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

Abstract

Treatment of pregnant rats with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), has been shown to produce symptoms similar to pre-eclampsia (i.e. elevated blood pressure, proteinuria and fetal growth retardation). After L-NAME infusion is initiated on day 17 or 18 of gestation, the blood pressure proceeds in a biphasic pattern (immediate rise, followed by a decline, then increasing again in the post-partum period). The blood pressure actually begins to rise prior to delivery on days 21-22, i.e. after progesterone withdrawal occurs, suggesting that these responses may be regulated by changes in steroid hormone concentrations during pregnancy. Therefore, we evaluated the effects of the different steroid hormones: progestins (progesterone, promegestone, levonorgestrel), antiprogestins (mifepristone), 17 beta-oestradiol or androgens (testosterone, dihydrotestosterone) on systolic blood pressure in pregnant, non-pregnant female and normal male rats with and without L-NAME treatment and spontaneously hypertensive male rats. The animals received continuous infusions of L-NAME (150 mg/kg/day) or vehicle through osmotic mini-pumps and daily s.c. injections of steroid hormones. In pregnant rats the pump was inserted on day 17 or 18 of gestation and steroid hormone injections were started on the first day following delivery at term and continued daily until post-partum day 10. In non-pregnant female or male rats steroid hormone injections were initiated 5 days after the L-NAME pump was inserted. Systolic blood pressure was measured daily from the tail with a pneumatic tail-cuff device. R5020 (1.5 mg/kg/day) significantly attenuated the blood pressure elevation induced by L-NAME during the post-partum period. Similarly, it lowered blood pressure in L-NAME treated non-pregnant female rats or male rats. R5020 also lowered blood pressure in spontaneously hypertensive male rats. Progesterone (6 mg/kg/day) had similar effects on blood pressure in the post-partum period, although it also lowered the blood pressure in control animals. Interestingly, administration of two different doses of levonorgestrel (0.3 and 1.5 mg/kg/day) did not decrease the blood pressure in either L-NAME-infused rats or controls. Mifepristone (RU486, 30 mg/kg/day) further increased blood pressure in L-NAME-treated rats post-partum. 17 beta-oestradiol (30 micrograms/kg/day) had no effect on blood pressure in either L-NAME infused rats in the post-partum period or controls, whereas both testosterone (0.3 mg/kg/day) and dihydrotestosterone (0.3 mg/kg/day) significantly attenuated the blood pressure increase after L-NAME, while raising the blood pressure in vehicle-infused animals. These results suggest that the control of systemic blood pressure during pregnancy may be modulated by steroid hormones. Progesterone may be the steroid hormone with the major action on vascular tension during pregnancy.