Antenatal betamethasone exposure is associated with lower ANG-(1-7) and increased ACE in the CSF of adult sheep.
Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. BM-exposed (BMX) offspring develop elevated blood pressure; decreased baroreflex sensitivity; and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6 mo of age. We compared components of the choroid plexus fourth ventricle (ChP4) and cerebral spinal fluid (CSF) RAS between control and BMX male offspring at 6 mo of age. In the choroid plexus, high-molecular-weight renin protein and ANG I-intact angiotensinogen were unchanged between BMX and control animals. Angiotensin-converting enzyme 2 (ACE2) activity was threefold higher than either neprilysin (NEP) or angiotensin 1-converting enzyme (ACE) in control and BMX animals. Moreover, all three enzymes were equally enriched by approximately 2.5-fold in ChP4 brush-border membrane preparations. CSF ANG-(1-7) levels were significantly lower in BMX animals (351.8 ± 76.8 vs. 77.5 ± 29.7 fmol/mg; P < 0.05) and ACE activity was significantly higher (6.6 ± 0.5 vs. 8.9 ± 0.5 fmol·min(-1)·ml(-1); P < 0.05), whereas ACE2 and NEP activities were below measurable limits. A thiol-sensitive peptidase contributed to the majority of ANG-(1-7) metabolism in the CSF, with higher activity in BMX animals. We conclude that in utero BM exposure alters CSF but not ChP RAS components, resulting in lower ANG-(1-7) levels in exposed animals.
Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, North Carolina;
Allyson C
AC
Marshall
Hossam A
HA
Shaltout
Nancy T
NT
Pirro
James C
JC
Rose
Debra I
DI
Diz
Mark C
MC
Chappell
D000367:Age Factors; D000803:Angiotensin I / Q000134:cerebrospinal fluid*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001623:Betamethasone / Q000008:administration & dosage / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D002831:Choroid Plexus / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D015536:Down-Regulation; D005260:Female; D005865:Gestational Age; D005938:Glucocorticoids / Q000008:administration & dosage / Q000633:toxicity*; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D015260:Neprilysin / Q000378:metabolism; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D007703:Peptidyl-Dipeptidase A / Q000134:cerebrospinal fluid*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012756:Sheep; D015854:Up-Regulation
D005938:Glucocorticoids; D010446:Peptide Fragments; D000803:Angiotensin I; D001623:Betamethasone; D007703:Peptidyl-Dipeptidase A; D000085962:Angiotensin-Converting Enzyme 2; D015260:Neprilysin; C118790:angiotensin I (1-7)
angiotensin peptidases; cerebral spinal fluid; choroid plexus; fetal programming; sheep