The effect of perimenopause on the pathogenesis of hypertension in female DOCA-salt rats

The risk of hypertension (HTN) in young females is lower than in young males, but this risk increases in postmenopausal females and surpasses that of age-matched males. The mechanisms by which fluctuating ovarian hormone environment during the menopause transition impacts the onset of HTN are poorly understood. Similarly, preventative and rehabilitative strategies to reduce HTN risk in peri- and postmenopausal females are lacking. Purpose: We aim to use an ovary-intact rat model of reproductive aging to accelerate the natural process of follicular loss and determine mechanisms contributing to the development of HTN in the Deoxycorticosterone (DOCA)-salt rat model. We hypothesize that induction of perimenopause by the chemical 4-vinylcyclohexene diepoxide (VCD) administration will increase the susceptibility to development of HTN in DOCA-salt rats. Methods: We repeated a daily dose of VCD for 15 days, which selectively destroys primordial and primary follicles in rodent ovaries to accelerate female rats into perimenopause. We then administered DOCA, in combination with a high-salt diet, to induce HTN in those rats. Female Sprague-Dawley rats at 28 post-natal day (pnd) were weighed and received subcutaneous injection of VCD (160mg/kg) for 15 consecutive days. Control rats were injected with a vehicle (corn oil; 2.5 mL/kg body weight). Under inhaled isoflurane anesthesia, 57 days after the first VCD/oil injection, uninephrectomy and telemetric pressure transducer (DSI) implantation were performed. After 2 weeks of recovery, a 100 mg/kg DOCA silicone or vehicle implant was placed subcutaneously. The animals were divided into oil+DOCA (N=3) and VCD (periestropause rats) +DOCA (N=6). DOCA-salt rats were provided 0.9% saline during the 21 days of DOCA protocol and mean arterial pressure (MAP) was continuously measured. Rats were housed weekly in metabolic cages for 24 hours to measure water intake and urine volume. At the end of the protocol the animals were anesthetized, and blood was collected into heparinized tubes for the measurement of anti-Mullerian hormone (AMH), estradiol (E2), and progesterone (P4) by ELISA. Results: The plasma concentrations of AMH were reduced in the periestropause animals compared to oil (VCD: ± 6.5 ng/mL; Oil: 19 ng/Ml; p= 0.0042) confirming the VCD-induced follicular depletion. The steady state increase in MAP (day 21 of DOCA-salt) was higher in periestropause (±45.7mmHg; p<0.0001) compared to oil (±28.6 mmHg). No differences were observed in the saline intake between the groups. The urinary volume excretion was higher in periestropause rats (146.6 mL) compared to oil (112.6 mL). Conclusions: Our data suggest that periestropause rats showed greater susceptibility to the development of HTN in a DOCA-salt rat model. The possible mechanisms involved in this increased HTN risk are still being investigated through measurements of hormone concentrations of estradiol, progesterone, in addition to urinary cytokines and copeptin. NIH R01 HL116476 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.