THE TERATOGENICITY OF N-OMEGA-NITRO-L-ARGININE METHYL-ESTER (L-NAME),A NITRIC-OXIDE SYNTHASE INHIBITOR, IN RATS

Exposure of gravid rats to the nitric oxide synthase inhibitor N-omega -nitro-L-arginine methyl ester (L-NAME) in drinking water or by implan ted osmotic minipumps significantly elevates maternal blood pressure, reducing uteroplacental perfusion, Administration by either route caus es fetal growth retardation, but oral exposure also causes hind limb r eduction malformations, The present study employed both oral and intra peritoneal routes to determine the period of sensitivity to developmen tal toxicity, dose-response, and possible fetotoxic mechanisms, Hind l imb hemorrhage occurred only in litters from dams exposed to oral dose s of 1 to 2 mg/mL from gestational days 15 through 17, In contrast to oral exposure, single intraperitoneal injections caused both fore and hind limb reductions at doses of 25 mg/kg and above administered on ge stational day 16 and later, Many other exposures that reduce uteroplac ental perfusion have been associated with vascular disruptive dysmorph ogenesis, These exposures include phenytoin, calcium channel inhibitor s, cocaine, and uterine vascular clamping, Limb hemorrhage induced by these exposures is usually limited to distal structures, typically pha langes, and the incidence of affected fetuses rarely exceeds 50%, By c ontrast, hemorrhage caused by L-NAME frequently involves entire limbs, extending into adjacent flank in severe instances, and 100% of fetuse s from treated dams may be affected, The basis of this difference and the differing defect patterns associated with the various routes of ex posure are unclear, but the generation of reactive oxygen species duri ng resumption of normal perfusion may play a role in this vascular dis ruption. (C) 1997 Elsevier Science Inc.