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Free radical formation and toxicity in the limb teratogenicity of L-NAME. a new mechanistic model of vascular disruption.
In studies of limb effects of exposure to N G -nitro-L -Arginine Methyl Ester (L-NAME), we examined the time course of vascular changes and the effectiveness of intraamniotic injection. Vascular engorgement and hemorrhage occurred within 4 hours of L-NAME treatment on gd-17 and direct injection effectively induced limb hemorrhage. Further studies examined protein nitration and electron transport inhibition.
L-NAME caused significant increases in nitrotyrosine (NT) formation in limb but not in heart or brain and promptly reduced electron transport rates in limb. Three agents, ฮฑ-phenyl-N-t-butylnitrone (PBN), a radical trap and inhibitor of inducible nitric oxide synthase (iNOS), allopurinol, an inhibitor of xanthine oxidase and aminoguanidine, a relatively specific inhibitor of iNOS, significantly moderated hemorrhage and protein nitration in distal limb. These results suggest that L-NAME directly effects fetal limb vasculature and indicate a cytotoxic role for peroxynitrite, the reaction product of nitric oxide and superoxide, a potent oxidant and nitrating agent. We propose that vascular disruption involves 2 sequential stages. In the prompt stage, nitric oxide ( โข NO) deficiency causes vascular leakage leading to ischemia that induces iNOS. The second stage, resulting from the consequent overproduction of โข NO and its reaction with superoxide, causes nitration and oxidation of cellular constituents, initiating apoptosis and/or necrosis.
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