Regulation of vascular adaptation during pregnancy and post-partum: effects of nitric oxide inhibition and steroid hormones

Treatment of pregnant rats with the nitric oxide synthase inhibitorNG-nitro-L-arginine methyl ester (L-NAME), has been shown toproduce symptoms similar to pre-eclampsia (i.e. elevated bloodpressure, proteinuria and fetal growth retardation). After L-NAMEinfusion is initiated on day 17 or 18 of gestation, the bloodpressure proceeds in a biphasic pattern (immediate rise, followedby a decline, then increasing again in the post-partum period).The blood pressure actually begins to rise prior to deliveryon days 21–22, i.e. after progesterone withdrawal occurs,suggesting that these responses may be regulated by changesin steroid hormone concentrations during pregnancy. Therefore,we evaluated the effects of the different steroid hormones:progestins (progesterone, promegestone, levonorgestrel), antiprogestins(mifepristone), 17-oestra-diol or androgens (testosterone, dihydrotestosterone)on systolic blood pressure in pregnant, non-pregnant femaleand normal male rats with and without L-NAME treatment and spontaneouslyhypertensive male rats. The animals received continuous infusionsof L-NAME (150 mg/kg/day) or vehicle through osmotic mini-pumpsand daily s.c. injections of steroid hormones. In pregnant ratsthe pump was inserted on day 17 or 18 of gestation and steroidhormone injections were started on the first day following deliveryat term and continued daily until post-partum day 10. In non-pregnantfemale or male rats steroid hormone injections were initiated5 days after the L-NAME pump was inserted. Systolic blood pressurewas measured daily from the tail with a pneumatic tail-cuffdevice. R5020 (1.5 mg/kg/day) significantly attenuated the bloodpressure elevation induced by L-NAME during the post-partumperiod. Similarly, it lowered blood pressure in L-NAME treatednon-pregnant female rats or male rats. R5020 also lowered bloodpressure in spontaneously hypertensive male rats. Progesterone(6 mg/kg/day) had similar effects on blood pressure in the post-partumperiod, although it also lowered the blood pressure in controlanimals. Interestingly, administration of two different dosesof Ievonorgestrel (03 and 1.5 mg/kg/day) did not decrease theblood pressure in either L-NAME-infused rats or controls. Mifepristone(RU486, 30 mg/kg/day) further increased blood pressure in L-NAME-treatedrats post-partum. 17-oestradiol (30 ng/kg/day) had no effecton blood pressure in either L-NAME infused rats in the post-partumperiod or controls, whereas both testosterone (03 mg/kg/day)and dihydrotestosterone (0.3 mg/kg/day) significantly attenuatedthe blood pressure increase after L-NAME, while raising theblood pressure in vehicle-infused animals. These results suggestthat the control of systemic blood pressure during pregnancymay be modulated by steroid hormones. Progesterone may be thesteroid hormone with the major action on vascular tension duringpregnancy.