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

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.

Conflict of interest statement

Conflict of Interest / Disclosure

None

Figures

Figure 1

Beta-exposed lambs had similar mean arterial pressure (MAP) compared to control lambs at 6weeks of age. AT1 receptor blockade using Candesartan (CV 11974, 0.3 mg/kg, i.v. injection) lowered MAP in beta treated group, A, while, AT7 blockade using 1 hour infusion of 700 ng/kg/min D-Ala7-Ang-(1–7) increased MAP in both groups, C. There were no effect of Beta-exposure on heart rate at this age and no effect of either of the blockers, B & D. Data are mean ± SEM, * P < 0.05 vs. control at baseline, # P< 0.05 vs Beta-exposed pre Candesartan or D-ala.

Figure 2

Antenatal betamethasone exposure was associated with impaired spontaneous baroreflex sensitivity (sBRS) measured by spectral analysis methods as high frequency alpha index (HFα), A; as sequence all (Seq-ALL), B; with no significant change in heart rate variability measured by standard deviation of beat to beat intervals (SDRR), C, and by root of mean successive differences (rMSSD), D. AT1 receptor blockade with Candesartan injection (CV, 0.3 mg/kg) improved baroreflex measures in Beta-exposed lambs to a level that is not different from the control 45 minutes post injection. Data are mean ± SEM, * P < 0.05 vs. Control at baseline, # P< 0.05 vs Beta-exposed pre Candesartan.

Figure 3

Antenatal betamethasone exposure had no significant effect on the sympathetic arc of the sBRS measured as low frequency alpha index (LFα), A, and no effect on the blood pressure variability measured as power of the spectral density of systolic arterial pressure in the low frequency range (LFSAP) in normalized units (nu), B. There was no significant effect on the sympathovagal balance measured by LFRRI/HFRRI ratio in this subgroup, C. AT1 receptor blockade with Candesartan (CV, 0.3 mg/kg) had no effect on these parameters in control or Beta-exposed lambs. Data are mean ± SEM, * P < 0.05 vs. Control at baseline.

Figure 4

Antenatal betamethasone exposure was associated with impaired spontaneous baroreflex sensitivity measured as high frequency alpha index (HFα), A; and as sequence all (Seq-ALL), B; and lower heart rate variability measured by standard deviation of beat to beat intervals (SDRR), C, and by root of mean successive differences (rMSSD), D. AT7 receptor blockade with 700 ng/kg/min D-Ala7-Ang-(1–7) infusion impaired all 4 measures of parasympathetic function in control lambs to a level that is not different from Beta-exposed lambs at baseline. There was no significant effect for the D-ala infusion on these measures in the Beta-exposed lambs. Data are mean ± SEM, * P < 0.05 vs. Control at baseline.

Figure 5

Antenatal betamethasone exposure had no significant effect on the sympathetic arc of the baroreflex sensitivity measured as low frequency alpha index (LFα), A, and no effect on the blood pressure variability measured as power of the spectral density of systolic arterial pressure in the low frequency range (LFSAP) in normalized units (nu), B. The sympathovagal balance measured by LFRRI/HFRRI ratio was similar in both groups at baseline, C. AT7 receptor blockade with 700 ng/kg/min D-Ala7-Ang-(1–7) infusion had no effect on LFα or LFSAP and it increased LF/HF ratio in control lambs. Data are mean ± SEM, * P < 0.05 vs. Control at baseline.