Acute AT(1)-receptor blockade reverses the hemodynamic and baroreflex impairment in adult sheep exposed to antenatal betamethasone.
To accelerate lung development and protect neonates from other early developmental problems, synthetic steroids are administered maternally in the third trimester, exposing fetuses that are candidates for premature delivery to them. However, steroid exposure at this point of gestation may lead to elevated blood pressure [mean arterial pressure (MAP)] during adolescence. We hypothesize that fetal exposure to steroids activates the renin-angiotensin system, inducing an elevation in blood pressure and attenuation of baroreflex sensitivity (BRS) that is angiotensin II dependent in early adulthood. To test this hypothesis, fetal sheep were exposed to betamethasone (Beta) or vehicle (control) administered to ewes at day 80 of gestation and delivered at full term. At 1.8 yr of age, male offspring were instrumented for conscious recording of MAP, heart rate, and measurement of BRS [as low-frequency-alpha, high-frequency-alpha, sequence (seq) UP, seq DOWN, and seq TOTAL]. Beta-exposed sheep (n = 6) had higher MAP than control sheep (n = 5) (93 + or - 2 vs. 84 + or - 2 mmHg, P < 0.01). Acute blockade of angiotensin type 1 receptors with candesartan (0.3 mg/kg iv) normalized MAP in Beta-exposed sheep (85 + or - 4 mmHg), with no effect in control sheep (82 + or - 3 mmHg). Before angiotensin type 1 blockade, BRS maximum gain was significantly lower in Beta-exposed vs. control sheep (11 + or - 3 vs. 26 + or - 3 ms/mmHg, P < 0.0.01). However, 45 min after candesartan injection, BRS was increased in Beta-exposed (21 + or - 5 ms/mmHg) and control (35 + or - 4 ms/mmHg) sheep. Heart rate variability (HRV) and blood pressure variability (BPV) revealed lower HRV (SD of beat-to-beat interval and root mean square of successive beat-to-beat differences in R-R interval duration) and higher BPV (SD of MAP, systolic arterial pressure in low-frequency range) in Beta-exposed sheep. Candesartan partially restored HRV in Beta-exposed sheep and fully corrected BPV. Thus, in utero exposure to synthetic glucocorticoids causes long-lasting programming of the cardiovascular system via renin-angiotensin system-dependent mechanisms.
Shaltout
Hossam A
HA
Hypertension and Vascular Research Center, Wake Forest Univ. School of Medicine, Hanes Bldg., 6th floor, Medical Center Blvd., Winston-Salem, NC 27157-1032, USA. hshaltou@wfubmc.edu
Rose
James C
JC
Figueroa
Jorge P
JP
Chappell
Mark C
MC
Diz
Debra I
DI
Averill
David B
DB
D000367:Age Factors; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D017704:Baroreflex / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology*; D001623:Betamethasone / Q000633:toxicity*; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D005865:Gestational Age; D005938:Glucocorticoids / Q000633:toxicity*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012756:Sheep; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D005938:Glucocorticoids; D013777:Tetrazoles; D001623:Betamethasone; C081643:candesartan