Abstract P153: Mineralocorticoid Receptor Inhibition Abolishes Sex-specific, Renin Angiotensin Aldosterone System-associated Salt Sensitivity in Female Mice

Abstract

Up to half of essential hypertension cases in women are associated with salt sensitive blood pressure (BP) increases, however, the sex-specific mechanisms of salt sensitivity in women are unknown. Our lab has shown that female mice are more sensitive to the hypertensive effects of aldosterone than male mice but it is unknown if aldosterone plays a role in salt sensitivity in female mice. We hypothesized that increasing dietary sodium via a high salt diet would increase blood pressure in female mice which would be abrogated by mineralocorticoid receptor (MR) antagonism. To determine salt sensitivity male and female Balb/C mice were implanted with radiotelemeters for continuous recording of BP. BP was recorded during baseline (7 days) and throughout the administration of a high salt (4% NaCl, HS) diet for 7 days with or without concurrent eplerenone supplementation (daily 200 mg/kg/day). Plasma and kidneys were then harvested. Systolic (SBP) and diastolic (DBP) BP were increased in female mice, but not in males, on HS (7.8±3.3 SBP and 7.8±4.0 DBP Δ change in mmHg in female (P<0.05) vs -3.7±3.1 SBP and 3.1±2.1 DBP in male, respectively, n=7-8). Plasma aldosterone levels were decreased in HS male mice compared to control (224±57 vs 151±19 pg/ml, n=3-5), however, increased modestly in HS females (254±56 vs 394±158 pg/ml, n=3-6). Preliminary data indicated that MR antagonism with eplerenone ablated increases in SBP and DBP in HS female mice, while having no effect on blood pressure in HS males (-22.8 SBP and -23.9 DBP Δ change in mmHg in female vs 1.0 SBP and -1.5 DBP in male, n=2). In addition, and in association with an absence of aldosterone suppression with HS, renal mRNA expression of renin (1.4±0.1-fold, P<0.05, n=5), angiotensinogen (4.4±0.2-fold, P<0.05, n=5), AT1 receptor (52.9±0.9-fold, P<0.05, n=5), MR (1.6±0.2-fold, P<0.05, n=5) and α-ENAC (1.3±0.0-fold, P<0.05, n=5) were increased in HS female mice compared to control females. These data indicate that BP increases in HS female mice are associated with unexpected increases in plasma aldosterone as well as mRNA expression of proteins associated with renin angiotensin aldosterone system activation, which may be novel mechanisms via which females have increased risk for salt sensitive hypertension.