LIMB REDUCTION DEFECTS AFTER PRENATAL INHIBITION OF NITRIC-OXIDE SYNTHASE IN RATS

To determine the influence of nitric oxide (NO) on vascular tone durin g fetal development, timed pregnant rats received the NO synthase inhi bitor N-G-nitro-L-arginine methyl ester for consecutive 4, 7, or 14 d before parturition (postorganogenesis). Offspring demonstrated limb re duction defects (incidence, 53%) involving either or both hindlimbs, w hereas forelimbs were uniformly spared. Defects were dose-dependent bu t independent of the duration of administration occurring with equal f requency in 4-, 7-, and 14-d treatment groups. Histologic analysis rev ealed features characteristic of vascular disruption with hemorrhagic necrosis and loss of structure. The defects were prevented by concurre nt maternal administration of L-arginine or the NO donors S-nitroso-N- acetyl-penicillamine and sodium nitroprusside. Defects were not seen a fter prenatal treatment with aminoguanidine. To study basal and agonis t-mediated NO release, newborn femoral and brachial arteries were cann ulated with a glass micropipette under constant pressure, and changes in intraluminal diameter (micrometers) were measured in response to ac etylcholine and the NO synthase inhibitor N-omega-nitro-L-arginine.