title: Effects of inhibition of the maternal renin-angiotensin system on maternal and fetal responses to drainage of fetal fluids.
abstract: To find out which of the effects of angiotensin converting enzyme (ACE) inhibitors on the fetus are due to their actions in the mother and which are direct effects due to blockade of the fetal renin-angiotensin system, enalapril (150 mg twice daily i.v.), which does not readily cross the sheep placenta, was given for 3 days to nine chronically catheterized pregnant ewes, 5 days after fetal urine and lung liquid had been continuously drained and while drainage of these fetal fluids continued. Drainage of fetal fluids was carried out so that a net sodium deficit would be incurred, and the dependency of the ewe on the activity of her renin-angiotensin system (RAS) for maintenance of her arterial pressure and fluid and electrolyte balance would be increased. During drainage of fetal fluids ewes drank more and increased their net water balance (p < 0.025). With enalapril, ewes became hypotensive (p < 0.005), but heart rate did not change. Maternal plasma potassium (K) levels increased (p < 0.05) and the plasma sodium to potassium ratio (Na:K) decreased (p < 0.005). Enalapril did not reduce maternal water intake nor change her urine output. After 5 days of drainage, fetal plasma K levels (p < 0.05) were higher and plasma Na:K (p < 0.025) was lower. After maternal enalapril, lung liquid flow and electrolyte excretion were transiently reduced (p < 0.05). Fetal plasma K levels increased further (p < 0.025) and plasma Na:K ratio decreased (p < 0.025 - p < 0.01). Fetal arterial PO2 was reduced 2 h after enalapril (p < 0.005) and was low on the last 2 days of treatment. Although fetal fractional reabsorption of K fell (p < 0.01) by the last day of enalapril treatment, the increase in fetal K excretion was not significant, because by this time sufficient enalapril was present in the fetal circulation to reduce glomerular filtration rate (GFR, p < 0.025 - p < 0.001). It is concluded that the toxicity of ACE inhibitors may be related to those effects in the ewe that lead to reduced fetal arterial oxygen levels and increased fetal plasma K levels. In the latter case it is postulated that inhibition of the maternal RAS may leave ewe and fetus deficient in aldosterone, leading to the rise in K levels. Thus the toxic effects of ACE inhibitors can be mediated through their effects on the mother, but their ability to cause fetal renal failure and oligohydramnios is due to their direct effects on the fetal RAS.
authors.affiliation: School of Physiology and Pharmacology, University of New South Wales, Sydney, Australia.
authors.forename: E R
authors.initials: ER
authors.lastname: Lumbers
authors.forename: C
authors.initials: C
authors.lastname: Bernasconi
authors.forename: J H
authors.initials: JH
authors.lastname: Burrell
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001826:Body Fluids / Q000502:physiology; D004322:Drainage; D004656:Enalapril / Q000494:pharmacology; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000502:physiology*; D007668:Kidney / Q000196:embryology / Q000502:physiology; D008168:Lung / Q000196:embryology / Q000502:physiology; D010100:Oxygen / Q000097:blood; D011188:Potassium / Q000097:blood; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000097:blood / Q000187:drug effects* / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology*; D012756:Sheep; D012964:Sodium / Q000097:blood
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D012964:Sodium; D011188:Potassium; D010100:Oxygen