of preeclampsia. In order to determine whether inhibition of nitric oxide synthetase (NOS) during the initial stage of placentation is associated with impaired placental development and maternal cardiovascular dysfunction, we studied the effect of N-nitro-arginine methyl ester (L-NAME), a NOS inhibitor, on morphological changes in the placenta, maternal blood pressure, and serum tumor necrosis factor-alpha (TNF-alpha) in pregnant rats during the initial stage of placentation.


METHODS
Pregnant Wister rats were treated during mid-gestation (days 8-14) with either L-NAME or saline. On day 20 of pregnancy the rats were killed, and maternal blood and placentas were extracted and examined.


RESULTS
In comparison with pregnant saline-treated control rats (blood pressure 119 +/- 9 mm Hg), pregnant rats treated with L-NAME displayed significant hypertension (blood pressure 178 +/- 7 mm Hg), which continued even after the withdrawal of L-NAME administration (P < 0.01). In L-NAME-treated pregnant rats, morphological examination showed decreased populations of placental trophoblast lineages, and a significant increase in placental trophoblast apoptosis. Serum TNF-alpha levels at day 20 of pregnancy were significantly higher in treated pregnant rats (21.2 +/- 9.6 pg/ml) than in control pregnant rats (3.3 +/- 2.8 pg/ml) (P < 0.01).


CONCLUSIONS
Inhibition of NOS at mid-gestation in pregnant rats is associated with increases in arterial pressure, placental apoptosis, and serum TNF-alpha, all of which have been implicated as being pathophysiological features of preeclampsia.
Tsukimori
Kiyomi
K
Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. tsuki@med.kyushu-u.ac.jp
Komatsu
Hajime
H
Fukushima
Kotaro
K
Kaku
Tsunehisa
T
Nakano
Hitoo
H
Wake
Norio
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005865:Gestational Age; D007150:Immunohistochemistry; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000097:blood; D010920:Placenta / Q000473:pathology*; D011225:Pre-Eclampsia / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D011247:Pregnancy; D011379:Prognosis; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester