Chronic estradiol - 17 β exposure increases superoxide production in the

1 Women are exposed to estrogen in several forms such as oral contraceptive pills and 2 hormone replacement therapy. Although estrogen was believed to be cardioprotective, 3 lately, its beneficial effects are being questioned. Recent studies indicate that oxidative 4 stress in the rostral ventrolateral medulla (RVLM) may play a role in the development of 5 hypertension. Therefore, we hypothesized that chronic exposure to low levels of 6 estradiol-17β (E2) leads to hypertension in adult cycling female Sprague Dawley (SD) 7 rats potentially through generation of superoxide in the RVLM. To test this hypothesis, 8 young adult (3-4 months old) female SD rats were either sham-implanted or implanted 9 (s.c.) with slow release E2 pellets (20 ng/day) for 90 days. A group of control and E210 treated animals were fed lab chow or chow containing resveratrol (0.84 g/ Kg of chow), 11 an antioxidant. Rats were implanted with telemeters to continuously monitor blood 12 pressure (BP) and heart rate (HR). At the end of treatment, the RVLM was isolated for 13 measurements of superoxide. E2 treatment significantly increased mean arterial 14 pressure (mm Hg) and HR (beats/min) compared to sham rats (119.6±0.8 vs. 105.1±0.7 15 and 371.7±1.5 vs. 354.4±1.3, p<0.0001 respectively). Diastolic and systolic BP were 16 significantly increased in E2-treated rats compared to control animals. Superoxide 17 levels in the RVLM (nmol/min*mg) increased significantly in the E2-treated group 18 (0.833±0.11) compared to control (0.532±0.04, p<0.05). Treatment with resveratrol 19 reversed the E2-induced increases in BP and superoxide levels in the RVLM. In 20 conclusion, these findings support the hypothesis that chronic exposure to low levels of 21 E2 induces hypertension and increases superoxide levels in the RVLM and that this 22 effect can be reversed by resveratrol treatment. 23