Glucocorticoids increase blood pressure in utero although the mechanisms responsible are unclear. This study investigated the role of angiotensin II (AII) in the hypertensive actions of cortisol in fetal sheep during late gestation.
Under general anaesthesia (1.5 % halothane in O2/N2O), vascular catheters were implanted into 27 sheep fetuses. From 124 ± 1 days of gestation (term 145 ± 2 days), the fetuses were infused I.V. for 5 days with either: (1) saline (0.9 % NaCl at 2.5 ml day-1, n = 6), (2) cortisol (3-5 mg kg-1 day-1, n = 7), (3) AII type 1 (AT1) receptor antagonist (GR138950, 1-3 mg kg-1 day-1 in saline, GRS, n = 7), or (4) cortisol and GR138950 (GRC, n = 7). For 2 days before and during the infusion, blood samples, arterial blood pressure and pressor responses to exogenous AII (100 ng kg-1) were obtained daily from the fetuses. All ewes and fetuses were killed according to UK legislation on the fifth day of infusion, and fetal aortae and femoral and carotid arteries were fixed in 10 % formaldehyde. Blood pressure, less amniotic pressure, was measured using pressure transducers and standard recording equipment, and plasma cortisol was measured by RIA. Tunica media area, smooth muscle cell (SMC) nuclei density and proliferation were assessed using histochemical staining (α-SMC actin, haematoxylin and proliferating cell nuclear antigen, respectively). All data were analysed by either one-way ANOVA or two-way ANOVA with repeated measures followed by the Student-Newman-Keuls test.
On all days of infusion, plasma cortisol was greater in both groups of cortisol-infused fetuses than in the respective control fetuses (P < 0.05), and GR138950 prevented the pressor response to exogenous AII. Over 5 days of infusion, blood pressure rose by a maximum of 7.6 ± 1.4 mmHg (mean ± S.E.M., P < 0.05) in cortisol, but not saline-infused, fetuses; GR138950 caused similar decreases in blood pressure in both GRS and GRC groups (P < 0.05). In GRS-treated fetuses, the fall in blood pressure was significant from the first day of infusion while in GRC-treated fetuses, the decrement was not significant until the second day (P < 0.05). There were no differences between the groups in tunica media area, or the number and density of total and dividing SMC in any of the vessels studied.
Therefore, in the sheep fetus, 5 days of AT1 receptor antagonism suppresses the cortisol-induced rise in blood pressure. These results suggest that cortisol may increase blood pressure within 24 h of administration by a mechanism that is independent of the fetal renin-angiotensin system. Thereafter, AII, via the AT1 receptor, may mediate, in part, the hypertensive effects of cortisol in utero, although this appears not to involve changes in arterial SMC number.
This work was supported by The Royal Society.