Effect of Anti‐hypertensive Treatment Lisinopril on Central Arterial Stiffness and Cognitive Functions in Adult Hypertensive Dahl Salt‐Sensitive Rats
Authors: Fenner Rachel Claire , Grigorova Yulia , McDevitt Ross , Ajamu Samuel , Shearon Jennifer , Wei Wen , Juhasz Ondrej , Long Jeffrey , Rapp Peter , Lakatta Edward , Fedorova Olga 
Published: April 2020

BackgroundIndependent of a high salt intake, Dahl Salt‐Sensitive rats (DSS) demonstrate an age‐associated increase in blood pressure (BP) and central arterial stiffness (CAS) accompanied by cognitive decline, i.e., DSS represent a model of vascular dementia. We hypothesized that anti‐hypertensive treatment ACE inhibitor lisinopril, in addition to BP decrease, will lower CAS and improve cognitive function in the adult DSS model of vascular dementia.MethodsForty male DSS were kept on normal salt diet (0.5% NaCl) for the duration of the study; 20 DSS were used as a non‐treated control (DSS‐C), and 20 DSS were continuously treated with lisinopril (15 mg/kg/day; DSS‐LIS) starting at 6‐mo of age. Systolic BP (SBP), pulse wave velocity (PWV), a marker of CAS (by Doppler echocardiography), open field test (OFT) to assess anxiety‐like behavior and locomotion, and cued reaction time task (CRTT) to assess executive functioning were performed at baseline (BL; 6‐mo of age) and repeated after 3 and 6‐mo of treatment. Morris Water maze (MWM) test was performed 6‐mo after treatment to assess hippocampal spatial memory. Animals were euthanized and aortas were weighed and stained with Verhoeff’s stain for elastin and collagen. The data were analyzed using 2‐way ANOVA repeated measures and t‐test and presented as mean ± standard error.ResultsAll 6‐mo old DSS rats displayed hypertension at BL; 9 and 12‐mo old DSS‐C showed no difference in SBP (Table
, Fig
1A). DSS‐LIS treated for 3‐mo and 6‐mo, i.e., at 9 and 12‐mo of age, showed a decreased SBP compared to their BL (Table
, Fig
1A). At both 3‐mo and 6‐mo post treatment, DSS‐LIS rats had lower SBP compared to DSS‐C (Table
, Fig
1A). PWV decreased in DSS‐LIS at 6‐mo post treatment compared to their BL and DSS‐C (Table
, Fig
1B). In MWM, DSS‐LIS had a higher path efficiency and traveled shorter distance when finding the invisible platform compared to DSS‐C (Table
, Fig
1C). In CRTT, DSS‐LIS had fewer premature responses than DSS‐C 3‐mo post treatment (Table
, Fig
1D) in challenging trials of a varied inter trial interval challenge test. There was no change in total distance traveled and distance traveled in the center in the first five minutes in OFT at all time points in DSS‐LIS compared to DSS‐C (Table
). At 6‐mo post treatment DSS‐LIS had lower aortic weight, less aortic medial wall collagen, unchanged elastin abundance, and greater elastin/collagen ratio compared to DSS‐C (Table
, Fig
1E,F).ConclusionChronic treatment with lisinopril effectively lowered SBP, gradually decreased CAS estimated by PWV, and reversed aortic remodeling in aged hypertensive DSS rats. In addition, lisinopril resulted in improved hippocampal spatial memory and reduced impulsive behavior demonstrating a beneficial cognitive effect of the treatment. Lisinopril did not alter anxiety‐like behavior or locomotion. Further studies will need to elucidate the effect of lisinopril on cerebral blood vessels and whether ACE inhibitor has a direct effect of the brain in addition to its effect on CAS.Support or Funding InformationThis research was supported entirely by the Intramural research Program of the NIH, National institute on Aging.Effect of Lisinopril on pulse wave velocity (PWV; A), systolic blood pressure (SBP; B), Path efficiency in MWM; C), Premature Responses at 10 sec ITI in CRTT; D), Collagen in medial aortic wall (E), and Aortic Weight (F). A–D, by 2‐way ANOVA linear mixed effect followed by Sidak post‐test: *P<0.05, **P<0.01, 9 or 12‐mo vs. 6‐mo BL; #P<0.05, ##P<0.01, DSSLIS vs. DSS‐C; †P<0.05 invisible vs. visible platform. E and F, by unpaired t‐test: ‡P<0.05, Lisinopril (LIS) vs. control (CON).Figure 1

Effect of lisinopril on physiological, behavioral and histochemical parameters in adult Hypertensive Dahl salt‐sensitive (DSS) rats

Control group (n=20)

Lisinopril group (n=20)

Age (months)

6

9

12

6

9

12

BW (g)

407±4

464±4
**

481±8
**

394±8

444±8
**

462±8
**

SBP (mmHg)

166±4

180±6

182±5
*

169±4

117±4
**
##

114±3
**
##

HR (b/min)

429±7

418±12

432±6

435±6

414±9

405±8
*

PWV (m/s)

5.3±0.2

5.4±0.3

5.9±0.3

5.5±0.3

4.6±0.2

4.3±0.1
**
##

Heart weight (g/kg BW)

3.09±0.07

2.42±0.03
††

Aorta weight (mg/mm/kg BW)

4.11±0.12

3.37±0.11
††

Collagen (%)

21.9±0.9

15.5±1.1
††

Elastin (%)

34.0±0.8

47.8±0.9
††

E/C ratio

1.6±0.1

3.2±0.3
†

MWM, Path efficiency invisible platform (percent)

22.7±3.4

43.0±5.5
†

MWM, distance to invisible platform (m)

9.7±0.7

7.5±0.7
†

CRTT, premature responses at 10 sec ITI (counts)

17.7±1.2

20.6± 0.8

18.3±1.4

16.2±1.3

16.5± 0.9

14.7±0.9
#

OFT total distance traveled 5 mins (cm)

750±23

750±38

679±40

762±23

815±44

645±27

OFT distance traveled in the center 5 mins (cm)

140±14

160±11

147±15

150±14

171±13

139±12

Values are expressed as mean±SEM.
By 2‐way ANOVA linear mixed effect followed by Sidak post‐test:
*P<0.05,
**P<0.0001, 9 or 12‐mo vs. 6‐mo BL;
#P<0.05,
##P<0.0001, DSS‐LIS vs. DSS‐C at 9 or 12‐mo.
By unpaired t‐test:
†P<0.05,
††P<0.01, DSS‐LIS vs. DSS‐C at 12‐mo.
SBP, systolic blood pressure; PWV, pulse wave velocity; HR, heart rate; BW, body weight; OFT, open field test; MWM, Morris Water Maze; ITI, Inter trial interval; CRTT, cued reaction time task