Angiotensin-(1-7) deficiency and baroreflex impairment precede the antenatal Betamethasone exposure-induced elevation in blood pressure

Hypertension. 2012 Feb;59(2):453-8. doi: 10.1161/HYPERTENSIONAHA.111.185876. Epub 2012 Jan 3.

Abstract

Betamethasone is administered to accelerate lung development and improve survival of premature infants but may be associated with hypertension later in life. In a sheep model of fetal programming resulting from exposure at day 80 of gestation to Betamethasone (Beta-exposed), adult sheep at 6 to 9 months or 1.8 years of age have elevated mean arterial pressure (MAP) and attenuated spontaneous baroreflex sensitivity (sBRS) for control of heart rate compared to age-matched controls associated with imbalances in angiotensin (Ang) II vs Ang-(1-7) tone. At 6 weeks of age, evoked BRS is already low in the Beta-exposed animals. In this study, we assessed the potential contribution of the renin-angiotensin system to the impaired sBRS. Female lambs (6 weeks old) with Beta exposure in utero had similar MAP to control lambs (78±2 vs 77±2 mm Hg, n=4-5 per group), but lower sBRS (8±1 vs 16±3 ms/mm Hg; P<0.05) and impaired heart rate variability. Peripheral AT1 receptor blockade using candesartan lowered MAP in both groups (≈10 mm Hg) and improved sBRS and heart rate variability in Beta-exposed lambs to a level similar to control. AT7 receptor blockade by infusion of D-ala Ang-(1-7) (700 ng/kg/min for 45 minutes) reduced sBRS 46%±10% in Beta-exposed vs in control lambs (P<0.15) and increased MAP in both groups (≈6±2 mm Hg). Our data reveal that Beta exposure impairs sBRS and heart rate variability at a time point preceding the elevation in MAP via mechanisms involving an imbalance in the Ang II/Ang-(1-7) ratio consistent with a progressive loss in Ang-(1-7) function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Angiotensin I / deficiency*
  • Angiotensin I / drug effects
  • Angiotensin I / pharmacology
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Animals, Newborn
  • Baroreflex / drug effects
  • Baroreflex / physiology*
  • Benzimidazoles / pharmacology
  • Betamethasone / adverse effects*
  • Betamethasone / pharmacology
  • Biphenyl Compounds
  • Blood Pressure / drug effects
  • Blood Pressure / physiology
  • Disease Models, Animal
  • Female
  • Glucocorticoids / adverse effects
  • Glucocorticoids / pharmacology
  • Heart Rate / drug effects
  • Hypertension / chemically induced*
  • Hypertension / physiopathology*
  • Peptide Fragments / deficiency*
  • Peptide Fragments / drug effects
  • Peptide Fragments / pharmacology
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced*
  • Prenatal Exposure Delayed Effects / physiopathology*
  • Receptor, Angiotensin, Type 1 / drug effects
  • Sheep
  • Tetrazoles / pharmacology

Substances

  • Angiotensin II Type 1 Receptor Blockers
  • Benzimidazoles
  • Biphenyl Compounds
  • Glucocorticoids
  • Peptide Fragments
  • Receptor, Angiotensin, Type 1
  • Tetrazoles
  • Angiotensin I
  • Betamethasone
  • angiotensin I (1-7)
  • candesartan