ACE Inhibitor, Lisinopril, Affects Age‐Associated Changes in Cardiovascular and Cognitive Function in Female Dahl Salt‐Sensitive Rats

Abstract

Background Aged Dahl Salt-Sensitive (DSS) rats develop central arterial stiffness (CAS) and hypertension on a normal salt (NS) diet. These changes have effects on cognition via brain structural changes associated with CAS. Previous results showed that ACE inhibitor lisinopril (Lis) improved cardiovascular and cognitive function in male DSS rats. Here we determined whether these effects of Lis on physiology and behavior could be achieved in age-matched female DSS rats. Methods Female DSS rats (n=23) were kept on a NS diet (0.5% NaCl) for the duration of the study. Baseline (BL) measurements were taken at 3- and 6-mo of age. After 6-mo measurements, rats were given either Lis in drinking water (15mg/kg/day, n=12) or control treatment (n=11). Final measurements were taken after 7-mo of Lis treatment, before tissues were collected for histochemistry using Verhoeff's stain for collagen and elastin. Systolic blood pressure (SBP) was measured using tail-cuff plethysmography. Pulse wave velocity (PWV), a measure of CAS, was measured by echocardiography. Open field test (OFT) was performed to assess anxiety-like behavior, and Morris water maze (MWM) was performed to assess spatial memory function. Rats were tested in an operant chambers attention challenge to assess attention and impulsivity. Statistical analyses were performed using Pearson correlation and 2-way ANOVA mixed effects model. Data are presented as mean ± SEM. Results At 3 and 6-mo of age, the treatment groups did not display differences in SBP or PWV. Following treatment, the Lis treated rats had lower SBP vs. controls (116 ± 3.7 vs. 187 ± 9.5 mmHg; p<0.01). Similarly, PWV was lower at 13-mo in treated vs. control rats (4.4 ± 0.3 vs. 5.7 ± 1.0 m/s; p<0.05) (Fig. 1A-B). Histochemical analysis revealed that the aortic media collagen abundance, a measure of fibrosis, was lower (18.5 ± 0.9% vs. 21.5 ± 0.8%, p<0.05) and the elastin/collagen ratio in the aortic media of treated rats was higher (2.5 ± 0.1 vs. 2.0 ± 0.1, p<0.05) than that of controls (Fig. 1C-D). Performance on the OFT at 13-mo compared to 6-mo BL indicated that the treated group had an increase in activity in the center of the field with age (+25% vs. BL) i.e., lower anxiety levels, while in control rats there was an opposite effect (-32% vs. BL) (Fig. 2A). PWV was negatively correlated with distance traveled in the center of the OFT at 13-mo (R=-0.672, P<0.05). MWM results showed that treated rats traveled a shorter distance to a hidden platform compared to control rats (6.5 ± 0.7 vs. 8.8 ± 0.9 m; p=0.039), indicating better spatial memory in the treated group (Fig. 2B). In the attention test at 13-mo of age, treated rats had more correct and fewer premature responses vs. control rats (Fig. 2C-D). Conclusion Female DSS rats show beneficial effects of Lis on cardiovascular and cognitive function. Lower SBP, reduced aortic fibrosis, and stabilized PWV in Lis treated female DSS rats were associated with improved behavioral test performance. The mechanistic basis of the effects of Lis on cognition via cerebrovascular and brain changes is being further investigated.