Comparison of ANG II in fetal and pregnant sheep: Metabolic clearance and vascular sensitivity

Fetal sheep appear less responsive to infused angiotensin II (ANG II) than pregnant ewes. This may reflect a greater fetal metabolic clearance rate (MCR(ANG II)) and thus lower plasma ANG II levels. We therefore determined fetal MCR(ANG II), half-life (T 1/2 ), and placental removal of ANG IL Fetal sheep (n = 13; 113-139 days of gestation) received 0.573-5.73 μg ANG II/min iv for 30 min while arterial pressure and heart rate were monitored. Serial blood samples were obtained before and during a 30-min infusion to measure ANG II and calculate MCR(ANG II) and after stopping the infusion to determine T 1/2 MCR(ANG II) was similar across gestation and at doses ≤2.29 μg/min (683 ± 49 vs. 74 ± 5 ml · min^-1 · kg^-1 for adults) but was 30-40% lower with 5.73 μg ANG II/min (494 ± 5 ml · min^-1 · kg^-1, P < 0.05). T 1/2 was 15-21 s. Fetal placental ANG II removal averaged 87 ± 3 vs. 20 ± 6% for uteroplacental removal; this was unaffected by dose and was linear with plasma ANG II levels, and saturation was not evident. Plasma ANG II levels rose proportionally with infusion rate and did not change significantly over time; thus fetal plasma ANG II concentrations can he predicted from MCR(ANG II). Measured and predicted ANG II levels at each infusion rate and time point were similar: r = 0.87, slope = 0.87 (P < 0.001). At equivalent predicted plasma ANG II levels fetal and maternal pressor responses were similar (P > 0.1); however, increases in umbilical vascular resistance exceeded those in uteroplacental vascular resistance (P < 0.03). Fetal MCR(ANG II) is ~ 10-fold greater than maternal, partially reflecting the extensive capacity of ANG II removal by the placental circulation. Contrary to previous conclusions, fetal-maternal pressor sensitivity to ANG II does not differ, whereas the placental vasculature is more sensitive to ANG II than the uteroplacental circulation.