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.
The effects of maternal administration of either an angiotensin II type 1 (AT1) receptor antagonist (GR138950) 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-1 h-1 (15.6, 80.7); P < 0.05) or captopril (+22.1 ng ml-1 h-1 (19.2, 28.8); P < 0.05). Maternal plasma concentrations of angiotensin II (AII) also increased by 871 pg ml-1 (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 (+11.6 ng ml-1 h-1 (1.2, 18.6); P < 0.05) or captopril (+59.3 ng ml-1 h-1 (41.7, 74.6); P < 0.05). These short-term changes in circulating renin and AII 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 microgram ml-1 (-0.58, -0.16); P < 0.05) and the fetus (-0.43 microgram ml-1 (-0.59, -0.09); P < 0.05). A long-term reduction in maternal plasma AII, and an increase in fetal plasma renin concentration, were associated with 1 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 AII activity, either by blockade of the AT1 receptor or by inhibition of AII 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 AII activity.
Forhead
A J
AJ
Physiological Laboratory, University of Cambridge, UK.
Broughton Pipkin
F
F
Sutherland
M F
MF
Fowden
A L
AL
D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000808:Angiotensinogen / Q000097:blood; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000502:physiology*; D005865:Gestational Age; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood / Q000187:drug effects / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D012756:Sheep
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001572:Benzofurans; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000808:Angiotensinogen; D000804:Angiotensin II; D002216:Captopril; D012083:Renin; C089586:saprisartan potassium