Inhibition of nitric oxide synthetase at mid-gestation in rats is associated with increases in arterial pressure, serum tumor necrosis factor-α, 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-α (TNF-α) 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-α 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-α, all of which have been implicated as being pathophysiological features of preeclampsia.