Comparison of angiotensin II type 1 receptor blockade and angiotensin‐converting enzyme inhibition in pregnant sheep during late gestation

• Published in: British journal of pharmacology 1996-09, Vol.119 (2), p.393-401
• Main Authors: Forhead, Alison J., Whybrew, Katherine, Hughes, Paul, Pipkin, Fiona Broughton, Sutherland, Mark, Fowden, Abigail L.
• Format: Article
• Language: English
• Subjects: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors - pharmacology; angiotensin‐converting enzyme inhibitor; Animals; Antihypertensive agents; AT1 receptor antagonist; Benzofurans - pharmacology; Biological and medical sciences; blood pressure; captopril; Captopril - pharmacology; Cardiovascular Physiological Phenomena; Cardiovascular system; Cardiovascular System - drug effects; Female; foetus; Gestational Age; GR138950; Hemoglobins - drug effects; Hemoglobins - metabolism; Medical sciences; Pharmacology. Drug treatments; Pregnancy; Pregnancy, Animal - drug effects; Pregnancy, Animal - metabolism; Pregnancy, Animal - physiology; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System - drug effects; Sheep
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15999.x

1 The effects of antagonism of the maternal renin‐angiotensin system (RAS) with either an angiotensin II type 1‐(AT1) specific receptor blocker (GR138950) or an angiotensin‐converting enzyme (ACE) inhibitor (captopril) were compared in chronically‐catheterised ewes and their foetuses during late gestation. 2 Daily from 127 ± 1 days of gestation until parturition at 145 ± 2 days, each ewe received i.v. either GR138950 (3 mg kg−1; n = 10), captopril (3 mg kg−1; n = 6) or an equivalent volume of vehicle solution (0.9% w/v saline; n = 10). 3 Within 2 h of drug administration, GR138950 abolished the maternal, but not the foetal, pressor responses to angiotensin II (AII; 100–188 ng kg−1, i.v.; P < 0.05), whereas captopril abolished both the maternal and foetal pressor 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 remained 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 (O2) content increased at 2 h in all GR138950‐treated and captopril‐treated ewes. Foetal arterial pH and oxygenation (O2 content, O2 saturation and PaO2) were reduced by a similar extent in both groups of drug‐treated ewes. 6 After one week of daily GR138950 administration, maternal blood pressure decreased from a pretreatment value of 96 ± 5 mmHg on day 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 in foetal blood pressure in all three groups of animals. 7 There were no long‐term effects of drug administration on maternal Hb concentration 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 ±