Aromatase Inhibition Increases Blood Pressure in Female Sprague Dawley Rats

Aromatase is a monooxygenase that catalyzes the rate‐limiting step of estrogen biosynthesis from androgens. Aromatase inhibitors are widely used for treatment of patients with hormone receptor‐positive breast cancer. However, the effects of aromatase inhibitors on cardiovascular and renal health in females are understudied. Given that estrogen is protective against cardiovascular disease and hypertension, we hypothesized that aromatase inhibition would elevate blood pressure in female Sprague Dawley rats. Twelve‐week‐old female rats (n=18) were implanted with radio‐telemetry transmitters to continuously monitor blood pressure. After baseline blood pressure recording, rats were randomly assigned to treatment with the aromatase inhibitor anastrozole (0.5 mg/kg/day) or vehicle (0.017% DMSO) in drinking water. Twenty days after treatment initiation, rats were shifted from a normal‐salt diet (NS, 0.49% NaCl) to a high‐salt diet (HS, 4% NaCl) for an additional 40 days. Twenty‐four‐hour urine samples were collected at baseline and during the NS and HS diet phases, while food and water intake were monitored. Rats were euthanized 60 days after treatment initiation, at which time the uterus weight was recorded and plasma was collected for LC‐MS/MS measurement of sex steroid concentrations. Body weight increased in both groups over the study period but was greater in the anastrozole‐treated than in the vehicle‐treated group at day 60 (278 ± 5 vs. 258 ± 4 g, respectively, n=9/group, p =0.005). The plasma estradiol to testosterone ratio was lower in the anastrozole‐treated group than in the vehicle‐treated group (2.23 ± 0.72 vs. 83.54 ± 13.13 pg/ng, respectively, n=9/group, p <0.0001), as was the plasma estrone concentration (1.12 ± 0.12 vs. 3.02 ± 0.69 pg/ml, respectively, n=9/group, p =0.016). Additionally, uterine weight was lower in the anastrozole‐treated group than in the vehicle‐treated group (0.08 ± 0.01 vs. 0.13 ± 0.01 g, respectively, n=9/group, p =0.001), which implies efficient blockade of aromatase enzyme function. Mean arterial pressure (MAP) increased in anastrozole‐treated rats during the NS diet phase and the HS diet phase (111.5 ± 1.1 and 113.1 ± 1.4, respectively, vs. 107.8 ± 1.2 mmHg at baseline, n=9, p <0.0001) but remained unchanged in vehicle‐treated rats (108.6 ± 1.5 at the HS diet phase vs. 108.0 ± 1.4 mmHg at baseline, n=9, p >0.05). Systolic and diastolic blood pressure followed the same pattern as MAP in both groups. Neither plasma aldosterone level nor endothelin‐1 level differed between treatment groups. Additionally, increased dietary salt intake promoted proteinuria and albuminuria in both treatment groups. In conclusion, chronic aromatase inhibition in vivo with anastrozole increases blood pressure in female Sprague Dawley rats fed a NS or a HS diet, indicating an important role for aromatase function in the maintenance of female cardiovascular health.