COMPARISON OF ANGIOTENSIN-II TYPE-1 RECEPTOR BLOCKADE AND ANGIOTENSIN-CONVERTING ENZYME-INHIBITION IN PREGNANT SHEEP DURING LATE-GESTATION

1 The effects of antagonism of the maternal renin-angiotensin system ( RAS) with either an angiotensin II type 1-(AT(1)) specific receptor bl ocker (GR138950) or an angiotensin-converting enzyme (ACE) inhibitor ( captopril) were compared in chronically-catheterised ewes and their fo etuses during late gestation. 2 Daily from 127+/-1 days of gestation u ntil parturition at 145+/-2 days, each ewe received i.v. either GR1389 50 (3 mg kg-1; n = 10), captopril (3 mg kg(-1); n = 6) or an equivalen t volume of vehicle solution (0.9% w/v saline; n = 10). 3 Within 2 h o f drug administration, GR138950 abolished the maternal, but not the fo etal, presser responses to angiotensin II (AII; 100-188 ng kg(-1), i.v .; P<0.05), whereas captopril abolished both the maternal and foetal p resser responses to angiotensin I (AI; 400-750 ng kg(-1), i.v.; P<0.05 ). 4 On the first day of treatment, maternal blood pressure decreased in all GR138950-treated (-21+/-4 mmHg; P<0.05) and captopril-treated ( -13+/-5 mmHg; P>0.05) ewes at 2 h after drug administration. Captopril also significantly decreased foetal blood pressure by 5+/-1 mmHg (P<0 .05). However, foetal blood pressure in the GR138950-treated animals r emained unchanged. Maternal and foetal heart rates were unaffected by any treatment. Uterine blood flow was significantly reduced within 2 h of both GR138950 (-130+/-20 ml min(-1); P<0.05) and captopril (-72+/- 16 ml min(-1); P<0.05) administration. 5 On the first day of treatment , maternal arterial haemoglobin (Hb) concentration and oxygen (O-2) co ntent increased at 2 h in all GR138950-treated and captopril-treated e wes. Foetal arterial pH and oxygenation (O-2 content, O-2 saturation a nd PaO2) were reduced by a similar extent in both groups of drug-treat ed ewes. 6 After one week of daily GR138950 administration, maternal b lood pressure decreased from a pretreatment value of 96+/-5 mmHg on da y 1 to 79+/-2 mmHg by day 7 (P<0.05). Captopril treatment had no long- term effect on maternal blood pressure. Although foetal blood pressure increased by 3+/-1 mmHg over a week of vehicle treatment (P<0.05), no significant differences were observed between the long-term changes i n foetal blood pressure in all three groups of animals. 7 There were n o long-term effects of drug administration on maternal Hb concentratio n or oxygenation, or on the foetal haematological parameters. However, changes in maternal PaCo2 observed in the GR138950-treated (+1.4+/-0. 5 mmHg; P<0.05) and captopril-treated (+3.3+/-1.1 mmHg; P>0.05) ewes w ere significantly different from those seen in the vehicle-treated ani mals (P<0.05). 8 There were no apparent adverse effects of maternal GR 138950 or captopril treatment on foetal viability. 9 The present study demonstrated that administration of either GR138950 or captopril to p regnant ewes effectively blocked the maternal RAS, and caused hypotens ion and a decrease in uterine blood flow. However, only captopril appe ared to cross the placenta to influence directly the RAS of the sheep foetus. This suggests that the fall in foetal oxygenation observed aft er AT(1)-specific receptor blockade and ACE inhibition originates prim arily from changes in the maternal and/or placental vasculature. Despi te these changes, neither GR138950 nor captopril were detrimental to t he outcome of pregnancy when foetal blood loss was kept to a minimum.