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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GFR falls with aging in humans and rats due to renal vasoconstriction and structural damage. The rate of deterioration is influenced by race/genetic background, environment, and sex, with females protected. Part of the female advantage relates to protective effects of estrogens. There is little information on impact of aging on the distribution/cardiovascular actions of the estrogen receptor subtypes. In rats, androgens may contribute to injury, but in men, high testosterone levels predict cardiovascular health. In women, the association is controversial. Nitric oxide deficiency contributes to the hypertension and renal dysfunction of aging, which may be delayed in the female.
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PMID:Sexual dimorphism of the aging kidney: role of nitric oxide deficiency. 1855 67

It has been shown that reactive oxygen species (ROS) contribute to the central effect of ANG II on blood pressure (BP). Recent studies have implicated an antihypertensive action of estrogen in ANG II-infused female mice. The present study used in vivo telemetry recording and in vitro living mouse brain slices to test the hypothesis that the central activation of estrogen receptors in male mice inhibits ANG II-induced hypertension via the modulation of the central ROS production. In male wild-type mice, the systemic infusion of ANG II induced a significant increase in BP (Delta30.1 +/- 2.5 mmHg). Either central infusion of Tempol or 17beta-estradiol (E2) attenuated the pressor effect of ANG II (Delta10.9 +/- 2.3 and Delta4.5 +/- 1.4 mmHg), and the protective effect of E2 was prevented by the coadministration of an estrogen receptor, antagonist ICI-182780 (Delta23.6 +/- 3.1 mmHg). Moreover, the ganglionic blockade on day 7 after the start of ANG II infusions resulted in a smaller reduction of BP in central Tempol- and in central E2-treated males, suggesting that estrogen inhibits the central ANG II-induced increases in sympathetic outflow. In subfornical organ slices, the application of ANG II resulted in a 21.5 +/- 2.5% increase in ROS production. The coadministration of irbesartan, an ANG II type 1 receptor antagonist, or the preincubation of brain slices with Tempol blocked ANG II-induced increases in ROS production (-1.8 +/- 1.6% and -1.0 +/- 1.8%). The ROS response to ANG II was also blocked by E2 (-3.2 +/- 2.4%). The results suggest that the central actions of E2 are involved in the protection from ANG II-induced hypertension and that estrogen modulation of the ANG II-induced effects may involve interactions with ROS production.
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PMID:Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species. 1859 99

Left ventricular (LV) hypertrophy commonly develops in response to chronic hypertension and is a significant risk factor for heart failure and death. The serine-threonine phosphatase calcineurin (Cn)A plays a critical role in the development of pathological hypertrophy. Previous experimental studies in murine models show that estrogen limits pressure overload-induced hypertrophy; our purpose was to explore further the mechanisms underlying this estrogen effect. Wild-type, ovariectomized female mice were treated with placebo or 17beta-estradiol (E2), followed by transverse aortic constriction (TAC), to induce pressure overload. At 2 weeks, mice underwent physiological evaluation, immediate tissue harvest, or dispersion of cardiomyocytes. E2 replacement limited TAC-induced LV and cardiomyocyte hypertrophy while attenuating deterioration in LV systolic function and contractility. These E2 effects were associated with reduced abundance of CnA. The primary downstream targets of CnA are the nuclear factor of activated T-cell (NFAT) family of transcription factors. In transgenic mice expressing a NFAT-activated promoter/luciferase reporter gene, E2 limited TAC-induced activation of NFAT. Moreover, the inhibitory effects of E2 on LV hypertrophy were absent in CnA knockout mice, supporting the notion that CnA is an important target of E2-mediated inhibition. In cultured rat cardiac myocytes, E2 inhibited agonist-induced hypertrophy while also decreasing CnA abundance and NFAT activation. Agonist stimulation also reduced CnA ubiquitination and degradation that was prevented by E2; all in vitro effects of estrogen were reversed by an estrogen receptor (ER) antagonist. These data support that E2 reduces pressure overload induced hypertrophy by an ER-dependent mechanism that increases CnA degradation, unveiling a novel mechanism by which E2 and ERs regulate pathological LV and cardiomyocyte growth.
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PMID:Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation. 1907 76

Interest in and use of "natural" remedies has grown exponentially in recent years. Compounds that have attracted considerable attention are the isoflavones, particular those found in soy. This review will provide a critical evaluation of our current understanding of the effects, mechanisms of action, and potential clinical applications of soy isoflavones in hypertension. Current data indicate that soy isoflavones, such as genistein and daidzein and equol, relax vascular smooth muscle both in vitro and in vivo via a combination of mechanisms including potentiation of endothelial-dependent and endothelial-independent vasodilator systems and inhibition of constrictor mechanisms. These effects involve both classical genomic as well non genomic actions. Isoflavone actions are mediated in part via interactions with estrogen receptors where soy isoflavones induce unique receptor conformations and exert tissue dependent effects similar to the selective estrogen receptor modulators. Signaling pathways such as ERK1/2, PI3-Kinase/Akt and cAMP contribute to isoflavone isoflavone activation of eNOS in the vasculature as well. Isoflavones also target the kidney to increase renal blood flow and sodium excretion. Finally, soy isoflavones interact with humoral systems such as the renin angiotensin. Data from animal studies show consistently that the aggregate effect of these actions is attenuation of hypertension. In contrast, studies in humans remain controversial. Recent data also suggest that analogues of isoflavones may possess unique vascular actions. Thus significant opportunity remains for study of the effects and mechanisms of action of soy isoflavones on hypertension in both animals and humans.
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PMID:Understanding the cardiovascular actions of soy isoflavones: potential novel targets for antihypertensive drug development. 1920 95

The present study tested the hypotheses that male and female rats respond differently to subcutaneous infusions of aldosterone (Aldo; 1.8 microg.kg(-1).h(-1), 1% NaCl to drink; 28 days) and that central estrogen plays a protective role against the development of hypertension. In rats with blood pressure (BP) and heart rate (HR) measured by Data Sciences International telemetry, chronic Aldo/NaCl treatment induced a greater increase in BP in males (Delta25.4 +/- 2.4 mmHg) than in females (Delta7.1 +/- 2.2 mmHg). Gonadectomy augmented Aldo/NaCl-induced hypertension in females (Delta18.2 +/- 2.0 mmHg) but had no effect in males (Delta23.1 +/- 2.9 mmHg). Immunohistochemistry for Fra-like activity was higher in the paraventricular nucleus of intact males, castrated males, and ovariectomized (OVX) females compared with intact females after 28 days of Aldo/NaCl treatment. In intact males, central 17beta-estradiol (E(2)) inhibited the Aldo/NaCl increase in BP (Delta10.5 +/- 0.8) compared with that in central vehicle plus systemic Aldo/NaCl (Delta26.1 +/- 2.5 mmHg) rats. Combined administration of E(2) and estrogen receptor antagonist ICI182780 (ICI) blocked the protective effect of E(2) (Delta23.2 +/- 2.4 mmHg). In intact females central, but not peripheral, infusions of ICI augmented the Aldo/NaCl (Delta20.4 +/- 1.8 mmHg) BP increase. Finally, ganglionic blockade after Aldo infusions resulted in a smaller reduction in BP in intact females (-23.9 +/- 2.5 mmHg) and in central estrogen-treated males (-30.2 +/- 1.0 mmHg) compared with other groups (intact males, -39.3 +/- 3.4; castrated males, -41.8 +/- 1.9; intact males with central E(2) + ICI, -42.3 +/- 2.1; OVX females, -40.3 +/- 3.3; and intact females with central ICI, -39.1 +/- 1.3 mmHg). Chronic Aldo infusion produced increases in NaCl intake and decreases in HR that were both similar in all groups. Taken together, the results indicate that central estrogen plays a protective role in the development of Aldo/NaCl-induced hypertension and that this may result from reduced sympathetic outflow.
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PMID:Sex differences and central protective effect of 17beta-estradiol in the development of aldosterone/NaCl-induced hypertension. 1927 Jan 92

The mRen2.Lewis congenic strain is an estrogen-sensitive model of hypertension whereby estrogen depletion produces a significant and sustained increase in blood pressure. The recent identification of G protein-coupled receptor 30 (GPR30) as a third estrogen receptor isotype prompted us to test the hypothesis that this novel receptor exhibits beneficial cardiovascular actions in the hypertensive female mRen2.Lewis rat. Intact female, ovariectomized female (OVX), and male mRen2.Lewis rats were treated with the selective GPR30 agonist G-1 or vehicle via osmotic minipump for 2 wk. G-1 significantly reduced systolic blood pressure in OVX (178 +/- 7 to 142 +/- 10 mm Hg, P < 0.001, n = 8) but not intact female (144 +/- 3 to 143 +/- 5 mm Hg, P > 0.05, n = 5) or male mRen2.Lewis rats (207 +/- 7 to 192 +/- 5 mm Hg, P > 0.05, n = 7). G-1 did not alter uterine or body weight in OVX, suggesting activation of a receptor distinct from estrogen receptor-alpha and -beta. In isolated aortic rings from OVX, G-1 reduced constriction in response to angiotensin II. Vascular angiotensin-converting enzyme and angiotensin type 1 receptor mRNA were also lower, whereas angiotensin-converting enzyme-2 mRNA was increased. G-1 treatment in OVX was not associated with alterations in either endothelial nitric oxide synthase expression or acetylcholine-induced relaxation. Immunohistochemical staining for GPR30 was evident in both the intima and media of the aorta. We conclude that the novel estrogen receptor GPR30 may contribute to the beneficial cardiovascular actions of estrogen in female mRen2.Lewis rats through regulation of vascular components of the renin-angiotensin system.
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PMID:Chronic treatment with the G protein-coupled receptor 30 agonist G-1 decreases blood pressure in ovariectomized mRen2.Lewis rats. 1937 94

Female mice are protected from the cerebrovascular dysfunction induced by angiotensin II (Ang II), an effect attributed to estrogen. We examined whether such cerebrovascular protection from Ang II is related to the estrous cycle. Cerebral blood flow was monitored by laser-Doppler flowmetry in anesthetized (urethane-chloralose) C57BL/6 female mice equipped with a cranial window. The phase of the estrous cycle was determined by vaginal smear cytology and plasma estrogen measurement. Ang II (0.25 microg/kg per minute, IV, 30 to 45 minutes) elevated arterial pressure (15 to 20 mm Hg) equally across the estrous cycle. However, in proestrus and estrus, phases in which estrogen is relatively high, Ang II did not impair the increase in the cerebral blood flow induced by neural activity or by endothelium-dependent vasodilators (P>0.05 from vehicle). In contrast, in diestrus (lower estrogen), Ang II induced a marked cerebrovascular dysfunction comparable to that of male mice. For example, the cerebral blood flow responses to whisker stimulation and to the endothelium-dependent vasodilator acetylcholine were attenuated by 41+/-12% and 49+/-12%, respectively (P<0.05; n=6 per group). The protection from the cerebrovascular effects of Ang II in proestrus was abolished by the estrogen receptor inhibitor ICI182,780. Ang II also increased production of free radicals in cerebral blood vessels in diestrus (+116+/-13%; P<0.05) but not in proestrus and estrus (P>0.05 from control). Topical treatment with ICI182,780 reestablished Ang II-induced oxidative stress in proestrus (P>0.05 from diestrus). We conclude that the protection from the neurovascular dysfunction induced by acute administration of Ang II in females depends on the estrous cycle and may underlie the increased propensity to cerebrovascular damage associated with low estrogen states.
Hypertension 2009 Aug
PMID:Estrous cycle-dependent neurovascular dysfunction induced by angiotensin II in the mouse neocortex. 1950 98

A decrease in bone mineral density has been reported to be associated with increased progression of aortic stenosis (AS). We hypothesized that osteoporosis treatment (OT) is associated with decreased progression of AS. We performed an observational study of patients with AS from our echocardiographic database comparing 18 patients on OT (bisphosphonates, calcitonin, or estrogen receptor modulators) with 37 patients not on OT. All patients had serial echocardiograms. Patients with mitral stenosis, aortic valve replacement, renal failure, calcium disorders, or left ventricular ejection fraction <40% were excluded. Aortic valve area (AVA) was calculated using the continuity equation. There was no significant difference in age, gender, renal function, hypertension, statin use, diabetes, or calcium level between the 2 groups. Mean baseline AVA was 1.33 cm(2) and not significantly different between groups. After a mean of 2.4 +/- 1.0 years, mean annual changes in AVA were -0.22 +/- 0.22 cm(2) in those not on OT and -0.10 +/- 0.18 cm(2) in patients receiving OT (p = 0.025). There was a graded association between AS progression rate and OT. In a multivariable analysis including age, gender, and statin use, only OT was associated with a change in AVA. In conclusion, OT is strongly and independently associated with decreased progression of AS. This association warrants investigation in a larger, prospective study.
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PMID:Osteoporosis treatment and progression of aortic stenosis. 1957 32

Premenopausal women have less cardiovascular disease and lower cardiovascular morbidity and mortality than men the same age. Our previous studies showed that female mice have lower mortality and better preserved cardiac function after myocardial infarction. However, the precise cellular and molecular mechanisms responsible for such a sex difference are not well established. Using cultured adult mouse cardiomyocytes, we tested the hypothesis that the survival advantage of females stems from activated estrogen receptors and Akt survival signaling pathways. Adult mouse cardiomyocytes were isolated from male and female C57BL/6J mice and treated with hydrogen peroxide (100 micromol/L) for 30 minutes. Cell survival was indicated by rod ratio (rod shaped cells:total cells), cell death by lactate dehydrogenase release, and positive staining of annexin-V (a marker for apoptosis) and propidium iodide (a marker for necrosis). In response to hydrogen peroxide(,) female adult mouse cardiomyocytes exhibited a higher rod ratio, lower lactate dehydrogenase release, and fewer Annexin-V-positive and propidium iodide-positive cells compared with males. Phospho-Akt was greater in females both at baseline and after hydrogen peroxide stimulation. The downstream molecule of Akt, phosphor-GSK-3beta (inactivation), was also higher, whereas caspase 3 activity was lower in females in response to hydrogen peroxide. Bcl-2 did not differ between sexes. Estrogen receptor-alpha was the dominant isoform in females, whereas estrogen receptor-beta was low but similar in both sexes. Our findings demonstrate that female adult mouse cardiomyocytes have a greater survival advantage when challenged with oxidative stress-induced cell death. This may be attributable to activation of Akt and inhibition of GSK-3beta and caspase 3 through an estrogen receptor-alpha-mediated mechanism.
Hypertension 2010 May
PMID:Female adult mouse cardiomyocytes are protected against oxidative stress. 2021 61

Steroid hormones such as aldosterone and estrogens have been increasingly appreciated as important physiological and pathophysiological regulators of cardiovascular functions. These actions are mediated in part by their 'traditional' steroid receptors - such as estrogen and mineralocorticoid receptors - via well-described transcriptional mechanisms. However, many of the effects of steroids occur over a time course not explained by these longer-term transcriptional mechanisms. These more rapid actions have been shown to have important effects on vascular reactivity and a wide range of second messengers and enzymes. Elucidating the mechanisms and biological impact of these rapid steroid effects has been confounded by our lack of appreciation of the cell types on which these steroids were mediating their rapid effects, and the receptor(s) with which they were interacting. Emerging insights from studies of the rapid vascular effects of both aldosterone and estradiol are helping to clarify these mechanisms. For aldosterone, its rapid effects on vascular reactivity have been variably described as vasodilator, vasoconstrictor or nonexistent. Recent studies have indicated that the net effect of aldosterone on vascular reactivity is dependent on its opposing actions, mediating vasodilation via an endothelial-dependent mechanism and/or vasoconstriction via a direct smooth muscle effect. Both of these mechanisms appear to be phosphoinositide-3 kinase dependent. Thus, appreciating the rapid vascular effects of aldosterone on a given vascular bed is likely to be dependent on appreciating the relative contribution of its endothelial versus its direct vascular smooth muscle effects. Furthermore, a shift in this balance of endothelial to vascular smooth muscle-mediated effects may be important in vascular dysregulation in hypertension and atherosclerotic disease. Studies elucidating the rapid vascular effects of estrogen on the mitogen-activated protein kinase (MAP), extracellular signal-regulated kinase (ERK) and its consequent effects on apoptosis have helped us understand the concept that the variability in directionality of rapid steroid responses may, in part, be related to their interactions with receptor systems mediating opposing effects. For estradiol, we have shown rapid effects via classical estrogen receptors inhibiting ERK activation and, consequently, apoptosis. In contrast, expression G protein-coupled receptor 30 (GPR30), a recently appreciated G protein-coupled receptor implicated in mediating the rapid cellular effects of estrogen, mediates diametrically opposed effects - stimulation of ERK and proapoptotic effects. A shift in the balance of estrogen receptor versus GPR30 regulation with aging, hypertension and/or atherosclerotic disease might critically shift the balance of beneficial versus harmful effects of estrogen on the vasculature.
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PMID:Rapid vascular effects of steroids - a question of balance? 2038 56


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