Clinical studies suggest that sleep apnea causes systemic hypertension. There is gender specificity in the incidence of sleep apnea. Premenopausal women have a lower occurrence of sleep apnea, whereas in postmenopausal women the incidence of sleep apnea is same as in males. Therefore, female sex hormone, estrogen, may protect women against the sleep apnea-induced hypertension. Intermittent hypoxia (IH) is used to mimic the arterial hypoxemia that occurs during sleep apnea. We examined whether chronic estrogen replacement affects blood pressure (BP) responses to IH in ovariectomized rats. Female Wistar rats aged 9 wk were ovariectomized and implanted with radiotelemetry devices for BP and heart rate measurements. After 4 wk, the rats were assigned either to a placebo-treated (Pla; n=15) group or a group treated with 17β-estradiol (E2; n=15) subcutaneously implanted with either placebo- or 17 β -estradiol (2.5 mg/90-day release) pellets. The atmosphere in IH chamber was controlled by the electronically regulated solenoid switches in a two-channel gas mixer, which gradually lowered oxygen in the chamber over 90 s from 21% to 4% O2. Chamber ware rapidly flushed with compressed air for the following 90 s to restore O2 to 21%. Rats were exposed to 20 cycles/h of IH or air-air for 8 h/day during the light phase (9:00-17:00) for 14 days. In the day after the series of IH exposure, mesenteric arteries were dissected from IH-exposed or control rats euthanized by overdoses of pentobarbitone. Using the arteries contracted with 3×10-6 M phenylephrine, we test relaxation responses to acetylcholine (Ach, 10-8-10-5 M) under inhibitions of endothelium-dependent vasodilators. The expression of endothelial nitric oxide synthase (eNOS) in the mesentery was examined by Western blot analysis. After 7 days, resting mean arterial pressure (MAP) was significantly elevated in IH rats of the Pla and E2 groups similarly during the light phase (IH-phase). On the other hand, during the dark phase (non-IH phase), only the Pla group exhibited the MAP elevation on day 7. However, the MAP in the E2 group was increased to the same level in the Pla group during light or dark phase on day 14. Sensitivity of Ach-induced endothelium-dependent NO (ED50) in mesenteric arteries was higher in the E2 group than that in the Pla group of IH rats. In addition, Western blot analysis showed that eNOS expression in mesentery was increased in the E2 group compared with the Pla group. This study suggests that estrogen replacement delayed the development of IH-induced hypertension in non-IH phase, at least partly, though enhancement in NO sensitivity in mesenteric arteries and over-expressed mesenteric eNOS in ovariectomized rats.