Estrogen Depletion Increases Blood Pressure and Hypothalamic Norepinephrine in Middle-Aged Spontaneously Hypertensive Rats

Abstract

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...

Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2.Lewis rats

“…In this regard, Cervenka et al (8) demonstrated increased sodium excretion following acute nNOS inhibition in intact but not denervated male mRen(2)27 rats, the founder strain to the current congenic strain. We do not know the status of the adrenergic system following ovariectomy in the mRen2.Lewis rat, although estrogen exerts an inhibitory influence on sympathetic activation (13,15,30,34). Moreover, estrogen depletion exacerbated the salt-dependent increase in blood pressure and renal injury (proteinuria) in the mRen2.Lewis rat, and altered NO levels in the kidney may well contribute to the sodium-sensitive phenotype (11).…”

Sex Steroids, Cardiovascular Disease, and Hypertension

“…The other drawback to most of the menopausal studies in animals is that ovariectomy does not cause hypertension and increased CVD. Two contradictions to this statement are the SHR female that, when ovariectomized at middle age and placed on high-salt diet, becomes more hypertensive 44 and the young ovariectomized Dahl saltsensitive rat that exhibits increased blood pressure compared with intact females independent of salt diet. 45 There are now 3 animal models that have been described that develop progressive hypertension and CVD with aging that can be used to better determine the changes that occur after menopause.…”

Novel Mechanisms Responsible for Postmenopausal Hypertension

“…Sheep, rabbits, nonhuman primates, rats, and mice have been used as models of various menopausal changes; 6 however, to our knowledge, there is no animal model of naturally occurring postmenopausal hypertension. There have been attempts to mimic menopause by ovariectomizing animals; 7,8 however, these have rarely taken into account the effect of aging and cessation of ovarian function. In any case, there is no normotensive animal model that exhibits hypertension with aging.…”