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Effect of maternal dexamethasone treatment on circulating and tissue angiotensin-converting enzyme concentration in fetal sheep

Presented at the Neonatal Society 2004 Summer Meeting (programme).

Johnson E, Giussani DA, Fowden AL, Forhead AJ

Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK

Introduction: Angiotensin-converting enzyme (ACE) catalyses the production of angiotensin II and the degradation of bradykinin. In adult life, the enzyme is primarily found in the pulmonary vasculature. However, in the fetus, pulmonary blood flow is relatively low, and the placenta is an alterative site of ACE activity. In preparation for birth, ACE content in the fetal circulation, lungs and kidneys increases towards term in association with the prepartum rises in cortisol and triiodothyronine (T3). Intravenous infusion of cortisol, dexamethasone (DEX) or T3 to the sheep fetus has been shown to elevate pulmonary, but not renal, ACE concentration. This study investigated the effect of maternal DEX treatment, in clinically relevant doses, on circulating and tissue ACE concentrations in fetal sheep.

Methods: From 125 days of gestation (term 145 2 days), 10 ewes carrying single fetuses were injected twice i.m. with either saline (0.9% NaCl, n = 5) or DEX (2 x 12 mg in 2 ml 0.9% NaCl, n = 5) at 24 hour intervals. Ten hours after the second injection, the ewes and fetuses were euthanised, and umbilical arterial blood, lungs and kidneys were collected. Plasma and tissue ACE concentrations were measured by a spectrophotometric enzyme assay, and plasma cortisol, T3 and thyroxine (T4) were determined by radioimmunoassay. Data (mean SEM) were analysed by unpaired t-test and linear regression.

Results: In the DEX-exposed fetuses, plasma cortisol was significantly lower (8.6 0.7 vs 16.1 2.8 ng ml-1, p < 0.05) and plasma T3 was significantly higher (0.77 0.05 vs 0.28 0.06 ng ml-1, p < 0.001) than in the control fetuses. Plasma T4 concentration was similar in the two groups of fetuses (saline 132.5 11.7 vs DEX 126.3 22.0 ng ml-1). Maternal DEX treatment caused significant increments in both plasma and pulmonary ACE concentration in the sheep fetus (Figure 1, p < 0.05). No significant difference in renal ACE was seen between the saline and DEX-exposed fetuses (saline 1.54 0.08 vs DEX 1.78 0.31 nmoles min-1 mg protein-1). When values from all fetuses were considered, significant correlations were observed between plasma T3 and ACE in both the plasma (r = 0.63, p < 0.05, n = 10) and lungs (r = 0.82, p < 0.005, n = 10).

Conclusions: Maternal DEX treatment increases circulating and pulmonary ACE concentrations in the sheep fetus. These findings have implications for glucocorticoid-induced maturation of the fetal renin-angiotensin system, and the control of cardiovascular and renal function over the perinatal period.

Acknowledgements: Supported by the BBSRC and Tommy's, the baby charity.

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