Effects of Lisinopril on Arterial Stiffness, Cerebral Blood Flow, Neuronal Viability and Cortical Thickness in Late‐Life Hypertension in Dahl‐S Rats
Authors: Cezayirli Defne S. , Ajamu Samuel , Fenner Rachel C. , Shearon Jennifer , Griogorova Yulia N. , Lakatta Edward G. , Spencer Richard G. , Fedorova Olga F. , Fishbein Kenneth W. , Bouhrara Mustapha 
Published: April 2020

BackgroundCardiovascular pathophysiology, including central arterial stiffness (CAS), has strong effects on cerebral microvasculature and perfusion and has been identified as a significant risk factor for dementia. Previously we demonstrated that greater aortic pulse wave velocity (PWV), a marker of CAS, was associated with lower hippocampal perfusion and lower neuronal density in adult Dahl salt‐sensitive (DSS) rats, which develop hypertension and cognitive decline with age even on a normal salt diet. The hypertensive 6‐mo old DSS rats exhibited an improvement in cardiovascular parameters when treated with an ACE inhibitor, lisinopril, for 6 months. In the current study, we aimed to assess the cerebral effects of lisinopril_in treating late‐life, established hypertension in the DSS model.MethodsMale DSS rats (n=22)_were fed normal salt diet (0.5% NaCl) for 18 months. After baseline measurements were taken at 16‐mo of age, DSS were administered lisinopril 15mg/kg BW/day in drinking water or vehicle for 2 months (n=11/group). Twelve 6‐mo old untreated DSS were used as cross‐sectional controls. Systolic blood pressure (SBP; by plethysmography), PWV (by echocardiography) and hippocampal N‐acetyl aspartate (NAA) concentration (a marker of neuronal density), hippocampal cerebral blood flow (CBF), cortical thickness and brain volumes (by MRI) were measured at 16‐mo and 18‐mo of age. A 7T Bruker Biospec scanner was used for measurements. NAA was assessed using 1H spectroscopy and CBF was measured in the right hippocampus using continuous arterial spin labeling (CASL). Hippocampal, ventricular and total brain volumes and cortical thickness were measured using a T2‐weighted RARE 3D pulse sequence and analyzed with Advanced Normalization Tools (ANTs). Hippocampal and ventricular volumes are presented as both absolute values and with normalization to total brain volume. Two‐way ANOVA linear mixed effects analyses were performed.ResultsSBP was higher in 16‐mo old DSS rats vs. 6‐mo controls; PWV was greater in 16‐monon‐treated DSS rats than in 6‐mo controls (Table
). Lisinopril effectively reduced SBP and PWV after 2‐mo of treatment in aged rats. Hippocampal CBF and NAA as well as hippocampal and ventricular volumes were not significantly affected by age or treatment (Table
). Hippocampal CBF (Fig.
1b) showed a declining trend for both treated and non‐treated rats from age 16 to 18‐mo. Treatment appeared to ameliorate the declining trend of NAA with age seen in non‐treated DSS rats, though no significance was observed (Fig.
1c). Changes in cortical thickness from 16‐mo to 18‐mo (Fig.
1d, e) were not different in treated and non‐treated rats (Fig.
1f).ConclusionThis study evaluated the association of age‐dependent changes in CAS with cerebral parameters in the DSS rat model. We found that lisinopril effectively reduced BP and PWV, even when administered to old hypertensive rats, but did not significantly affect brain parameters. These results indicate that a longer treatment period may be needed to alter hippocampal blood flow and neuronal viability.Support or Funding InformationSupported by the NIH/NIA Intramural Research Program.Longitudinal changes in PWV (a), CBF (b), NAA concentration (c) and cortical thickness (d–f) in non‐treated (NT) and lisinopril‐treated (T) rats. Data presented as mean±SEM. Dashed lines are controls. By 2‐way ANOVA repeated measures: *p<0.05 **p<0.01, 18 vs. 16‐mo; #p<0.05, NT vs. T at 18‐mo. Mean thickness change from 16 to 18‐mo for all NT (d) and T (e). Red, thickening; blue, thinning (mm). P‐value map comparing thickness change between NT and T (f); here, p values >0.05 displayed as 0.05Figure 1
Effect of lisinopril on cardiovascular and cerebral parameters in hypertensive Dahl salt‐sensitive rats

6‐mo old controls n=12

16‐mo old pre‐treatment (NT) n=11

18‐mo old post‐treatment (NT) n=11

16‐mo old pre‐treatment (T) n=11

18‐mo old post‐treatment (T)n=9

Body weight (g)

400 ±6

509 ± 6
*

498 ±5

498 ± 10
*

492 ± 13

Heart rate (BPM)

418 ± 7

435 ± 8
*

447 ±9

434±10
*

427 ± 14

SBP (mmHg)

162 ± 4

187 ± 4
*

183 ±6

188 ± 3
*

154 ± 7
##
††

PWV (m/s)

5.3 ±0.3

7.0 ± 0.5

10.8 ±0.7
##

7.1 ± 0.2

5.4 ± 0.3
#
†

Hippocampal CBF (mL/100g tissue/min)

177 ± 9

185 ± 12

181 ±11

179 ± 15

174 ± 11

N‐acctyl aspartate (mM)

6.4 ± 0.3

6.9 ± 0.4

6.2 ± 0.2

6.3 ± 0.3

6.5 ± 0.2

Hippocampal volume (mm3)

60.5 ± 0.6

63.2 ± 0.6

62.6 ± 0.6

63.6 ± 0.5

62.2 ± 0.7

Ventricular volume (mm3)

12.7 ± 0.2

12.0 ± 0.3

12.1 ± 0.1

12.2 ± 0.2

12.1 ± 0.1

Total brain volume (mm3)

1876 ± 16

1836 ± 32

1855 ± 10

1856 ± 19

1842 ± 12

Hippocampal/TBV (×1000)

32.3 ± 1.3

34.5 ± 0.6

33.8 ±0.4

34.3 ± 0.3

33.8 ± 0.4

Vcntricular/TBV (×1000)

6.8 ± 0.1

6.6 ± 0.0

6.5 ± 0.1

6.6 ± 0.1

6.6 ± 0.1

Values arc expressed as mean ± SEM. NT, non‐treatment; T, lisinopril treatment; SBP, systolic blood pressure; PWV, pulse wave velocity; CBF, cerebral blood flow; TBV, total brain volume (olfactory bulb, cerebellum and brainstem excluded).
By 2‐way ANOVA linear mixed effects analysis followed by Sidak post‐test:
*p<0.01, 16‐ mo vs. 6‐mo controls;
#p<0.05,
##p<0.01, 18‐mo vs. 16‐mo;
†p<0.05,
††p<0.01, non‐treatment vs. treatment rats at 18‐mo