Angiotensin II Type 1 Receptor‐Mediated Hypothalamic Paraventricular Nucleus Neuroinflammation And Blood Brain Barrier Disruption Contribute To Age‐Dependent Hypertension In Male, But Not Female, Sprague Dawley Rats

Abstract

AimAging is a risk factor for the development of hypertension. Recently, neuroinflammation in cardio‐regulatory centers of the brain, specifically the hypothalamic paraventricular nucleus (PVN), has been identified as a potential driver of hypertension via sympathetically‐mediated mechanisms. We hypothesize neuroinflammatory mechanisms contribute to the progression of age‐dependent hypertension.MethodsIn male (M) Sprague Dawley (SD) rats aged 3, 8, and 16 months old (MO) and female (F) SD rats aged 3 and 16 MO femoral artery cannulation was used to measure mean arterial pressure (MAP; mmHg) and assess sympathetic tone to the vasculature (ΔMAP; mmHg) via depressor response to ganglionic blockade (i.v. hexamethonium 30 mg/kg). Global sympathetic tone was assessed as plasma norepinephrine (nmol/L) via ELISA. Blood brain barrier (BBB) dysfunction in the PVN was assessed via PVN FITC extravasation following co‐infusion of FITC‐Dextran (10 kDa) and rhodamine B isothiocyanate‐Dextran (70 kDa). Immunohistochemistry was performed in male rats only for microglia (CD11b/c), astrocytes (GFAP), interleukin 6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐α) in the PVN. MAP, assessments of sympathetic tone, BBB dysfunction, and microglia and astrocyte activity were also measured in 16 MO M rats treated with subcutaneous (s.c.) losartan, an Angiotensin II Type 1 Receptor (AT1R) antagonist, for 21 days (s.c. 3 mg/kg/day; N=6/group).ResultsM, but not F, SD rats develop age‐dependent hypertension (MAP [mmHg] 3 MO M 124±4, 8 MO M 138±5, 16 MO M 153±5, p<0.05; 3 MO F 132±5, 16 MO F 133±4), increased vascular sympathetic tone (ΔMAP to hexamethonium [mmHg] 3 MO M ‐34±7, 8 MO M ‐68±5, 16 MO M ‐60±9, p<0.05; 3 MO F ‐36±8, 16 MO F ‐34±8) and increased global sympathetic tone (Plasma NE [nmol/L] 3 MO M 39±6, 8 MO M 44±8, 16 MO M 58±9, p<0.05; 3 MO F 44±6, 16 MO F 46±7). In M rats only, BBB dysfunction occurs at 8 MO and 16 MO‐ F rats do not exhibit BBB disruption with age (% FITC extravasation [% area] 3 MO M 1.5±1.0, 8 MO M 9.4±1.3, 16 MO M 9.8±2.6, p<0.05; 3 MO F 1.3±0.6, 16 MO F 2.67±1.37). Further, 16 MO M rats exhibit significant neuroinflammation indicated by increased astrocyte reactivity and microglial activation, and increased IL‐6 and TNF‐α expression in the PVN. Following losartan administration in 16 MO M rats, there is a significant decrease in MAP, vascular and global sympathetic tone. BBB disruption is attenuated and neuroinflammation is ameliorated following losartan treatment as shown by a decrease in microglial activation and astrocytic reactivity.ConclusionsAge‐dependent hypertension develops in a sex‐dependent manner in the SD rat, potentially due to a protective effect of female sex steroids. Amelioration of neuroinflammation and reduction of BBB disruption via AT1R antagonism attenuates hypertension, vascular tone and global sympathetic outflow in an age‐dependent manner in male rats. These results indicate that PVN neuroinflammation modulates sympathetic nervous system activity and age‐related control of blood pressure in male rats potentially by an AT1R‐mediated mechanism.