FETAL GROWTH-RETARDATION IN RATS MAY RESULT FROM APOPTOSIS - ROLE OF PEROXYNITRITE

Administration of the nitric oxide synthase (NOS) inhibitor NG-nitro-L -arginine methyl ester (L-NAME) results in fetal growth retardation. T his study was designed to further examine the influence of NO on fetal growth, specifically, the potential role of inducible NOS and to eval uate the possibility that apoptosis contributed to uteroplacental dysf unction. L-NAME administration caused a paradoxical increase in NO syn thesis determined by direct detection of NO by electrochemistry, nitri te accumulation, and cGMP levels, indicating that a lack of NO was not the cause of the fetal growth retardation. Additionally, supplemental L-arginine or NO donors failed to reverse the effects of L-NAME on fe tal and placental size. Administration of low dose endotoxin (30 mu g/ kg IP daily for 6 d) also caused significant reductions in fetal and p lacental size and increased NO synthesis comparable to that seen with L-NAME. Inducible NOS was constitutively expressed in the pregnant ute rus (smooth muscle and epithelia) and placenta (sinusoids and macropha ges) but was absent in the nonpregnant state as determined by RT-PCR a nd immunohistochemistry. Neither L-NAME nor endotoxin modified the exp ression of iNOS. In situ evidence for apoptosis (DNA fragmentation) wa s minimal to absent in control pregnant rats, but markedly evident in the placenta (decidua) and uterus of rats treated with L-NAME or endot oxin. Immunohistochemical evidence for nitrotyrosine, a marker for per oxynitrite formation, was absent in control rats but colocalized with apoptosis in the L-NAME and LPS groups. We conclude that L-NAME-induce d fetal growth retardation is not due to a lack of NO, but as for endo toxin, results from a net reduction in cellular proliferation due to t he induction of apoptosis, possibly in response to peroxynitrite forma tion.