The Effects of an ACE Inhibitor Lisinopril on Cardiovascular and Cognitive Function in Old Hypertensive Dahl Salt‐Sensitive Rats
Authors: Shearon Jennifer , Fenner Rachel , Grigorova Yulia , Juhasz Ondrej , McDevitt Ross , Ajamu Samuel , Zernetkina Valentina , Wei Wen , Lakatta Edward , Fedorova Olga 
Published: April 2020

Background

Dahl Salt‐Sensitive (DSS) rats develop hypertension and cognitive decline with increased age, even on a normal salt diet, i.e. DSS represent a model of vascular dementia. Pulse wave velocity (PWV), a measure of central arterial stiffness (CAS), also increases with age in DSS rats. As blood pressure (BP) and CAS increase, the demand on the heart and other organs becomes larger. This leads to cardiovascular tissue fibrosis and remodeling in these overworked organs. Previously, an ACE inhibitor, Lisinopril, has been shown to effectively treat these symptoms in the DSS model when administered beginning at 6‐mo of age. This experiment tested whether these beneficial effects could still be achieved when Lisinopril treatment was started at an older age in DSS rats.

Methods

Male DSS rats (n=32) were kept on a normal salt diet (0.5% NaCl) for the duration of the study. Following initial measurements at 16‐mo of age, animals were either given Lisinopril administered through their water (15mg/kg/day, n=11) or control (n=11) treatment for 2‐mo. Six DSS rats were used as a cross‐sectional control at 3‐mo of age. Systolic BP (SBP) and heart rate were measured in conscious animals using tail‐cuff plethysmography. PWV was measured in anesthetized animals by echocardiography. Open field test (OFT) was used as a measurement of exploratory and anxiety‐like behavior. Measurements were taken at 16 and 18‐mo of age, then 18‐mo rats were sacrificed for tissue collection. Tissues were tested for collagen and elastin abundance using histochemistry. Statistical analyses were performed using 2‐way ANOVA mixed effects analysis and t‐test. The data are presented as mean ± SEM.

Results

The 16‐mo DSS rats had higher SBP in comparison to 3‐mo old baseline (187.8 ± 2.4 mmHg vs. 142 ± 3 mmHg) and PWV (7.1 ± 0.3 m/s vs. 4.3 ± 0.5 m/s). At 18‐mo of age, untreated animals were still hypertensive, while Lisinopril treated animals had significantly lower SBP vs. 16‐mo. PWV in untreated animals significantly increased from 16 to 18‐mo (Table
), demonstrating the progression of their CAS with increased age. Conversely, PWV in treated animals significantly decreased with treatment (Table
). Heart and aortic weights and aortic medial collagen abundance were significantly reduced in the rats treated with Lisinopril (Table
; Figure
). OFT results did not reveal any significant differences between control and treated group, although after Lisinopril administration DSS rats exhibited numerically higher activity in the center of the field than control rats (Table
).

Conclusion

It was demonstrated that an ACE inhibitor administered to old hypertensive DSS rats dramatically improved BP and reversed CAS and cardiovascular remodeling. Thus, the initiation of anti‐hypertensive treatment in older age is still effective in reversal of the main symptoms of cardiovascular disease. We suggest that longer treatment may be needed to significantly improve cognitive functions and anxiety levels.

Support or Funding Information

Effect of Lisinopril treatment on pulse wave velocity (PWV; A), systolic blood pressure (SBP; B), weights of the heart (C) and aorta (D). A and B, by 2‐way ANOVA, repeated measures, followed by Sidak post‐test. A: drug effect, P<0.0001; time, n/s; drug‐time interaction, P<0.0001. B: drug effect, P<0.05; time effect, P<0.0001, drug‐time interaction, P<0.0001. Sidak post‐test: *P<0.05, **P<0.0.01, 18‐mo vs. 15‐mo; #P<0.05, lisinopril vs. control. C and D, by unpaired t‐test.

Figure 1

Physiological, histochemical and behavioral parameters in 15‐mo old Dahl‐S rats before and after 3‐mo of Lisinopril and vehicle (control) treatment

15‐mo old (baseline)

18‐mo old (2‐mo of treatment)

Control group, n = 11

Lisinopril group, n = 10

Control group, n = 11

Lisinopril group, n = 9

Body weight (g)

509 ± 6

498 ± 10

498 ± 5

492 ± 13

Heart rate (beats/min)

435 ± 8

434 ± 10

447 ± 9

427 ± 14

SBP (mmHg)

187 ± 4

188 ± 3

184 ± 7

152 ± 7

PWV (m/s)

7.0 ± 0.6

7.1 ± 0.3

10.8 ± 1.0

5.4 ± 0.3

Heart weight (g/kg BW)

‐

‐

3.70 ± 0.30

2.93 ± 0.10

Aorta weight (mg/mm/kg BW)

‐

‐

4.96 ± 0.23

4.35 ± 0.14

Collagen in aortic media (% to total)

‐

‐

19.6 ± 1.0

14.0 ± 0.3

Elastin in aortic media (% to total)

‐

‐

30.6 ± 1.4

31.1 ± 2.1

Elastin/Collagen ratio

‐

‐

1.6 ± 0.1

2.2 ± 0.1

OFT distance total (cm)

217 ± 18

199 ± 18

199 ± 18

173 ± 18

OFT distance in center (cm)

38 ± 10

47 ± 7

25 ± 6

38 ± 10

OFT VA total (count)

83 ± 10

60 ± 10

49 ± 5

43 ± 10

OFT VA in center (count)

12 ± 4

8 ± 2

4 ± 2

10 ± 5

Values are expressed as mean±SE. By 2‐way ANOVA linear mixed effect followed by Sidak post‐test:

*P<0.05, 18‐mo vs. 15‐mo;

**P<0.0001, 18‐mo vs. 15‐mo;

#P<0.0001, Lisinopril vs. control. By unpaired t‐test:

†P<0.01 vs. 18‐mo control.

SBP, systolic blood pressure; PWV, pulse wave velocity; BW, body weight; OFT, open field test; VA, vertical activity.

Acknowledgement

Supported by NIH/NIA Intramural Research Program