Effects of losartan on the cardiovascular system, renal haemodynamics and function and lung liquid flow in fetal sheep.
1. The angiotensin type 1 (AT1) receptor antagonist, losartan (10 mg/kg) was infused intravenously into nine chronically catheterized fetal sheep (125-132 days gestation). Losartan reduced the fetal systolic (P <0.01) and diastolic (P <0.01) pressor response to 5 microg angiotensin II (AngII) i.v. from 27.4 +/- 1.5 to 7.4+/-0.9 and from 17.5 +/- 1.3 to 5.4 +/- 0.6 mmHg, respectively, after 1 h and to 6.1 +/- 0.5 and 4.4 +/- 0.5 mmHg, respectively, after 2 h. Maternal pressor responses to 5 microg AngII i.v. were unchanged. Fetal mean arterial pressure decreased (P <0.05) after losartan administration, but fetal heart rate did not change. 2. Fetal haematocrit increased (P <0.05), fetal PO2 decreased (P <0.01), PCO2 did not change and pH decreased (P <0.01), as did plasma bicarbonate levels (P <0.01) following administration of losartan. Thus, losartan induced a fetal metabolic acidosis. 3. Fetal placental blood flow did not change following administration of losartan. In the fetal kidney, losartan caused a decrease in vascular resistance (P <0.01) and an increase in blood flow (P <0.05). Glomerular filtration rate decreased (P <0.05); thus, filtration fraction decreased (P <0.01). There was no change in the fractional reabsorption of sodium and glomerulotubular balance was maintained. Free water clearance decreased (P <0.01) and became negative. Urine flow decreased (P <0.01), the excretion rates of sodium, potassium and chloride did not change, but the urinary sodium: potassium ratio decreased (P <0.05). There was a decrease in lung liquid flow (P <0.05) following losartan. 4. It is concluded that the fetal renin-angiotensin system (RAS) is important in the maintenance of fetal arterial pressure, the regulation of fetal renal blood flow and is essential in the maintenance of fetal glomerular function. Further, these actions of AngII are mediated via functional AT1 receptors. These effects of losartan on the fetal cardiovascular system, renal blood flow and function are similar to those observed following captopril administration. Thus, the effects of angiotensin converting enzyme (ACE) inhibition in the foetus are due to the blockade of the fetal RAS and are independent of any direct effects on bradykinin or prostaglandin levels.
Stevenson
K M
KM
School of Physiology and Pharmacology, University of New South Wales, Sydney, Australia.
Gibson
K J
KJ
Lumbers
E R
ER
D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001826:Body Fluids; D005260:Female; D005333:Fetus / Q000187:drug effects*; D007093:Imidazoles / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D019808:Losartan; D008168:Lung / Q000187:drug effects; D011247:Pregnancy; D012079:Renal Circulation / Q000187:drug effects*; D012756:Sheep; D013777:Tetrazoles / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D014563:Urodynamics / Q000187:drug effects
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D019808:Losartan