scholarly journals High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism

2015 ◽  
Vol 2015 ◽  
pp. 1-7
Author(s):  
Tahereh Safari ◽  
Mehdi Nematbakhsh ◽  
Roger G. Evans ◽  
Kate M. Denton
Keyword(s):  
Angiotensin Ii ◽  
Replacement Therapy ◽  
Hormone Replacement ◽  
Renal Perfusion ◽  
Ovariectomized Rats ◽  
High Dose ◽  
Ang Ii ◽  
Renal Vasoconstriction ◽  
Increased Risk ◽  
Angiotensin Type 2 Receptor

Physiological levels of estrogen appear to enhance angiotensin type 2 receptor- (AT2R-) mediated vasodilatation. However, the effects of supraphysiological levels of estrogen, analogous to those achieved with high-dose estrogen replacement therapy in postmenopausal women, remain unknown. Therefore, we pretreated ovariectomized rats with a relatively high dose of estrogen (0.5 mg/kg/week) for two weeks. Subsequently, renal hemodynamic responses to intravenous angiotensin II (Ang II, 30–300 ng/kg/min) were tested under anesthesia, while renal perfusion pressure was held constant. The role of AT2R was examined by pretreating groups of rats with PD123319 or its vehicle. Renal blood flow (RBF) decreased in a dose-related manner in response to Ang II. Responses to Ang II were enhanced by pretreatment with estradiol. For example, at 300 ng kg−1 min−1, Ang II reduced RBF by45.7±1.9% in estradiol-treated rats but only by27.3±5.1% in vehicle-treated rats. Pretreatment with PD123319 blunted the response of RBF to Ang II in estradiol-treated rats, so that reductions in RBF were similar to those in rats not treated with estradiol. We conclude that supraphysiological levels of estrogen promote AT2R-mediated renal vasoconstriction. This mechanism could potentially contribute to the increased risk of cardiovascular disease associated with hormone replacement therapy using high-dose estrogen.

Angiotensin II conditions the slow component of autoregulation of renal blood flow

1993 ◽  
Vol 264 (3) ◽  
pp. F515-F522 ◽  
Author(s):  
W. A. Cupples
Keyword(s):  
Blood Flow ◽  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Slow Component ◽  
Renal Perfusion ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Renal Vasoconstriction ◽  
Renal Autoregulation ◽  
Fitting In

Release of a suprarenal aortic clamp results in angiotensin-dependent, arterial pressure-mediated renal vasoconstriction. The experiments reported here were designed to show whether this represents operation of autoregulation and whether the slow component of autoregulation is affected by angiotensin II (ANG II). They were performed using halothane-anesthetized Sprague-Dawley rats. In the 1st experiment renal perfusion pressure (RPP) was reduced in steps from spontaneous level to 45 mmHg and then returned in steps to the spontaneous level. The autoregulatory plateau was left-shifted some 20-30 mmHg, with the lower limit of autoregulation reduced from approximately 85 mmHg on the downward leg to approximately 60 mmHg on the upward leg. This resetting was blocked by captopril. Two experiments examined low pressure autoregulation in more detail. After RPP was reduced, three pairs of steps between 65 and 75 mmHg were performed. Significant renal vasodilatation was observed after downward pressure steps in both experiments. Time constants (tau) of resistance adjustment were recovered from most steps by curve fitting. In both experiments tau down = 0.07 +/- 0.01 Hz was faster than tau up = 0.04 +/- 0.01 Hz. Blockade of ANG II by enalaprilat or by the AT1-receptor blocker losartan potassium significantly inhibited regulatory vasodilatation and vasoconstriction at low RPP. Also, tau down = 0.04 +/- 0.01 Hz collapsed to the value of tau up = 0.04 +/- 0.01 Hz. These results demonstrate a significant role for ANG II in renal autoregulation. They show that ANG II is necessary for autoregulation to reset to operate at reduced arterial pressure and to defend a lower blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy

2021 ◽  
Vol 22 (13) ◽  
pp. 7222
Author(s):  
Yoshinori Okamoto ◽  
Hideto Jinno ◽  
Shinji Itoh ◽  
Shinya Shibutani
Keyword(s):  
Hormone Replacement Therapy ◽  
Replacement Therapy ◽  
Hormone Replacement ◽  
Metabolic Activation ◽  
Ovariectomized Rats ◽  
Estrogenic Potential ◽  
Carcinogenic Potential ◽  
Induced Tumors ◽  
Carcinogenic Effects ◽  
17Β Estradiol

Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE2) or 4-chloro-17β-estradiol (4-ClE2) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17β-Estradiol (E2) frequently induced mammary tumors while both 2-ClE2 and 4-ClE2 did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE2) nor 4-chloro-17α-ethinylestradiol (4-ClEE2) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E2 may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE2 and 4-ClE2 administered subcutaneously and 2-ClEE2 and 4-ClEE2 given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E2. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT.

Risks and Benefits of Hormone Replacement Therapy

Cephalalgia ◽  
2000 ◽  
Vol 20 (3) ◽  
pp. 164-169 ◽  
Author(s):  
B de Lignières ◽  
E A MacGregor
Keyword(s):  
Hormone Replacement Therapy ◽  
Replacement Therapy ◽  
Hormone Replacement ◽  
Mortality And Morbidity ◽  
Oestrogen Deficiency ◽  
Disease Mortality ◽  
Increased Risk ◽  
Deficiency Diseases ◽  
Symptomatic Side ◽  
Natural Progesterone

Menopause, the permanent cessation of menstruation, is due to ovarian failure, which may lead to oestrogen deficiency diseases, particularly osteoporosis, cardiovascular disease and cerebrovascular disease. Mortality and morbidity caused by these conditions can be modified by using hormone replacement therapy, but the benefits of this therapy must be weighed against the increased risk of breast cancer and the symptomatic side-effects the treatment may cause. The combination of transdermal oestrogen and natural progesterone offers the most favourable risk-to-benefit profile.

Membrane potential measurements in renal afferent and efferent arterioles: actions of angiotensin II

1997 ◽  
Vol 273 (2) ◽  
pp. F307-F314 ◽  
Author(s):  
R. Loutzenhiser ◽  
L. Chilton ◽  
G. Trottier
Keyword(s):  
Angiotensin Ii ◽  
Perfusion Pressure ◽  
Rat Kidney ◽  
Renal Perfusion ◽  
Membrane Potentials ◽  
Ang Ii ◽  
Ca Channels ◽  
Renal Perfusion Pressure

An adaptation of the in vitro perfused hydronephrotic rat kidney model allowing in situ measurement of arteriolar membrane potentials is described. At a renal perfusion pressure of 80 mmHg, resting membrane potentials of interlobular arteries (22 +/- 2 microns) and afferent (14 +/- 1 microns) and efferent arterioles (12 +/- 1 microns) were -40 +/- 2 (n = 8), -40 +/- 1 (n = 45), and -38 +/- 2 mV (n = 22), respectively (P = 0.75). Using a dual-pipette system to stabilize the impalement site, we measured afferent and efferent arteriolar membrane potentials during angiotensin II (ANG II)-induced vasoconstriction. ANG II (0.1 nM) reduced afferent arteriolar diameters from 13 +/- 1 to 8 +/- 1 microns (n = 8, P = 0.005) and membrane potentials from -40 +/- 2 to -29 +/- mV (P = 0.012). ANG II elicited a similar vasoconstriction in efferent arterioles, decreasing diameters from 13 +/- 1 to 8 +/- 1 microns (n = 8, P = 0.004), but failed to elicit a significant depolarization (-39 +/- 2 for control; -36 +/- 3 mV for ANG II; P = 0.27). Our findings thus indicate that resting membrane potentials of pre- and postglomerular arterioles are similar and lie near the threshold activation potential for L-type Ca channels. ANG II-induced vasoconstriction appears to be closely coupled to membrane depolarization in the afferent arteriole, whereas mechanical and electrical responses appear to be dissociated in the efferent arteriole.

Interactions between adenosine and angiotensin II in controlling glomerular filtration

1985 ◽  
Vol 248 (3) ◽  
pp. F340-F346 ◽  
Author(s):  
J. E. Hall ◽  
J. P. Granger ◽  
R. L. Hester
Keyword(s):  
Renal Failure ◽  
Angiotensin Ii ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Enzyme Inhibitor ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Renal Vasoconstriction ◽  
Ischemic Renal Failure ◽  
Constrictor Response

This study examined interactions between adenosine (Ado) and angiotensin II (ANG II) in controlling renal blood flow (RBF) and glomerular filtration rate (GFR). In six normal dogs, intrarenal Ado infusion (1.0 mumol/min) transiently decreased RBF, but during sustained Ado infusion RBF increased to 122 +/- 7% of control, although GFR remained at 75 +/- 6% of control. Blockade of ANG II formation with the converting enzyme inhibitor SQ 14225 (n = 6) almost abolished the transient decrease in RBF but did not prevent the sustained fall in GFR caused by Ado. When circulating ANG II was held constant by intravenous infusion of SQ 14225 and 20 ng . kg-1 . min-1 of ANG II (n = 6), Ado transiently decreased RBF but the return of RBF was much slower than in normal dogs and RBF did not increase above control. Maintenance of constant circulating ANG II did not prevent Ado-mediated decreases in GFR. These observations suggest that Ado-mediated reductions in GFR do not depend entirely on ANG II and may be due to dilation of efferent arterioles by Ado. However, the transient renal vasoconstriction caused by Ado depends on ANG II, and data from this study suggest that part of the waning constrictor response to Ado is due to suppression of renin secretion and endogenous ANG II formation. In circumstances where high ANG II levels are maintained (i.e., ischemic renal failure), Ado may be capable of causing sustained renal vasoconstriction.

Liver Abnormalities in Turner’s Syndrome – Effects of Estrogen Replacement Therapy

2021 ◽  
Author(s):  
Fedor István ◽  
Eva Zold ◽  
Zsolt Barta
Keyword(s):  
Replacement Therapy ◽  
Estrogen Replacement Therapy ◽  
Inflammatory Diseases ◽  
Hormone Replacement ◽  
Turner's Syndrome ◽  
Estrogen Replacement ◽  
Turner’S Syndrome ◽  
Estrogen Production ◽  
Organ Systems ◽  
Increased Risk

Abstract BackgroundTurner’s syndrome is one of the most frequently reported sex chromosomal abnormality, affecting approximately 40 in every 100,000 live female births. Due to insufficient estrogen production, induction of puberty and sexual development requires hormone replacement. The syndrome affects several organ systems with diverse clinical features (cardiovascular, reproductive, hepato-biliary). There is also an increased risk of developing immune-mediated inflammatory diseases (IMID). Hepatobiliary alterations embrace a broad spectrum of possible manifestations, from asymptomatic mild hypertransaminasemia to overt hepatitis and even cirrhosis. Although exogenous estrogen hormones might cause liver dysfunction, in Turner’s syndrome hormone replacement can even alleviate the derangement of laboratory values and might prove beneficial in preventing the progression of hepatic architectural alterations.FindingsWe report two patients, in whom cessation of estrogen replacement therapy lead to worsening of hepatic and cholestatic enzyme values. These changes were later alleviated by recommencing estrogen hormone administration. We aim to summarize the available literature on estrogen hormone replacement therapy in Turner’s syndrome. We also provide a brief overview on the role of estrogen hormones in the pathology associated with the syndrome. ConclusionsOur findings are confirming, that estrogen replacement therapy has beneficial effects on hepatic enzymes and liver related laboratory studies in Turner’s syndrome. Therefore it is recommended for physicians not to withdraw estrogen replacement, even with elevated concentrations of liver and cholestatic enzymes in Turner’s syndrome patients.

Abstract P288: Systemic Administration of an Angiotensin Type-2 Receptor Agonist Decreases Renal Regulatory T Cells

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Ellen E Gillis ◽  
Jennifer C Sullivan
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Critical Role ◽  
High Dose ◽  
Ang Ii ◽  
Osmotic Minipump ◽  
Angiotensin Type 2 Receptor ◽  
Angiotensin Type

There is increasing evidence supporting a critical role of the immune system in the development of hypertension. Our lab has previously reported sex differences in the renal T cell profile in both Spontaneously Hypertensive Rats (SHR) and Angiotensin II (Ang II) models of hypertension, with females having more anti-inflammatory regulatory T cells (Tregs) than males. Ang II has a well-defined role in the activation of pro-inflammatory T cells in hypertension via the angiotensin type-1 receptor (AT1R). Less is known about the role of the angiotensin type-2 receptor (AT2R) in the regulation of immune cells, although the AT2R has been shown to be cardioprotective and AT2R expression is greater in females than males. Based on the potential anti-hypertensive role of AT2Rs, we hypothesized that administration of an AT2R agonist, Compound 21 (C21), would increase renal Tregs, and this increase would be greater in females due to greater AT2R expression. Male and female SHR (10 weeks of age, n=3-4) were implanted with telemetry units for continuous monitoring of mean arterial pressure (MAP). Following 10 days of recovery, baseline MAP was recorded for 5 days. Rats were then divided into the following treatment groups: surgical controls, low dose C21 (150 ng/kg/min, sc by osmotic minipump), high dose C21 (300 ng/kg/min, sc by osmotic minipump). Kidneys were harvested after 2 weeks of treatment and flow cytometry was performed on whole kidney homogenates. MAP was not altered by C21 treatment in males (137±4 vs 134±4 vs 134±4 mmHg; n.s.) or females (128±2 vs 136±5 vs 134±4 mmHg; n.s.). Interestingly, despite having no effect on MAP, there was a significant decrease in renal CD3 + CD4 + FoxP3 + Tregs in females following both low and high doses of C21 (data expressed as % CD3 + CD4 + cells: 6±0.6 vs 3±0.6 vs 3.5±1.3 %, respectively; p=0.02). Tregs decrease in males following the high dose of C21 only (data expressed as % CD3 + CD4 + cells: 3.3±0.3 vs 3.3±0.5 vs 1.7±0.7 %, respectively; p=0.05). Total CD3 + T cells, CD3 + CD4 + T cells, and Th17 cells were not altered by C21 treatment. In conclusion, AT2R activation suppresses renal Tregs, and females are more sensitive than males. These data suggest a novel role for AT2R regulation in the kidney in hypertension.

Meta-Analysis

2005 ◽  
Vol 44 (01) ◽  
pp. 127-135 ◽  
Author(s):  
D. Böhning
Keyword(s):  
Breast Cancer ◽  
Hormone Replacement Therapy ◽  
Replacement Therapy ◽  
Mixed Model ◽  
Unobserved Heterogeneity ◽  
Meta Analysis ◽  
Hormone Replacement ◽  
Large Trial ◽  
Increased Risk ◽  
The One

Summary Objectives: This contribution provides a unifying concept for meta-analysis integrating the handling of unobserved heterogeneity, study covariates, publication bias and study quality. It is important to consider these issues simultaneously to avoid the occurrence of artifacts, and a method for doing so is suggested here. Methods: The approach is based upon the meta-likelihood in combination with a general linear nonparametric mixed model, which lays the ground for all inferential conclusions suggested here. Results: The concept is illustrated at hand of a meta-analysis investigating the relationship of hormone replacement therapy and breast cancer. The phenomenon of interest has been investigated in many studies for a considerable time and different results were reported. In 1992 a meta-analysis by Sillero-Arenas et al. [1] concluded a small, but significant overall effect of 1.06 on the relative risk scale. Using the meta-likelihood approach it is demonstrated here that this meta-analysis is due to considerable unobserved heterogeneity. Furthermore, it is shown that new methods are available to model this heterogeneity successfully. It is argued further to include available study covariates to explain this heterogeneity in the meta-analysis at hand. Conclusions: The topic of HRT and breast cancer has again very recently become an issue of public debate, when results of a large trial investigating the health effects of hormone replacement therapy were published indicating an increased risk for breast cancer (risk ratio of 1.26). Using an adequate regression model in the previously published meta-analysis an adjusted estimate of effect of 1.14 can be given which is considerably higher than the one published in the meta-analysis of Sillero-Arenas et al. [1]. In summary, it is hoped that the method suggested here contributes further to a good meta-analytic practice in public health and clinical disciplines.

Hormone replacement therapy in women with breast cancer. Do the risks outweigh the benefits?

1996 ◽  
Vol 14 (3) ◽  
pp. 997-1006 ◽  
Author(s):  
J A Roy ◽  
C A Sawka ◽  
K I Pritchard
Keyword(s):  
Breast Cancer ◽  
Replacement Therapy ◽  
Postmenopausal Women ◽  
Hormone Replacement ◽  
Risks And Benefits ◽  
Previous Diagnosis ◽  
Increased Risk ◽  
History Of ◽  
Expected Benefits ◽  
Meta Analyses

PURPOSE To review critically the literature regarding effects of estrogen replacement therapy (ERT)/combined estrogen and progesterone replacement therapy (HRT) on the risk of breast cancer and on other health risks and benefits in postmenopausal women, with a focus on risks and benefits in women with a previous diagnosis of breast cancer. METHOD A literature search was conducted using Medline, Cancerline, and the bibliographies of reports published as of March 1995. All five published meta-analyses that examined the risk of breast cancer in relation to ERT/HRT in otherwise healthy women were critically reviewed. All known reports of women with a history of breast cancer given ERT/HRT subsequent to diagnosis and additional reports regarding the benefits of ERT/HRT were also reviewed. RESULTS None of the five meta-analyses demonstrated a significantly increased risk of developing breast cancer in ever users compared with never users of ERT/HRT. Current use may be associated with a small increased risk. This increased risk should be balanced by the expected benefits of ERT/HRT on quality of life, bone metabolism, and cardiovascular function. Preliminary information does not suggest a major detrimental effect of ERT/HRT in women with a previous diagnosis of breast cancer, but these reports include few women with limited follow-up data. There are no randomized trials in women with a previous diagnosis of breast cancer. CONCLUSION In healthy postmenopausal women, the benefits associated with ERT/HRT outweigh the risks. In women with a previous diagnosis of breast cancer, the balance of risks and benefits should be explored in randomized controlled trials.

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