Pre-eclampsia-like conditions produced by nitric oxide inhibition: effects of L-arginine, D-arginine and steroid hormones

The aim of this study was to establish that inhibiting nitricoxide (NO) production with N^G-nitro-L-arginine methyl ester(L-NAME) results in high blood pressure conditions in chronicallytreated pregnant rats. To validate the model,the effects ofL-arginine (the substrate for NO) and Darginine (the stereoisomerof L-arginine which is not substrate for NO synthesis) werestudied on blood pressure and fetal weights. The effects ofa progesterone agonist, promegestone (R5020) and 17-oestradiolwere also explored. The NO synthase inhibitor L-NAME was chronicallyinfused s.c. into pregnant rats from day 17 of gestation, eitheralone or with the simultaneous infusion of L-arginine and injectionsof sex steroid hormones (promegestone and oestradiol), compoundsthat may act in the pathogenic pathways of pre-eclampsia. Systolicblood pressure was measured daily. Weight and mortality of pupswere recorded immediately after delivery. Blood pressure waselevated significantly in rats treated with L-NAME for only1 day following infusion; there was a consistent decline duringthe next 3 days of pregnancy followed by a dramatic and significantrise just prior to delivery and post-partum. Fetal weights werereduced significantly in the L-NAMEtreated rats. Co-treatmentof L-NAME-infused rats with L-arginine reversed both the increasein blood pressure and the decrease in fetal weights observedwith L-NAME alone. R5020, but not oestradiol, also reduced bloodpressure and increased fetal weights in the L-NAME-treated animals.NO appears to play essential roles in the regulation of bloodpressure during pregnancy, as well as in fetal perfusion andfetal weights at delivery. This study also indicates that progesterone,and not oestrogen, may regulate the vascular adaptations duringnormal pregnancy. LArginine and progesterone agonists like promegestonemay have beneficial effects on the high blood pressure levelsand reduced fetal weights associated with pre-eclampsia.