The effect of chronic stimulation and inhibition of the renin-angiotensin system on hepatic angiotensinogen concentrations in the late gestation ovine fetus.
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文摘
Angiotensinogen, the primary substrate for renin in the fetal circulation, may play a major role in the regulation of the fetal RAS. Chronic activation of the RAS by the infusion of enalaprilat decreases plasma angiotensinogen, while chronic inhibition of the RAS by the infusion of Angiotensin II (AII) increases plasma angiotensinogen. Our objective is to correlate angiotensinogen concentration in the fetal liver, the major site of synthesis, with changes in the plasma angiotensinogen concentration seen with chronic stimulation and inhibition of the RAS. Eighteen late gestation fetal sheep were prepared with arterial and venous femoral catheters and an intra-amniotic catheter. Fetuses were studied at least 4 days post-operatively at a mean gestational age of 129 ± 1 days. Each fetus was infused for 72 hours with D5W (n=7), enalaprilat (n=5), or AII (n=6). Fetal arterial blood samples were obtained prior to and after the infusion. Fetal arterial blood pressure was recorded continuously for a control period, the initial 4 hours of infusion, then daily. Liver angiotensinogen content was measured indirectly by incubating liver homogenates (in 0.1M phosphate, 1.5M (NH4)2SO4 protease inhibitor solution, pH5.7) with excess renin for 30 minutes at 37° C. Data were analyzed using ANOVA and p<0.05 was considered statistically significant. Fetal arterial blood gases and hematocrit were normal in all groups prior to infusion. The liver tissue angiotensinogen concentration was 269 ± 33 ng angiotensin I (AI)/gm/hr in the control animals, decreasing to 204 ± 13.3 ng AI/gm/hr with enalaprilat infusion and increasing to 385 ± 61 ng AI/gm/hr with AII infusion. This correlated with a plasma angiotensinogen concentration of 660 ± 40 ng AI/ml/hr after control infusion, 104 ± 53 ng AI/ml/hr after enalaprilat infusion, and 847 ± 45 ng AI/ml/hr after AII infusion. In conclusion, the hepatic concentration of angiotensinogen correlates with changes in the plasma concentration of angiotensinogen, decreasing with activation of the RAS by enalaprilat infusion and increasing with inhibition of the RAS by AII infusion. This suggests that regulation of the plasma angiotensinogen concentration may occur at the level of hepatic synthesis in the late gestation fetus.