Haemodynamic responses to an angiotensin II receptor antagonist (GR 117289) in maternal and fetal sheep.
An AT1-specific angiotensin II receptor antagonist (GR117289; 1 mg/kg I.V. bolus) was administered daily to ten chronically catheterized, normotensive ewes during late pregnancy (from 126 +/- 1 days) until parturition (139 +/- 1 days); five control animals received an equivalent volume of vehicle solution. Following drug administration, mean maternal blood pressure decreased from 87 +/- 1 mmHg to a minimum of 79 +/- 1 mmHg at 0.5 h (P < 0.05; n = 10) and remained low for 4-6 h without any concomitant change in fetal blood pressure or maternal and fetal heart rates. In animals fitted with flow probes, uterine blood flow decreased from 443 +/- 21 to 363 +/- 27 ml/min at 0.5 h post-drug (P < 0.05; n = 6); this change was positively correlated with the reduction in maternal blood pressure. The mean decrements in uterine and umbilical blood flows measured by steady-state infusion of tritiated water were -611 +/- 171 ml/min at 4-6 h (P < 0.05; n = 5) and -71 +/- 19 ml/min at 0.5-1 h (P < 0.05; n = 5), respectively. Significant reductions (P < 0.05; n = 10) in fetal arterial oxygen tension (-1.6 +/- 0.4 mmHg), saturation (-6.6 +/- 1.6%) and content (-0.3 +/- 0.1 mumol/ml) were evident at 0.5 h post-drug and were maintained for 6-12 h. Umbilical oxygen delivery decreased at 0.5-1 h following drug administration (P < 0.01; n = 5), but was unaccompanied by any significant change in fetal oxygen consumption. Chronic decreases in daily fetal pH and blood oxygen content occurred in GR117289-treated ewes. There were no significant differences in gestational length or neonatal outcome between vehicle- and GR117289-treated groups of ewes with single fetuses.
Forhead
A J
AJ
Physiological Laboratory, University of Cambridge, UK.
Fowden
A L
AL
Silver
M
M
Hughes
P
P
Broughton-Pipkin
F
F
Sutherland
M F
MF
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005328:Fetal Viability / Q000187:drug effects; D005333:Fetus / Q000098:blood supply / Q000502:physiology*; D005865:Gestational Age; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D009539:Nicotinic Acids / Q000494:pharmacology*; D011247:Pregnancy; D012039:Regional Blood Flow / Q000502:physiology; D012756:Sheep / Q000196:embryology / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology*; D014599:Uterus / Q000098:blood supply
D057911:Angiotensin Receptor Antagonists; D009539:Nicotinic Acids; D013777:Tetrazoles; C078790:GR 117289