The nitric oxide synthesis inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) causes limb defects in mouse fetuses: protective effect of acute hyperoxia.
In the present study the relationship between exposure to the nitric oxide synthesis inhibitor Nomega-nitro-l-arginine methyl ester (l-NAME) and the induction of limb defects, with respect to stage specificity and dose dependency, was investigated in the mouse. ICR (CD-1) mice were dosed s.c with l-NAME at 50 or 90 mg/kg on gestation d 12, 13, 14, 15, or 16. A group of animals treated with vehicle on gestation d 14 served as control. Uterine contents were evaluated for teratogenesis on gestation d 18. A treatment-related disruption of limb development was noted. The effect was dose dependent and phase specific. l-NAME became teratogenically operational on gestation d 13 and elicited its maximum effect on gestation d 14, whereas no significant teratogenicity was observed when exposure occurred after gestation d 15. In utero exposure to l-NAME also reduced embryo viability relative to controls. When the higher dose was injected on gestation d 16, a significant number of dams delivered preterm. In a parallel study, the ability of hyperoxia to prevent limb teratogenesis was investigated. To this aim, a group of l-NAME-treated animals (90 mg/kg s.c. on gestation d 14) were exposed to 98 to 100% O(2) for 12 h. l-NAME-treated mice breathing room air served as positive controls. In response to hyperoxia, a significant decrement of l-NAME-induced limb defects was found. This study characterizes for the first time the teratogenic capacity of l-NAME in the mouse. Results obtained with hyperoxia fit the hypothesis that hypoxic tissue damage may play a contributory role in l-NAME-induced limb defects.
Tiboni
Gian Mario
GM
Sezione di Ostetricia e Ginecologia, Dipartimento di Medicina e Scienze dell'Invecchiamento, Facoltà di Medicina e Chirurgia, Università "G d'Annunzio," Chieti, Italy. tiboni@unich.it
Giampietro
Franca
F
Di Giulio
Camillo
C
D000818:Animals; D021461:Animals, Outbred Strains; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D018496:Hyperoxia / Q000503:physiopathology*; D000860:Hypoxia / Q000139:chemically induced / Q000503:physiopathology; D017880:Limb Deformities, Congenital / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology; D011247:Pregnancy; D013723:Teratogens / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D013723:Teratogens; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester