Sex Differences in Age-Dependent Hypertension, Renal Sodium Handling and the Salt Sensitivity of blood pressure in male and female Sprague-Dawley Rats

Introduction: Hypertension (HTN) is the leading preventable cause of premature death worldwide and high salt (HS) intake is the strongest dietary risk factor for HTN. The salt sensitivity of blood pressure (SSBP), an increase in blood pressure (BP) with HS intake, affects ~50% of hypertensive individuals and ~25% of normotensive individuals (increase HTN risk). In humans, HTN and the SSBP develop in age- and sex-dependent manner across the lifespan and menopause (midlife loss of estrogen) increases the incidence of HTN and the SSBP in women. Previously, we have shown that intact male (M), but not intact female (F), Sprague-Dawley (SD) rats develop age-dependent HTN, impaired renal sodium excretion, and the SSBP, possibly due to lack of menopause in F SD rats. Thus, we hypothesized that ovariectomy (OVRX) at midlife, to model the loss of the estrogen following menopause, would induce HTN, impaired renal sodium handling, and the SSBP in F SD rats. Methods: In M and F SD rats at 3-, 8-, and 16-months-old (MO), and separate groups of 8 MO F rats that underwent a sham procedure or OVRX with either placebo or estradiol replacement (s.c. estradiol valerate in 1.5 mg extended-release pellet) and were studied 6-weeks post OVRX that were either maintained on a normal salt (NS; 0.6% NaCl) or challenged with a HS diet (4% NaCl) for 21-days. In all rats, mean arterial pressure (MAP) was measured via femoral artery catheter and fractional excretion of Na + (FENa), 24-h Na + balance, and the renal excretory response to acute 5% body weight volume expansion) were assessed. Results: M, but not F, SD rats develop age-dependent HTN (MAP mmHg: 3 MO M: 121±3, 8 MO M: 140±4*, 16 MO M: 151±3*†, 3 MO F: 130±3, 8 MO F: 132±3, 16 MO F: 131±4), impaired renal Na + excretion (FENa %: 3 MO M: 0.69±0.13, 8 MO M: 0.49±0.09*, 16 MO M: 0.36±0.11*†, 3 MO F: 0.74±0.08, 8 MO F: 0.71±0.12, 16 MO F: 0.66±0.09; 24-h Na + balance mEq: 3 MO M: 0.34±0.06, 8 MO M: 0.48±0.12, 16 MO M: 0.68±0.061*†, 3 MO F: 0.26±0.04, 8 MO F: 0.31±0.03, 16 MO F: 0.29±0.05; acute 5% body weight volume expansion %total volume load excreted: 3 MO M: 86±4, 8 MO M: 63±5*, 16 MO M: 30±5*†, 3 MO F: 82±8, 8 MO F: 80±8, 16 MO F: 83±6; acute 5% body weight volume expansion %total Na + load excreted: 3 MO M: 76±6, 8 MO M: 55±8*, 16 MO M: 22±6*†, 3 MO F: 77±5, 8 MO F: 72±5, 16 MO F: 74±5) and the SSBP (MAP mmHg on HS diet: 3 MO M: 123±3, 8 MO M: 143±6*, 16 MO M: 160±4*†‡, 3 MO F: 132±4, 8 MO F: 133±5, 16 MO F: 130±3). OVRX was validated by plasma estradiol levels (estradiol pg/mL: Sham OVRX: 16.15±4.5, OVRX+Placebo: 0.58±0.2#, OVRX+17βE2: 19.15±3.1) as measured by LC/MS. Following OVRX, 8 MO F placebo but not 17βE2 rats developed HTN (MAP mmHg: Sham OVRX: 131±2, OVRX+Placebo: 141±2#, OVRX+17βE2: 129±1), impaired renal Na + handling (FENa %: Sham OVRX: 0.79±0.07, OVRX+Placebo: 0.34±0.04#, OVRX+17βE2: 0.81±0.06; 24-h Na + balance mEq: Sham OVRX: 0.31±0.04, OVRX+Placebo: 0.72±0.08#, OVRX+17βE2: 0.34±0.05; acute 5% body weight volume expansion %total volume load excreted: Sham OVRX: 81±7, OVRX+Placebo: 50±8#, OVRX+17βE2: 80±8; acute 5% body weight volume expansion %total Na + load excreted: Sham OVRX: 74±5, OVRX+Placebo: 43±5#, OVRX+17βE2: 75±3) and the SSBP (MAP mmHg: Sham OVRX: 131±2, OVRX+Placebo: 141±2‡#, OVRX+17βE2: 129±1). *p< 0.05 compared to 3 MO within sex; †p< 0.05 compared to 8 MO within the sex; ‡p< 0.05 compared to respective NS group; #p< 0.05 compared to respective 8 MO Sham OVRX group. Conclusions: Our findings suggest midlife loss of estrogen contributes to the development of age-dependent HTN via increased renal sodium retention, which may lead to the SSBP. We speculate estrogen supplementation may mitigate age-related impairments in renal sodium handling and BP regulation in postmenopausal women. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.