Abstract 118: Fetal Betamethasone Exposure Enhances the Peptide Ratio of Angiotensin II to Angiotensin-(1-7) in the Dorsal Medulla of Adult Sheep

Abstract

Betamethasone (BMS) is administered to women entering into early preterm labor to facilitate fetal lung development and decrease infant mortality; however, fetal steroid exposure may lead to deleterious consequences long term. In a sheep model of BMS exposure in utero, we show elevated mean arterial pressure (MAP) and decreased baroreflex sensitivity (BRS) for control of heart rate at 6- and 20-months (mo) of age. The changes in MAP and BRS are associated with alterations in components of both the circulating and intra-renal renin-angiotensin systems (RAS) that may ultimately shift the balance to the pro-hypertensive peptide, angiotensin (Ang) II. In the brain solitary tract nucleus, Ang II actions through the AT 1 receptor oppose the beneficial actions of Ang-(1-7) at the mas receptor for BRS regulation. We found decreased expression of the mas protein in the dorsal medulla of BMS-exposed animals at 6- and 20- months of age with no changes in the AT 1 receptor expression. To determine whether tissue Ang peptides may contribute to altered BRS, the present study utilized three selective radioimmunoassay (RIAs) to quantify Ang I, Ang II and Ang-(1-7) in the dorsal medulla of 6-mo old male sheep. Comparisons of tissue peptide concentrations were not significantly different between groups; however, BMS-exposed offspring have a significant increase in the ratio of Ang II to Ang-(1-7) (Control: 0.61 ± 0.11, BMS: 2.3 ± 0.62; p<0.05). There was a significant increase in the ratio of Ang II to Ang I (Control: 0.66 ± 0.20, BMS: 2.35 ± 0.46), with no change in the ratio of Ang-(1-7) to Ang I. The altered peptide ratios potentially reflect a decrease in the ACE2 enzyme, which converts Ang II to Ang-(1-7), and an increase in ACE activity which concerts Ang I to Ang II. Future studies are required to determine enzymatic activity in dorsal medullary tissue, but data are consistent with previous observations on altered ACE and ACE2 in the circulation and kidney of BMS-exposed animals. We conclude that BMS-depedent fetal programming may influence the central RAS through alterations in the balance of Ang II and Ang-(1-7) that contribute to the elevated MAP, lower BRS, and altered renal function in this model. Support: HD0474584