Effects of Lisinopril on Arterial Stiffness, Cerebral Blood Flow and Cortical Thickness in Hypertensive Dahl‐S Rats
Authors: Ajamu Samuel , Fenner Rachel , Khattar Nikkita , Grigorova Yulia , Juhasz Ondrej , Rapp Peter , Lakatta Edward , Bouhrara Mustapha , Spencer Richard , Fedorova Olga , Fishbein Kenneth 
Published: April 2020

Study objectives

Central arterial stiffness (CAS), associated with hypertension, is likely underlies the stiffening of cerebral arterial wall resulting in cerebral hypoperfusion, neuronal density loss and cognitive decline. We previously found associations between pulse wave velocity (PWV), a marker of CAS, and hippocampal cerebral blood flow (CBF) and neuronal density in 6‐mo old hypertensive Dahl salt‐sensitive (Dahl‐S) rats. This study examined the effect of ACE inhibitor, Lisinopril, on cardiovascular and brain parameters in hypertensive Dahl‐S rats.

Methods

Male Dahl‐S rats (n=32) were fed with a normal salt diet (0.5% NaCl) for a duration of study. Systolic blood pressure (SBP), PWV (by echocardiography); hippocampal N‐acetyl aspartate (NAA) concentration, hippocampal CBF were measured at 6‐mo of age (baseline) and after 3‐mo and 6‐mo of Lisinopril (15mg/kg body weight/day in drinking water; n=14) or control (n=18) treatment. NAA was measured using proton spectroscopy in a 7T Bruker Biospec MRI scanner; CBF was measured using continuous arterial spin labeling (CASL) in the coronal slice with the largest hippocampal area; cortical thickness (CT) analysis was done using a T2 weighted RARE 3D image (n=12). Advanced Normalization Tools (ANTs) were used for the CT estimation. T‐test and 2‐way ANOVA linear mix effect model analyses were performed in R, EXCEL and MATLAB. Data presented as mean±SE.

Results

At 6‐mo of age, the Dahl‐S rats developed advanced hypertension vs. 3‐mo (SBP: 164±4 vs. 141±3 mmHg; P<0.01, t‐test). SBP of non‐treated (NT) animals was steadily high at all time points while treated animals exhibited a decrease in SBP at 9‐mo vs. 6‐mo of age. SBP remained low from 9‐mo to 12‐mo of age (Fig.
1a). In treated animals, PWV decreased at all timepoints after 6‐mo of age. For NT animals, PWV remained steady from 6‐mo to 9‐mo but increases from 9‐mo to12‐mo of age (Fig.
1b). Hippocampal CBF of NT animals decreased in a downwards trend but remain stabilized in the treated group across timepoints (Fig.
1c). Likewise, the hippocampal NAA, among treated animals remained stabilized, while in NT animals this parameter fluctuated with an eventual downwards trend (Fig.
1d). The mean difference maps of the CT for the NT and treated rats are similar except for the regions denoted by the red arrows when comparing treated to NT (Fig.
2a–b). The occipital region showed cortical thickening (blue) and parietal region showed cortical thinning (yellow). The P value maps show that those regions of significant thickening and thinning are greater in the treated vs. NT rats (Fig.
2c–d).

Conclusion

The posterior cerebral artery is a dominant source of perfusion to the hippocampus and the occipital lobe; thus, our findings suggest a coherent pattern through which CAS can affect the cerebral arteries in hypertensive Dahl‐S rats. Lisinopril treatment decrease CAS and improve regional CBF and neuronal density. Therefore, CAS may be a therapeutic target for vascular dementia.

Support or Funding Information

The work was supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health.

Longitudinal changes in cardiovascular parameters in Lisinopril treated Dahl‐S rats. Systolic blood pressure SBP (a), pulse wave velocity PWV (b), hippocampal CBF (c), and NAA (d) in Lisinopril treated (T) and nontreated (NT) rats. By 2‐way ANOVA Linear Mixed Effects: *p < 0.001 vs. age‐matched treated rats; #p < 0.03 vs. 6‐mo, ## p <0.001 vs. 6‐mo; by paired T‐test (c, d): * p = 0.07 vs. 6‐mo; # p = 0.06 vs. 9‐mo NT.

Figure 1

Mean Differences in Cortical Thickness and their p value maps (6‐mo subtracted by 12‐mo). Mean difference between age 6‐mo and 12‐mo of (a) nontreated animals and (b) lisinopril treated animals. Blue indicates regions of thickening. Yellow indicated regions of thinning. Occipital and parietal regions indicated by the red arrows. P value map of nontreated animals (c) and lisinopril treated animals (d). All insignificant p values > 0.05 were revalued as 0.05 for visualization purposes.

Figure 2