Abstract-In male spontaneously hypertensive rats (SHR) a high NaCl diet increases arterial pressure via a reduction in anterior hypothalamic nucleus norepinephrine release. Young female SHR are relatively well protected from this NaCl-sensitive hypertension, but depletion of both endogenous and dietary estrogens greatly exacerbates NaCl-sensitive hypertension. This study tests the hypothesis that estrogen also protects late middle-aged female SHR from NaCl-sensitive hypertension and that this effect is mediated by an estrogen-related effect on hypothalamic norepinephrine release. Ten-month-old female SHR were ovariectomized and placed on a phytoestrogen-free diet containing either basal or high NaCl. Each rat was implanted with a silastic tube containing 17 estradiol or vehicle. Three months later, arterial pressure and hypothalamic norepinephrine metabolite levels (MOPEG) were measured. On the basal NaCl diet, estrogen-depleted rats displayed increased arterial pressure (12 mm Hg) and decreased anterior hypothalamic nucleus MOPEG (20%). Both effects were reversed by estrogen treatment. In all groups, the high NaCl diet increased arterial pressure by over 35 mm Hg and reduced anterior hypothalamic nucleus MOPEG by Ͼ60%. Across all groups, there was a significant inverse correlation between arterial pressure and anterior hypothalamic nucleus MOPEG. These data suggest that both dietary NaCl excess and estrogen depletion raise arterial pressure in middle-aged female SHR by a decreasing hypothalamic norepinephrine. Key Words: estrogen Ⅲ norepinephrine Ⅲ sodium Ⅲ sympathetic nervous system Ⅲ blood pressure H ypertension significantly contributes to premature death in the fastest-growing segment of the population, ie, adults over 65 years of age. 1 The incidence of hypertension in this age group is about 60%. [2][3][4] Further, between 30% and 50% of hypertensive patients are NaCl-sensitive, ie, they display a significant (Ͼ10%) increase in blood pressure when placed on a high NaCl diet (200 to 250 mEq Na ϩ /d for 7 days). The NaCl-sensitive hypertensive patients, in contrast to normotensive and NaCl-resistant hypertensive subjects, fail to suppress plasma norepinephrine (NE) after the ingestion of a diet high in NaCl. 5,6 These and other studies suggest that the sympathetic nervous system contributes importantly to NaCl-sensitive hypertension in aging humans. 7,8 Several lines of evidence indicate that, compared with men, premenopausal women have a lower rate of hypertension. After menopause this relative protection appears to be lost, and women experience a rapid rise in hypertension (including salt-sensitive hypertension). 9,10 This increase appears to be related to the menopausal loss of estrogen. Our studies in spontaneously hypertensive rats (SHR) demonstrate that young female SHR (compared with age-matched male SHR) have a lower arterial pressure and a reduced hypertensive response to excess dietary NaCl. 11 Elimination of most endogenous estrogen by ovariectomy causes no significant change in arterial pressur...