Cardiovascular, Cerebral and Behavioral Response to Anti‐Hypertensive Treatment in Female Dahl Salt Sensitive Rats

Abstract

Background Cerebrovascular disease is associated with central arterial stiffness (CAS), which can lead to reduced brain blood supply, neuronal density loss and cognitive impairment. Dahl salt sensitive (DSS) rats represent a model of vascular dementia and have a compromised renin-angiotensin system, develop CAS, hypertension, and hippocampal memory decline with age on a normal salt (NS) diet. Lisinopril (LIS), an angiotensin converting enzyme inhibitor, effectively treated this pathology in aged male DSS rats. We investigated the relationship between systolic blood pressure (SBP), pulse wave velocity (PWV), a marker of CAS, hippocampal blood flow (CBF), neuronal density and anxiety in female DSS rats treated with LIS. Methods Female DSS rats (n=23) were fed a NS diet (0.5% NaCl) for the duration of the study. Rats were administered LIS (15mg/kg BW/day in drinking water, n=12) or control treatment (CTRL; n=11) for 7-mo beginning at 6-mo of age. The following measurements were assessed at 6-mo (baseline; BL) and at 13-mo of age: SBP (by plethysmography), PWV (by echocardiography), CBF (by continuous arterial spin labeling), and hippocampal N-acetyl aspartate concentration (NAA; by proton magnetic resonance spectroscopy). In open field test (OFT; a metric of anxiety, a precursor to symptoms of dementia) travel activity (distance) and rearing durations (vertical activity; VA) in the center of the field were collected as measures of exploratory behavior. Pearson's correlation matrix and 2-way ANOVA mixed effects model analyses were performed. Results At BL, the treatment groups were not different in any parameters except heart rate (HR). At 13-mo CTRL, SBP and PWV increased, CBF, total distance, total VA and distance in center of the OFT decreased compared to BL. In 13-mo LIS group, SBP and PWV were lower compared to 13-mo CTRL; 13-mo LIS group had higher HR and lower SBP, CBF and total VA in OFT compared to BL (Table 1). At 6-mo, NAA and VA were marginally correlated. HR and central distance were significantly correlated (Table 2A). For 13-mo CTRL, SBP positively correlated with PWV and NAA. NAA negatively correlated with distance in center. HR negatively correlated with distance in center and VA in center (Table 2B). This relationship with HR was reversed for 13-mo LIS group, for which PWV and CBF were negatively associated with central distance and central VA, while NAA was negatively correlated with central VA only (Table 2C). Conclusion In both CTRL and LIS groups, advancing age adversely affected hippocampal perfusion, but not neuronal density. ChronicLIS treatment reduced hypertension and PWV but did not affect cerebral parameters in aged female DSS rats. Increased level of anxiety, known to predate cognitive decline, was associated with PWV for LIS group, suggesting that CAS can adversely affect brain structures and function. CTRL and LIS groups showed differences in associations between cerebral, behavioral, and cardiovascular parameters. Further analyses will be conducted to investigate the role of sex hormones and their associations with age in the patterns observed.