The teratogenicity of N(omega)-nitro-L-ariginine 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 implanted osmotic minipumps significantly elevates maternal blood pressure, reducing uteroplacental perfusion. Administration by either route causes fetal growth retardation, but oral exposure also causes hind limb reduction malformations. The present study employed both oral and intraperitoneal routes to determine the period of sensitivity to developmental toxicity, dose-response, and possible fetotoxic mechanisms. Hind limb hemorrhage occurred only in litters from dams exposed to oral doses 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 gestational day 16 and later. Many other exposures that reduce uteroplacental perfusion have been associated with vascular disruptive dysmorphogenesis. These exposures include phenytoin, calcium channel inhibitors, cocaine, and uterine vascular clamping. Limb hemorrhage induced by these exposures is usually limited to distal structures, typically phalanges, and the incidence of affected fetuses rarely exceeds 50%. By contrast, hemorrhage caused by L-NAME frequently involves entire limbs, extending into adjacent flank in severe instances, and 100% of fetuses from treated dams may be affected. The basis of this difference and the differing defect patterns associated with the various routes of exposure are unclear, but the generation of reactive oxygen species during resumption of normal perfusion may play a role in this vascular disruption.
Fantel
A G
AG
Department of Pediatrics, University of Washington, Seattle 98195-6320, USA.
Nekahi
N
N
Shepard
T H
TH
Cornel
L M
LM
Unis
A S
AS
Lemire
R J
RJ
D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects; D004334:Drug Administration Schedule; D004480:Ectromelia / Q000139:chemically induced; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects*; D006470:Hemorrhage; D006614:Hindlimb / Q000002:abnormalities / Q000187:drug effects / Q000473:pathology; D007274:Injections, Intraperitoneal; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000633:toxicity*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects
D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester