Treatment with losartan, an AT1 receptor blocker, improves cognitive and cardiovascular function in a Dahl salt‐sensitive rat model of age‐associated vascular dementia.

Abstract Background Dementia is characterized by progressive cognitive impairment (CI), which is accompanied by decline in reasoning, planning and memory. Cardiovascular diseases are the major contributors to the pathogenesis of vascular dementia and affect mainly the aging population. Even on a normal salt diet, Dahl salt‐sensitive (DSS) rats exhibit age‐associated hypertension and CI. We hypothesized, that anti‐hypertensive treatment with the angiotensin II receptor blocker losartan (LOS) would improve cardiovascular and cognitive function in aged DSS rats. Method Male DSS rats (n=30) were kept on a normal salt diet (0.5% NaCl) for the duration of the study. Baseline measurements were taken at 6‐mo of age. After that, treatment with 30mg/kg/day of LOS, added to the drinking water (n=14), or control (n=16) was started and continued for 6‐mo. Systolic blood pressure (SBP), aortic pulse wave velocity (aPWV), a measure of aortic stiffness, and behavioral testing in a visually cued reaction task to assess attention and inhibitory control were assessed every 3‐mo. Elevated plus maze (EPM) and Morris Water Maze (MWM) tests were performed at 12‐mo of age to measure anxiety‐like behavior and to evaluate spatial memory, respectively. Data were analyzed by 2‐way repeated measures ANOVA or t‐tests as applicable. Result Prior to the treatment, LOS and control groups did not display differences in any parameter analyzed. Control rats exhibited gradual increase in SBP and aPWV from 6 to 12‐mo of age. Following 3‐ and 6‐mo of treatment, LOS rats exhibited lower SBP and aPWV vs. controls (Table 1). At 12‐mo of age, LOS rats had improved performance in the reaction task (Figure 1), and exhibited lower anxiety levels, spending less time on the closed arm in EPM and 1.5‐fold more time in the open arm vs. control rats. LOS rats also spent less time to find a hidden platform in the MWM vs. controls, indicating that LOS treatment improved spatial memory (Table 1). Conclusion Improvement of cardiovascular function and reduction in aortic stiffness by LOS were associated with better attentional control and memory and lower anxiety levels, demonstrating an association of CI with cardiovascular changes in the DSS rat model of vascular dementia.