Effects of Estrogen Replacement Therapy on the Renin-Angiotensin System in Postmenopausal Women

Schunkert, Heribert; Danser, A.H. Jan; Hense, Hans‐Werner; Derkx, F. H. M.; ̈rzinger, Susanne Ku; Riegger, Gu ̈nter A.J.

doi:10.1161/01.cir.95.1.39

Cited by 366 publications

(255 citation statements)

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“…However, in men and women who had PRA measured serially for 9 years, PRA was higher in postmenopausal women than premenopausal women. 14,15 PRA is also increased in PMR at age 18 months. 9 Furthermore, treatment of PMR with losartan, an AT1 receptor antagonist, normalizes their blood pressure (Yanes and Reckelhoff, unpublished data, 2004).…”

Section: Does the Ras Play A Role In Postmenopausal Hypertension?mentioning

confidence: 82%

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Novel Mechanisms Responsible for Postmenopausal Hypertension

2004

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Abstract-Blood pressure increases in many women after menopause. Hypertension is one of the major risk factors for cardiovascular disease. However, the mechanisms responsible for the postmenopausal increase in blood pressure are yet to be elucidated. Various humoral systems have been proposed to play a role in postmenopausal hypertension, such as changes in estrogen/androgen ratios, increases in endothelin and oxidative stress, and activation of the renin-angiotensin system (RAS). In addition, obesity, type II diabetes, and activation of the sympathetic nervous system are common in postmenopausal women and may also play important roles. However, progress in elucidating the mechanisms responsible for postmenopausal hypertension has been hampered by the lack of a suitable animal model. The aging female spontaneously hypertensive rat (SHR) exhibits many of the characteristics found in postmenopausal women. In this review, some of the possible mechanisms that could play a role in postmenopausal hypertension are discussed, as well as the characteristics of the aged female SHR as a model to study. Key Words: endothelin Ⅲ renin-angiotensin system Ⅲ oxidative stress Ⅲ obesity Ⅲ diabetes mellitus Ⅲ sympathetic nervous system B efore menopause, blood pressure is typically lower in women than in age-matched men. 1 In aging men and women, systolic and diastolic blood pressures increase, although in later years the diastolic plateaus or even declines. [1][2][3] However, in postmenopausal women, the prevalence of hypertension and cardiovascular disease risk increases regardless of ethnic origin. Results from the National Health and Nutrition Examination Survey (NHANES III) showed that in Hispanic women and non-Hispanic black women, the prevalence of hypertension was similar to, or higher than, that in men by age 60 years. 4 In non-Hispanic white populations, the prevalence of hypertension was higher in women than in men by age 70 years. 4 The increase in blood pressure in postmenopausal women does not occur as soon as the ovary becomes senescent, but rather over a number of years. 5 The mechanisms responsible for the increased blood pressure in women after menopause are not known. This review focuses on the use of the spontaneously hypertensive rat as a model of postmenopausal hypertension and evaluates the possible mechanistic roles of the sex hormones, oxidative stress, endothelin, renin-angiotensin system (RAS), weight gain, and sympathetic activation in postmenopausal hypertension. Animal Model for the Study of Postmenopausal HypertensionThe elucidation of mechanisms responsible for postmenopausal hypertension has been stunted by lack of an animal model. 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 ova...

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Section: Does the Ras Play A Role In Postmenopausal Hypertension?mentioning

confidence: 82%

“…14, 15 The PMR also has an increase in PRA compared with young females ( Figure 5). In contrast, in the aging male SHR, the PRA decreases such that the PRAs are similar in old males and females.…”

Section: Characterization Of the Postcycling Shr As A Model Of Postmementioning

confidence: 90%

Novel Mechanisms Responsible for Postmenopausal Hypertension

2004

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“…Estrogen has been shown to down-regulate AT 1 receptors that play a major role in the regulation of BP and fluid balance and could account for the association of estrogen deficiency with hypertension, atherosclerosis, and arteriosclerosis (28). Contrasting with these actions, estrogen has also been shown to promote the production of angiotensinogen (29), and it is this dichotomy of estrogen's action on the renin-angiotensin system that has led to the proposition by Fischer and colleagues (27) that the overall effects of estrogen on the vasculature may very much depend on a shift in the balance between the dilatory and constrictor mechanisms. In high renin models, for example, the mRen2Lewis rat, estrogen is as effective as an AT 1 receptor antagonist in limiting the severity of hypertension (30).…”

Section: Discussionmentioning

confidence: 99%

Aromatase-Deficient (ArKO) Mice Have Reduced Blood Pressure and Baroreflex Sensitivity

Head

Obeyesekere

Jones³

et al. 2004

Endocrinology

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Aromatase-deficient (ArKO) mice are deficient in estrogens due to deletion of the aromatase gene. We hypothesized that there may be changes in the cardiovascular system of ArKO mice because of evidence linking estrogens with improved cardiovascular outcomes and the induction of the glucocorticoid-metabolizing enzyme, 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2), gene in the kidney, which is important for the regulation of blood pressure (BP). BP and baroreflex sensitivity (BRS) in female conscious ArKO mice were compared with those in age-and weight-matched wild-type (WT) mice. Power spectral analysis was used to determine cardiovascular variability and BRS. Although systolic BP was similar in the two groups, diastolic and mean BPs were lower in the ArKO mice (؊6.3 ؎ 1.9 and ؊4.6 ؎ 2.1 mm Hg, respectively).Heart rate (HR) was greater in the ArKO mice (؉36 ؎ 6 beats/ min). The mean BP in WT mice was 105 mm Hg, and the HR was 481 beats/min. In the autonomic frequency range, BP variability was 74% greater, and HR variability was only 26% that in WT mice. The BRS of ArKO mice was 46% of the value observed in WT mice. 11␤HSD2 levels were unaltered in ArKO mice, except in the kidney, where they were only 10% of WT levels. Estradiol administration to ArKO mice restored renal 11␤HSD2 to WT levels. The results show that ArKO mice have lower diastolic BP, but increased BP variability, perhaps due to an impaired BRS. Thus, aromatase activity is critical for normal autonomic control of the heart and, hence, for reducing the deleterious effects of high BP variability. (Endocrinology 145: 4286 -4291, 2004)

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“…[3][4][5] The vascular effects of estrogens are not completely understood. Estrogens lower plasma lipoproteins, 3 influence the renin-angiotensin system, 6,7 exert antioxidative properties, 8 and may act as calcium-blocking agents. 9 In addition, estrogens exert direct effects on the vessel wall, such as an increase of vascular NO production and modulation of endothelial NO synthase (eNOS [NOS III]) expression.…”

mentioning

confidence: 99%

Endothelial Dysfunction and Oxidative Stress During Estrogen Deficiency in Spontaneously Hypertensive Rats

et al. 2001

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Background-Postmenopausal estrogen deficiency is associated with an increased cardiovascular risk, hypertension, and oxidative stress. Angiotensin type 1 (AT 1 ) receptor regulation is involved in the pathogenesis of atherosclerosis. To characterize vascular function, oxidative stress, and AT 1 receptor regulation during estrogen deficiency, ovariectomized spontaneously hypertensive rats (SHR) were investigated in comparison with sham-operated animals and with ovariectomized rats receiving estrogen replacement therapy with 17␤-estradiol. Methods and Results-Arterial blood pressure was similar in all 3 groups investigated. Five weeks after ovariectomy, endothelial dysfunction in aortic rings was observed, which was reversed by estrogen replacement therapy. Estrogen deficiency led to an enhanced vasoconstriction by angiotensin II. Vascular superoxide production was significantly increased compared with that in sham-operated rats, as measured by lucigenin chemiluminescence assays. Estrogen substitution normalized the production of free radicals in the vessel wall. Vascular AT 1 receptor expression was significantly upregulated by estrogen deficiency, as shown by quantitative reverse transcription-polymerase chain reaction, whereas endothelial NO synthase mRNA expression and NO release were unchanged. Five-week treatment of the animals with the AT 1 receptor antagonist irbesartan prevented endothelial dysfunction in ovariectomized rats and normalized the vascular production of free radicals. Conclusions-In

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Effects of Estrogen Replacement Therapy on the Renin-Angiotensin System in Postmenopausal Women

Abstract: Aside from a well-documented induction of angiotensinogen, ERT is related to a substantial suppression of renin, a phenomenon that might have received little attention because of widely used indirect measurements of the hormone.

Cited by 366 publications

References 35 publications

Novel Mechanisms Responsible for Postmenopausal Hypertension

Novel Mechanisms Responsible for Postmenopausal Hypertension

Aromatase-Deficient (ArKO) Mice Have Reduced Blood Pressure and Baroreflex Sensitivity

Endothelial Dysfunction and Oxidative Stress During Estrogen Deficiency in Spontaneously Hypertensive Rats

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