Tempol Decreases Mean Arterial Pressure in Hypertensive Western Diet-Fed Hyperandrogenemic Females

Background: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy and major cause of hyperandrogenemia in women. PCOS women are at increased risk of cardiovascular diseases and hypertension (HTN). Obesity aggravates the cardiometabolic phenotype in PCOS. Although clinical trials testing the antihypertensive effects of antioxidants have typically not been successful in human cohorts, studies in male rats suggest that oxidative stress plays an important role in mediating HTN. Tempol (antioxidant; superoxide dismutase mimetic) has been shown to decrease blood pressure (BP) in different male models of HTN. Our group previously showed that Tempol fails to reduce BP in young intact, ovariectomized or aging hypertensive females, suggesting sex differences in the depressor effects of tempol independent of sex steroid levels. The present study was designed to test the hypothesis that tempol lacks a depressor effect on BP in hypertensive hyperandrogenemic females. Methods: At 4 weeks of age, female Sprague Dawley (SD) rats were implanted (s.c.) with either 5α-dihydrotestosterone pellets (7.5 mg/90 d; hyperandrogenemic females (HAF)) or placebo pellets (CON), that were replaced throughout life. At 4 wks of age, HAF and CON rats werealsostarted on western diet (WD; high fat and high sucrose content) or control diet (CD), thus forming 4 groups; CON-CD, CON-WD, HAF-CD and HAF-WD. Body composition was determined biweekly until 22 weeks (~ 6 months of age), then females were euthanized and serum levels of sex steroids were measured by LC/MS-MS [n=5-7/group]. At 7-12 months of age, another set of females were implanted with radiotelemetry transmitters in the abdominal aorta to measure mean arterial pressure (MAP) [n=6-7/group] at baseline and upon treatment with tempol (30 mg/kg/d, drinking water). Results: Although fat mass significantly increased in HAF-CD compared to CON-CD starting at 16 weeks of age, it was significantly higher in HAF-WD compared to CON-CD, CON-WD and HAF-CD starting at 14 weeks, and continued to be higher until 22 weeks of age (49.1 ± 13 vs 15.6 ± 2, 24.7 ± 3 and 33.6 ± 6 g, respectively, p < 0.05). On the other hand, lean mass was similar in HAF-CD and HAF-WD and significantly higher in both groups compared to CON-CD and CON-WD starting at 8 weeks until 22 weeks of age (315.1 ± 28 and 306.8 ± 43 vs 244.5 ± 16 and 254.0 ± 26 g, respectively, p < 0.05). Despite the similar levels of serum estradiol in the 4 groups, both HAF-CD and HAF-WD had 2-4-fold increase in their serum DHT levels compared to CON-CD and CON-WD (35.2 ± 6 and 38.0 ± 2 vs 8.1 ± 1 and 17.1 ± 2 ng/ml, respectively, p < 0.05). Upon treatment with tempol, MAP significantly decreased in HAF-WD, compared to baseline MAP in the same group (116 ± 3 vs 122 ± 1 mmHg at baseline, p < 0.05). Meanwhile, there was no change in MAP with tempol treatment compared to MAP at baseline in CON-CD (107 ± 1 vs 109 ± 1 mmHg, p > 0.05), CON-WD (107 ± 2 vs 109 ± 2 mmHg, p > 0.05) or HAF-CD (115 ± 2 vs 118 ± 1 mmHg, p > 0.05) groups. Conclusion: The blood pressure-lowering effects of tempol in females are only evident under conditions of combined exaggerated obesity and hyperandrogenemia suggesting a role for oxidative stress in HTN in PCOS females with exaggerated obesity. Future studies will determine the role of mitochondria-derived reactive oxygen species in HTN in PCOS. AHA-24DIVSUP1273026 (JA), NIH-NIGMS P20GM121334, AHA-22CDA938320 and 2024 Dean Franklin Award (NMS). This abstract was presented at the American Physiology Summit 2025 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.