Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ESTRADIOL”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,099 records · Page 61Linked to original sources
PubMed2000

Acute effects of 17beta-estradiol on ventricular and vascular hemodynamics in postmenopausal women.

Because premenopausal women have lower cardiovascular morbidity than postmenopausal women, it has been proposed that estrogen may have a protective role. Estrogen is involved in smooth muscle relaxation both through its specific receptor as well as through calcium channel blockade. This study examined the acute effect of estradiol on invasive cardiovascular hemodynamics in 18 postmenopausal women (age 62.6 +/- 7.6 years, means +/- SD). The effect of estradiol on left ventricular chamber performance was studied in 9 women using simultaneous left ventricular pressure-volume recordings. In a further group of 9 women, the acute effect of estradiol on arterial function was assessed using input impedance (derived from simultaneous aortic pressure and flow recordings), pressure waveform analysis, and pulse wave velocity. After 2 mg micronized 17beta-estradiol was administered, serum estradiol levels increased from 50.9 +/- 21.9 to 3,190 +/- 2,216 pmol/l, P < 0.0001. There was no effect of estradiol on either left ventricular inotropic or lusitropic function. There was no acute effect of estradiol on arterial impedance, reflection coefficient, augmentation index, or pulse wave velocity. There was a trend to decreased heart rate and cardiac output in both groups of 9 women. Because heart rate and cardiac output were common to both hemodynamic data sets, results for these parameters were pooled. Across all 18 women, there was a small but significant decrease in heart rate (69.2 +/- 10.4 vs. 67.2 +/- 9.9 beats/min, P = 0.02), as well as a significant decrease in cardiac output (4.82 +/- 1.77 vs. 4.17 +/- 1.56 l/min, P = 0.002). Despite achieving supraphysiological serum levels, this study found no significant effect of acute 17beta-estradiol on ventricular or large artery function.

Aorta↗
PubMed1993

Tamoxifen antagonizes the effects of estradiol on energy balance and estrous behavior in Syrian hamsters.

Ovariectomized Syrian hamsters were treated with estradiol benzoate (5 micrograms/day for 4 wk), tamoxifen (500 micrograms/day), an antiestrogen that competes with estradiol for central and peripheral estrogen receptors, or both estradiol benzoate and tamoxifen. As expected, estradiol treatment caused significant decreases in body weight and fat content without affecting food intake. Given alone, tamoxifen had no effect on body weight or composition, but when given concurrently, tamoxifen significantly attenuated the effects of estradiol. These results stand in contrast to findings in rats where nonsteroidal antiestrogens, including tamoxifen, mimic the effects of estradiol on body weight and energy metabolism and are completely devoid of any antiestrogenic actions. As in rats, tamoxifen was a potent inhibitor of estrous behavior, whether induced with estradiol alone or with sequential treatment with estradiol and progesterone. Again, as in rats, tamoxifen acted as an antagonist and a weak estrogen agonist on uterine weight. These findings support the notion that the relative agonistic and antagonistic actions of tamoxifen, and other antiestrogens, vary with species and with the estrogen-sensitive endpoint being investigated.

Animals↗
PubMed1994

Effects of estradiol on lipoprotein lipase activity and lipid availability in exercised male rats.

The effects of 17 beta-estradiol 3-benzoate (10 micrograms.0.1 ml sunflower oil-1 x 100 g body wt-1) and exercise on tissue lipid content and lipoprotein lipase (LPL) activity were determined in male rats. Estradiol administration significantly (P < 0.05) increased fatty acid contents of resting adipose, plasma, and white and red vastus muscle tissues and red vastus muscle triacylglycerol. Adipose and plasma fatty acids and red and white vastus muscle triacylglycerol were significantly higher in exercised estradiol-administered animals than in exercised oil-administered animals. Estradiol administration significantly reduced resting adipocyte LPL activity by 71% and increased myocardial LPL activity by 96%. After exercise, red vastus LPL activity was significantly increased by 76% in estradiol-administered animals compared with oil-administered animals. Ratios of red vastus to adipose LPL activity and myocardial to adipose LPL activity at rest and after exercise were significantly greater in estradiol-administered than in oil-administered animals. Estradiol administration significantly increased the ratio of white vastus to adipose LPL activity of exercised animals. These data indicate that estradiol increases the availability of lipid substrate to exercising muscle from multiple sources, including adipose, plasma, and intracellular muscle triacylglycerol. The absolute increases in muscle LPL activity, combined with a greater ratio of muscle to adipose LPL activity, lead to increased distribution of plasma triacylglycerol-derived fatty acids toward muscle.

Adipose Tissue↗
PubMed2000

Estradiol modulates long-term synaptic depression in female rat hippocampus.

Fluctuating estradiol levels in the adult, female rat modify the anatomical and functional organization of the hippocampal CA1 region. When systemic levels of estradiol are low, e.g., on estrus or in ovariectomized (OVX) rats, long-term synaptic potentiation is difficult to induce in vivo. However, little is known about the role of this ovarian hormone in long-term synaptic depression. Using multiple conditioning paradigms, we assess the magnitude of long-term depression (LTD) at CA3-CA1 synapses in vitro from adult, ovariectomized rats as a function of systemic estradiol replacement. In hippocampal slices from control OVX rats with low levels of estradiol, a low-frequency (2 Hz), asynchronous conditioning stimulation protocol does not produce LTD at 1 h postconditioning. However, this same protocol induces robust LTD in slices from estradiol-treated OVX rats. When the conditioning frequency is increased to 4 Hz, slices from both groups of rats show robust LTD in vitro. At an even higher conditioning frequency (10 Hz), the 2-Hz-based observations are reversed; no consistent changes in synaptic transmission are observed in slices from estradiol-treated OVX rats, but those from control rats (OVX + oil) show robust LTD. Thus estradiol reduces the frequency threshold for LTD induction at the CA3-CA1 synapses. Further, regardless of the conditioning frequency employed, where robust LTD is seen, its induction depends on normally functioning N-methyl-D-aspartate (NMDA) receptors during conditioning. The shift in conditioning frequency needed to elicit LTD is consistent with a decrease in NMDA receptor activation with decreasing estradiol levels.

Animals↗
PubMed2006

Effects of raloxifene on circulating prolactin and estradiol levels in premenopausal women at high risk for developing breast cancer.

BACKGROUND: Prolactin is a peptide hormone necessary for normal breast development that may contribute to breast tumorigenesis. Estrogen is a significant positive regulator of prolactin synthesis; therefore, raloxifene, a selective estrogen receptor modulator under study as a breast cancer prevention agent, may modulate both estradiol and prolactin levels by inhibiting estradiol from binding to its receptor. METHODS: Premenopausal women at increased risk for invasive breast cancer participated in a pilot chemoprevention trial and were given 60 mg raloxifene daily for 24 months. Fasting serum samples collected at baseline and after 12 months on drug were used to measure circulating prolactin, estradiol, and sex hormone binding globulin (SHBG) levels. RESULTS: Of the 27 subjects who completed 12 months of raloxifene, 23 had paired prolactin samples, and 20 had paired estradiol and SHBG samples. Prolactin levels did not significantly change with raloxifene treatment, but SHBG levels increased (mean change = 7.3 nmol/L; P = 0.0001; 95% confidence interval, 3.9-10.7). Estradiol (mean change = 42 pg/mL; P = 0.048; 95% confidence interval, 1-84 pg/mL) levels were elevated when comparing 15 of the 20 women with paired estradiol measurements who also had both of these samples taken during the early follicular phase of the menstrual cycle. CONCLUSIONS: This report is the first to examine the long-term effects of raloxifene on prolactin, estradiol, and SHBG levels in premenopausal women who are also at increased risk for developing invasive breast cancer. Raloxifene had no significant effect on prolactin levels but did increase estradiol and SHBG measurements.

Adult↗
PubMed1999

Psychological and endocrine responses to psychosocial stress and dexamethasone/corticotropin-releasing hormone in healthy postmenopausal women and young controls: the impact of age and a two-week estradiol treatment.

In this placebo-controlled double-blind study, psychological and endocrine stress responses were investigated in healthy postmenopausal placebo-treated women (n = 15; 60-75 years; placebo via transdermal patches), healthy postmenopausal estradiol-treated women (n = 13; 60-79 years; 0.1 mg 17beta-estradiol daily via transdermal patches) and young controls (n = 15; 20-31 years; untreated). The aged subjects received estradiol or placebo treatment for 14 days. All subjects were then exposed to the 'Trier Social Stress Test' (TSST) and the dexamethasone (Dex)-human corticotropin-releasing hormone (hCRH) test (100 microgram hCRH after premedication with 1.5 mg Dex). Psychological parameters including perceived stressfulness, mood and subjective well-being were measured by visual analog scales, a mood questionnaire and a mood diary, respectively. Results show that the TSST induced significant increases in adrenocorticotropin (ACTH), free salivary cortisol, total plasma cortisol and heart rates (all p < 0.0001). Regardless of age, comparable hormonal response patterns were observed in the TSST as indicated by similar peak levels and recovery phases. Visual analog scales confirmed that the same amount of stress was experienced by young and elderly subjects. In both age groups, hCRH injection after Dex premedication provoked significant increases in ACTH, free salivary cortisol and total plasma cortisol (all p < 0.0001). In contrast to the psychosocial stressor, elderly women were found to respond with a markedly enhanced cortisol response compared to young controls in the Dex-CRH test (p < 0.025). Additional investigation of morning cortisol profiles could not reveal any age-related differences in basal hypothalamus-pituitary-adrenal (HPA) axis activity. Following estradiol treatment, estradiol levels significantly increased only in substituted postmenopausal women (p < 0.001) reaching concentrations typically found in younger women during the follicular phase of the menstrual cycle. Corticosteroid-binding globulin levels did not differ significantly between groups. When confronted with the TSST, no response differences emerged between the three groups. However, estradiol treatment appeared to blunt the total plasma cortisol response in the Dex-CRH test, resulting in smaller increases in untreated premenopausal women and estradiol-treated postmenopausal women compared to placebo-treated postmenopausal women (p < 0.02). In sum, no response differences were observed after confrontation with a psychosocial stress test in our sample of healthy elderly subjects. As shown with the Dex-CRH test, our data suggest that the negative feedback of the HPA axis in elderly women is altered. Moreover, the current data suggest that estradiol replacement may modulate HPA feedback sensitivity in humans.

Adrenocorticotropic Hormone↗
PubMed2000

Progesterone prevents estradiol-induced dendritic spine formation in cultured hippocampal neurons.

Estradiol has been shown to cause an increase in dendritic spine density in cultured hippocampal neurons, an effect mediated by downregulation of brain-derived neurotrophic factor (BDNF) and glutamic acid decarboxylase (GAD), and the subsequent phosphorylation of cAMP response element binding protein (CREB) in response to enhanced activity levels. Interestingly, progesterone was shown to counteract the effects of estradiol on dendritic spine density in vivo and in vitro. The present study examined how progesterone may act to block the effects of estradiol in the molecular cascade of cellular events leading to formation of dendritic spines. Progesterone did not affect the estradiol-induced downregulation of BDNF or GAD, but it did block the effect of estradiol on CREB phosphorylation. The latter effects of progesterone on the pCREB response and spine formation were reversed by indomethacin, which prevents the conversion of progesterone to the neurosteroid tetrahydroprogesterone (THP). We therefore examined if the progesterone effects were caused by its active metabolite THP. Progesterone treatment caused a 60-fold increase in THP in the culture medium. THP itself enhanced spontaneous GABAergic activity in patch-clamped cultured neurons. Finally, THP blocked the estradiol-induced increase in spine density. These results suggest that progesterone, through conversion to THP, blocks the effects of estradiol on dendritic spines not via a direct nuclear receptor interaction but by counteracting the enhanced excitability produced by estradiol in the cultured network.

Animals↗
PubMed2002

Effect of 17beta-estradiol on intracellular Ca(2+) levels in renal tubular cells.

The effect of 17beta-estradiol on intracellular Ca(2+) concentrations ([Ca(2+)](i)) in Madin Darby canine kidney cells was investigated by using the fluorescent dye fura-2. 17Beta-estradiol (5-100 micromol/l) induced instantaneous increases in [Ca(2+)](i) in a concentration-dependent manner. Ca(2+) removal inhibited 45 +/- 15% of the Ca(2+) signal. In Ca(2+)-free medium, pretreatment with 50 micromol/l 17beta-estradiol abolished the [Ca(2+)](i) increases induced by 2 micromol/l carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler), 1 micromol/l thapsigargin (an endoplasmic reticulum Ca(2+) pump inhibitor) and 50 micromol/l brefeldin A (an antibiotic which disperses the Golgi complex), but pretreatment with brefeldin A, CCCP and thapsigargin only partly inhibited the 17beta-estradiol-induced [Ca(2+)](i) signal. Adding 3 mmol/l Ca(2+) increased [Ca(2+)](i) in cells pretreated with 5-100 micromol/l 17beta-estradiol in Ca(2+)-free medium. Pretreatment with 1 micromol/l U73122 to abolish the formation of inositol-1,4,5-trisphosphate inhibited 50% of the Ca(2+) release induced by 50 micromol/l 17beta-estradiol. 17Beta-estradiol (20 micromol/l) also increased [Ca(2+)](i) in human bladder cancer cells and prostate cancer cells. Collectively, this study shows that 17beta-estradiol evoked a significant internal Ca(2+) release and external Ca(2+) entry possibly in a nongenomic manner.

Animals↗
PubMed2005

Effect of nitric oxide synthase inhibition on changes induced by estradiol in bladders from ovariectomized rabbits.

PURPOSE: Our current study was designed to determine whether estradiol-induced increases in bladder blood flow could be inhibited by N(omega)-nitro-L-arginine methyl ester (L-NAME), and thus whether nitric oxide was involved in estrogen-linked female bladder blood flow alterations. MATERIALS AND METHODS: Sixteen female New Zealand White rabbits were separated into 4 groups of 4 rabbits each. (1) Sham group received sham operation and injections of vehicle (peanut oil). (2) Ovariectomy (OVX) group received ovariectomies and injections of vehicle. (3) Ovariectomy+estrogen (OVX+E) group received ovariectomy and injections of 17beta-estradiol (1 mg/kg) dissolved in peanut oil. (4) Ovariectomy+estradiol+L-NAME (OVX+E+L-NAME) group received ovariectomies and injections of 17beta-estradiol and L-NAME. All treatments were continued for 4 weeks. At 4 weeks after treatment, each rabbit was anesthetized and cystometries were performed. After cystometry, blood flow to the detrusor muscle and mucosa was determined by standard fluorescent microsphere infusion technique. Then four longitudinal detrusor strips and two rings of descending thoracic aorta were mounted in individual 15 ml baths containing oxygenated Tyrode's solution at 37 degrees C. Contractile responses to several agents were determined. Full-thickness sections of detrusor were fixed and embedded in paraffin for alpha-actin immunostaining. RESULTS: In the bladder: (1) Estradiol resulted in an increases in bladder weight and blood flow; L-NAME inhibited these increases. (2) OVX resulted in a decreased cystometric capacity; estradiol resulted in increased capacity which was attenuated by L-NAME treatment. (3) OVX resulted in significantly decreased contractile responses to all forms of stimulation; estradiol resulted in significantly increased contractile responses which were attenuated by L-NAME treatment. (4) OVX resulted in a significant decrease in the volume-fraction of smooth muscle in the detrusor; estradiol resulted in a significant increase which was attenuated by L-NAME. CONCLUSIONS: These findings strongly support the hypothesis that nitric oxide plays a major role in the alterations in blood flow mediated by changing circulating estrogen and that these changes mediate at least in part the cystometric and contractile changes induced by alterations in circulating estrogen.

Analysis of Variance↗
PubMed1986

[3H]estradiol and its metabolites in the brain, pituitary gland, and reproductive tract of the male rhesus monkey. A combined autoradiographic and chromatographic study.

Previous studies have shown that [3H]estradiol is the major nuclear metabolite of [3H]testosterone in the hypothalamus, preoptic area and amygdala of the male rhesus monkey, and it has been proposed that some of the stimulatory effects of testosterone on male sexual behavior may be mediated by estradiol-concentrating neurons. To map these neurons and identify metabolites, 4 castrated male rhesus monkeys were each injected with 0.47 mCi/kg [3H]estradiol, and the brains were removed 60 min later. Left halves were frozen for thaw-mount autoradiography, and right halves were used to isolate cell nuclei from different brain regions. A fifth animal was used to validate the methodology. Radioactive steroids were identified and measured by high performance liquid chromatography. Brain areas previously shown to contain labeled neurons after [3H]testosterone administration were also labeled after [3H]estradiol, including medial preoptic nucleus (n.), anterior hypothalamic area, bed n. of stria terminalis, ventromedial n., premammillary n., and corticomedial amygdala. Some areas not labeled after [3H]testosterone were labeled after [3H]estradiol, including lateral septal n., arcuate n., paraventricular n., claustrum, entorhinal cortex, and spinal cord. The pars distalis of the pituitary gland was heavily labeled. Most (83%) of the radioactivity in cell nuclei was [3H]estradiol while [3H]estrone was a major metabolite (25%) in supernatants. In the brain, the highest nuclear concentration of [3H]estradiol was in the hypothalamus (249.2 +/- 20.0 fmol/mg DNA), although in the previous experiments with [3H]testosterone, the highest nuclear concentrations of [3H]estradiol were found in the amygdala. We interpret these results to indicate that local metabolic differences in the brain may underlie some of the different behavioral effects of gonadal steroids in primates.

Animals↗
PubMed1996

Estradiol alters ethanol-induced effects on beta-endorphin and met-enkephalin levels in specific brain regions of ovariectomized rats.

The present investigation was conducted to evaluate the effects of estradiol on ethanol-induced alterations of beta-endorphin (beta-EN) and met-enkephalin (ME) levels in specific brain regions of ovariectomized rats. Female Sprague-Dawley rats (100-124 g) adapted to a 12-hour light, 12-hour dark illumination cycle were used in these studies. Animals were ovariectomized under pentobarbital anesthesia. After a recovery period of 14 days, ethanol (3 g/kg as 22.5% solution in saline, i.p.), estradiol (50 micrograms/kg in 0.2 ml of olive oil, s.c. in the dorsal neck region), or a combination of ethanol and estradiol were administered to rats at 11:00 h. Control animals were injected intraperitoneally with 2 ml saline and subcutaneously with 0.2 ml olive oil. Animals were sacrificed by decapitation 2 h later. The brains were immediately removed; the cortex, hippocampus, hypothalamus, and midbrain were dissected and their beta-EN and ME levels were measured by radioimmunoassay. Ethanol administration significantly decreased both beta-EN and ME levels in the hypothalamus. Administration of estradiol alone also resulted in a significant decrease in beta-EN and ME levels in the hypothalamus. Additionally, concurrent administration of ethanol and estradiol showed a decrease in the levels of beta-EN and ME in the hypothalamus. Co-administration of ethanol with estradiol also caused a significant decrease in the levels of beta-EN in midbrain. However, ME levels were increased in the midbrain after concurrent administration of estradiol and ethanol. ME levels also increased in the hippocampus and cortex after co-administration of estrogen and ethanol. These results clearly indicate that estradiol significantly alters ethanol-induced effects on beta-EN and ME levels in specific brain regions of ovariectomized rats. The present findings may in part explain sex differences in alcohol effects.

Animals↗
PubMed1981

Cytoplasmic and nuclear binding of estradiol in the brain and pituitary of old female rats.

The subcellular distribution of estradiol following the in vivo administration of 3H-estradiol, cytosol and nuclear estrogen receptor after in vitro incubation with 3H-estradiol were studied in young adult female rats (3-6 months old) and old female rats (over 18 months old). After intravenous injection of 3H-estradiol, with or without deithylstilbestrol pretreatment, significantly higher cytosol uptake of estradiol in the pituitary, dorsal hypothalamus and corticomedial amygdala (AMYG) with concomitant significantly lower nuclear uptake in the preoptic area (POA) and basomedial hypothalamus (BMH) and a tendency of lower nuclear uptake in AMYG and pituitary of old noncyclic (NC) rats as compared with young adult female rats were observed. The uterus of NC rats had a low ratio of milligrams of protein per milligram wet weight as compared with young rats and the nuclear binding 1 h after the injection was significantly lower than that of young rats when the value was expressed as disintegrations per minute per milligram weight but not when expressed as disintegrations per minute per milligram protein. Assays of cytosol and nuclear estrogen receptor after in vitro incubation with 3H-estradiol revealed that old prolonged vaginal cornification (PVC) rats did not react estradiol priming with increased nuclear receptors in the pooled brain tissues of AMYG, POA and BMH, anterior pituitary and uterus. These results indicate that there seems to be an impaired translocation of estradiol from cytosol to nucleus in old PVC rats.

Aging↗
PubMed1996

Inhibition of transplant coronary arteriosclerosis in rabbits by chronic estradiol treatment is associated with abolition of MHC class II antigen expression.

BACKGROUND: Accelerated coronary arteriosclerosis is a major complication in long-term survivors of cardiac transplantation. Estrogen prevents transplant arteriosclerosis in experimental cardiac and aortic allografts and may act by an immune mechanism. METHODS AND RESULTS: New Zealand White rabbits immunosuppressed with cyclosporine were recipients of cardiac allografts from Dutch Belted rabbits. The recipients received either estradiol or placebo daily until they were killed 6 weeks later. Histological cross sections of the cardiac allograft were used for quantification of major histocompatibility complex (MHC) class II antigen expression, T lymphocytes, and macrophages by immunohistochemistry using monoclonal antibodies. MHC class II antigen expression was not detectable in allograft coronary arteries from any of the estradiol-treated recipients, whereas this antigen expression was present in the allograft coronary arteries from all the placebo-treated recipients. Macrophage and lymphocyte infiltration of the allograft coronary artery myointima was significantly less frequent in the estradiol-treated group. Rejection was moderate but slightly less in the estradiol-treated group. These findings were associated with a 60% decrease in allograft coronary artery myointimal thickening (determined by morphometry) in the estradiol-treated compared with the placebo-treated group. CONCLUSIONS: Estradiol treatment of cardiac allograft recipients abolishes MHC class II antigen expression in the coronary arteries and decreases macrophage infiltration in all three layers of the vessel wall, whereas T-lymphocyte infiltration is decreased only in the myointima. These findings are associated with estradiol inhibition of myointimal proliferation. Thus, estradiol treatment may have a beneficial effect on graft arteriosclerosis through immune mechanisms.

Animals↗
PubMed1997

Long-term estradiol replacement decreases contractility of guinea pig coronary arteries to the thromboxane mimetic U46619.

BACKGROUND: Estradiol replacement therapy reduces the incidence of coronary artery disease. Current evidence suggests that estradiol may stimulate the production of endothelium-derived NO and thereby reduce the contractile response of vascular smooth muscle. We investigated the effect of long-term replacement of estradiol on NO release and its effect on coronary artery contractility. METHODS AND RESULTS: Female guinea pigs were ovariectomized and allowed to recover for 100 days. Pellets containing 17 beta-estradiol (0.25, 0.5, 1.5, and 7.5 mg released over 21 days) were placed subcutaneously for 19 to 20 days. Animals were then anesthetized, and the coronary arteries were excised and cut into ring segments. Rings were placed in small-vessel myographs for measurement of isometric force. Contractile responses of coronary arteries to cumulative addition of U46619 (10(-10) to 10(-5) mol/L), a thromboxane mimetic, were measured in the presence and absence of nitro-L-arginine (LNA), a selective NO synthase inhibitor, and methylene blue, a guanylate cyclase inhibitor. Low (0.25-mg) but not high (0.5-, 1.5-, or 7.5-mg) doses of estradiol inhibited the maximal contractile responses to U46619 compared with arteries from untreated castrated animals. In addition, both LNA and methylene blue potentiated contractile responses to U46619 of arteries from animals receiving 0.25 and 0.5 mg but not 1.5 and 7.5 mg estradiol. Negative log EC50 values were significantly inhibited at 0.25 and 7.5 mg but unaffected at 0.5 and 1.5 mg estradiol compared with castrated animals. CONCLUSIONS: Estradiol at low doses may protect against vasospasm by stimulating endothelium-derived NO release and inhibiting coronary artery contractility.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1997

Physiological concentrations of estradiol attenuate endothelin 1-induced coronary vasoconstriction in vivo.

BACKGROUND: Estrogens are cardioprotective hormones and are reported to have antianginal properties. We examined the effect of physiological concentrations of 17beta-estradiol on coronary reactivity in anesthetized female farm pigs. METHODS AND RESULTS: Epicardial coronary cross-sectional area (CSA) was assessed by two-dimensional intravascular ultrasound, average coronary peak flow velocity (APV) by intravascular Doppler velocimetry, and coronary blood flow (CBF) was calculated. Dose-response curves to intracoronary endothelin-1 (ET-1, 1 pmol/L to 10 nmol/L), the selective ET(B) receptor agonist sarafotoxin (1 pmol/L to 10 nmol/L), and serotonin (0.1 nmol/L to 1 micromol/L) were assessed before and after a 10-minute infusion of intracoronary estradiol (1 nmol/L). Before estradiol administration, ET-1 induced significant dose-dependent decreases in CSA, APV, and CBF. Estradiol attenuated ET-1-induced epicardial vasoconstriction (P<.001) as well as ET-1-induced decreases in APV (P=.05) and CBF (P=.012). In an additional five pigs, vehicle (DMSO) had no effect on ET-1-induced coronary vasoconstriction. Before estradiol administration, sarafotoxin induced no net change in CSA but induced increases in APV and CBF, the extent of which did not change significantly after estradiol. Serotonin induced small decreases in CSA but increased APV and CBF. Estradiol did not influence serotonin-induced changes in CSA, APV, or CBF. CONCLUSIONS: We conclude that estradiol attenuates ET-1-induced vasoconstriction, possibly through effects on the ET(A) receptor, because selective ET(B) receptor-induced stimulation with sarafotoxin remained unchanged. Such an effect on the ET(A) receptor may relate to the antianginal properties of estrogens.

Animals↗
PubMed1997

Amelioration of ischemia- and reperfusion-induced myocardial injury by 17beta-estradiol: role of nitric oxide and calcium-activated potassium channels.

BACKGROUND: 17Beta-estradiol increases the production of nitric oxide (NO) and prostacyclin and opens Ca2+-activated K+ (K(Ca)) channels. Whether these effects of 17beta-estradiol reduce infarct size and the incidence of ventricular arrhythmia was investigated in dogs subjected to myocardial ischemia and reperfusion. METHODS AND RESULTS: Infarct size was measured in open-chest dogs after 90 minutes' occlusion of the left anterior descending coronary artery and a subsequent 6 hours of reperfusion. Infusion of 17beta-estradiol into the coronary artery was initiated 10 minutes before coronary occlusion and continued until after 1 hour of reperfusion, with the exception of the occlusion period. The difference in NO concentration between coronary venous and arterial blood 10 minutes after the onset of reperfusion was significantly greater in dogs treated with 17beta-estradiol (10 ng x kg(-1) x min(-1)) than in control animals. Infarct size (13.1+/-3.0% versus 43.7+/-5.4% of the area at risk) and the incidence of ventricular arrhythmia during ischemia and reperfusion periods were significantly reduced in the 17beta-estradiol group. Both N(G)-nitro-L-arginine methyl ester (an inhibitor of NO synthase) and iberiotoxin (a blocker of K(Ca) channels) reduced both the infarct size-limiting effect (infarct size, 29.3+/-3.0% and 31.7+/-2.1%, respectively) and the antiarrhythmic effect of 17beta-estradiol; indomethacin (an inhibitor of cyclooxygenase) did not attenuate the beneficial effects of 17beta-estradiol. CONCLUSIONS: 17Beta-estradiol reduced both myocardial infarct size and the occurrence of ischemia- and reperfusion-induced ventricular arrhythmias, which appear to be mediated by NO and the opening of K(Ca) channels in canine hearts.

Animals↗
PubMed2002

CYP450- and COMT-derived estradiol metabolites inhibit activity of human coronary artery SMCs.

The purpose of this study is to test the hypothesis that the inhibitory effects of estradiol in human coronary vascular smooth muscle cells are mediated via local conversion to methoxyestradiols via specific cytochrome P450s (CYP450s) and catechol-O-methyltransferase (COMT). The inhibitory effects of estradiol on serum-induced cell activity (DNA synthesis, cell number, collagen synthesis, and cell migration) were enhanced by 3-methylcholantherene, phenobarbital (broad-spectrum CYP450 inducers), and beta-naphthoflavone (CYP1A1/1A2 inducer) and were blocked by 1-aminobenzotriazole (broad-spectrum CYP450 inhibitor). Ellipticine, alpha-naphthoflavone (selective CYP1A1 inhibitors), and pyrene (selective CYP1B1 inhibitor), but not ketoconazole (selective CYP3A4 inhibitor) or furafylline (selective CYP1A2 inhibitor), abrogated the inhibitor effects of estradiol on cell activity, a profile consistent with a CYP1A1/CYP1B1-mediated mechanism. The inhibitory effects of estradiol were blocked by the COMT inhibitors OR486 and quercetin. The estrogen receptor antagonist ICI 182,780 blocked the inhibitory effects of estradiol, but only at concentrations that also blocked the metabolism of estradiol to hydroxyestradiols (precursors of methoxyestradiols). Western blot analysis revealed that coronary smooth muscle cells expressed CYP1A1 and CYP1B1. Moreover, these cells metabolized estradiol to hydroxyestradiols and methoxyestradiols, and the conversion of 2-hydroxyestradiol to 2-methoxyestradiol was blocked by OR486 and quercetin. These findings provide evidence that the inhibitory effects of estradiol on coronary smooth muscle cells are largely mediated via CYP1A1- and CYP1B1-derived hydroxyestradiols that are converted to methoxyestradiols by COMT.

2-Methoxyestradiol↗
PubMed2001

Estrogen receptor-mediated, nitric oxide-dependent modulation of the immunologic barrier function of the endothelium: regulation of fas ligand expression by estradiol.

BACKGROUND: Premenopausal women have a lower incidence of coronary artery disease than postmenopausal women or same-age men. Although the mechanisms of this apparent relative protection against atherosclerosis remain ill defined, estradiol, which is present in higher concentrations before menopause, is considered to play a central role. Recently, Fas ligand (FasL) expression by the vascular endothelium has been shown to inhibit the migration of inflammatory cells into the vessel wall, an event that is considered crucial for the development of atherosclerosis. METHODS AND RESULTS: The regulation of endothelial FasL expression by estradiol was investigated in vivo and in vitro. In an ovariectomized, cholesterol-clamped rabbit model, FasL expression was shown to be downregulated by elevations in serum cholesterol, which also resulted in invasion of the arterial wall by macrophages. Estradiol replacement resulted in restoration of FasL expression, with resultant inhibition of leukocyte traffic across the endothelium. Inhibition of NO production by addition of L-NAME to the drinking water of the estradiol-treated rabbits abrogated these effects. In vitro, estradiol is shown to regulate FasL expression at the transcriptional level via an estrogen receptor-mediated, NO-dependent mechanism. CONCLUSIONS: Estradiol transcriptionally regulates endothelial FasL expression by a mechanism involving at least one of the estrogen receptors. In an animal model of atherosclerosis, estradiol restores FasL expression, which is suppressed by atherogenic levels of serum cholesterol. The maintenance of endothelial FasL expression by estradiol may represent a mechanism of estrogen's apparent antiatherogenic effect.

Animals↗