Effects of NO synthase inhibitors, arginine-deficient diet, and amiloride in pregnant rats.

This study tests the hypothesis that nitric oxide synthase (NOS) inhibition is linked to NG-nitro-L-arginine methyl ester (L-NAME)-mediated intrauterine growth retardation (IUGR) and fetal limb reduction deficits (LRD) in pregnant dams. Administration of L-NAME (1 mg/ml) or aminoguanidine (AG, 500 micrograms/ml) in the drinking water or intraperitoneal administration of L-N5-(1-iminoethyl)-ornithine (L-NIO, 10 mg.kg-1.day-1) on gestational days 13-20 decreased nitrite and nitrate plus nitrate (RNI) levels in the urine and plasma and decreased RNI in incubates of aorta and fetal limbs compared with pregnant rats given amiloride (50 micrograms/ml) or water (control). Although all drugs caused fetal IUGR, only L-NAME and amiloride caused fetal deaths and LRD. Urine and tissue levels of RNI were unchanged in rats fed and arginine-free diet (AFD) on gestational days 13-20, and yet fetal IUGR, deaths, and LRD were prevalent. L-NAME potentiated the fetal abnormalities and resorptions. Plasma arginine concentrations decreased with AFD > > L-NAME > L-NIO. Plasma ornithine, a precursor for polyamine synthesis, decreased with AFD and increased with L-NAME. Thus inhibition of NOS is not linked to LRD. The ability of L-NAME and amiloride to produce fetal IUGR and LRD may result from L-NAME-mediated modulation of amino acid delivery to the fetus and amiloride-mediated inhibition of protein synthesis. Finally, IUGR appears unrelated to LRD.