Changes in the maternal and fetal renin‐angiotensin systems in response to angiotensin II type 1 receptor blockade and angiotensin‐converting enzyme inhibition in pregnant sheep during late gestation

Abstract

SUMMARYThe effects of maternal administration of either an angiotensin II type 1 (AT1) receptor antagonist (GR 138950) or an angiotensin-converting enzyme (ACE) inhibitor (captopril) on the renin-angiotensin system (RAS) were investigated in chronically catheterized ewes and their fetuses during late gestation. From 127 + 1 days of gestation until parturition at 145 + 2 days, each ewe received daily I.v. injections of GR138950 (3 mg kg-1, n = 10 animals) or captopril (3 mg kg-1, n = 6) or an equivalent volume of vehicle solution (0.9 % NaCl, n = 10). On the first day of treatment, plasma renin concentrations in the pregnant ewe increased within 2 h of administration of either GR138950 (median change followed by lower and upper quartiles (25 %, 75 %): +38-3 ng ml-' h-1 (15.6, 80.7); P < 0.05) or captopril (+22.1 ng ml-1 h-' (19.2, 28.8); P < 0.05). Maternal plasma concentrations of angiotensin II (All) also increased by 871 pg ml-' (555, 1340; P < 0 05) in the GR138950-treated ewes. In the fetuses of both groups of drug-treated animals, an increase in plasma renin concentration was observed within 2 h of maternal treatment with either GR138950 (+1 1.6 ng ml-' h-' (1.2, 18.6); P < 0 05) or captopril (+59-3 ng ml-' h-' (41.7, 74.6); P < 0.05).These short-term changes in circulating renin and All concentrations observed in the pregnant ewe were sustained after 1 week of GR138950 administration. In addition, 1 week of GR138950 treatment decreased plasma angiotensinogen (Ao) concentrations in both the ewe (-0.36 jug ml-1 (-0 58, -0.16); P < 0.05) and the fetus (-0 43 ,ug ml-1 (-0 59, -0.09); P < 0.05). A long-term reduction in maternal plasma All, and an increase in fetal plasma renin concentration, were associated with I week of captopril administration. Neither drug had any consistent efFect on plasma ACTH or cortisol concentrations in the pregnant ewe or fetus. These findings show that, during ovine pregnancy, antagonism of maternal All activity, either by blockade of the AT1 receptor or by inhibition of All synthesis, induces changes in the circulating components of the RAS in the mother and fetus. In both the pregnant ewe and fetus, the RAS is shown to be activated by suppression of All activity.

Role of Angiotensin II in the Periovulatory Epidermal Growth Factor-Like Cascade in Bovine Granulosa Cells In Vitro1

“…To minimize potential confounding effects of renin-angiotensinogen molecules in serum [32], we employed a granulosa cell culture system in which treatments were applied under defined conditions. Bovine ovaries were collected from adult cows, irrespective of stage of the estrous cycle, at a local abattoir and were transported to the laboratory in PBS at 358C containing penicillin (100 IU/ml), streptomycin (100 lg/ml), and fungizone (1 lg/ml).…”

Renal growth retardation following angiotensin II type 1 (AT1) receptor antagonism is associated with increased AT2 receptor protein in fetal sheep

“…In the GR-treated fetuses, the activity of the AT 2 receptor in the kidney is likely to increase not only by upregulation of receptor protein content but also by binding of elevated circulating levels of AII. Plasma AII concentration is raised during AT 1 receptor antagonism due to a decrease in feedback inhibition of renin production by AII via AT 1 receptors (Forhead et al 1997, de Gasparo et al 2000.…”

“…In addition, the extent to which AT 1 receptor blockade influences renal expression of the AT 1 and AT 2 receptor subtypes is unknown in the developing kidney. Changes in AT 2 receptor expression are of particular interest as the unblocked receptor subtype is exposed to high concentrations of AII following loss of negative feedback on renin release during AT 1 -specific receptor antagonism (Forhead et al 1997, de Gasparo et al 2000.…”

A “cure” for preeclampsia: Improving neonatal outcomes by overcoming excess fetal placental vascular resistance

“…125 More recently it has been found that the RAAS system is more active in the placental vascular beds of preeclamptics compared to normal patients. 127 Angiotensin II from the mother is probably required for trophoblast invasion of the endometrium in mammals. 126 There is a very active RAAS system in the fetus and this becomes more active with Angiotensin converting enzyme (ACE) blockade.…”