Am J Physiol Heart Circ Physiol. 2002 Sep;283(3):H1169-80.
Estrogen increases iNOS expression in the ovine coronary artery.
Mershon JL, Baker RS, Clark KE.
Department of Obstetrics and Gynecology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0526, USA.
Estrogen is believed to protect postmenopausal women from coronary vascular disease, in part by increasing production of nitric oxide (NO). In this study, we investigated the possibility that transcriptional activation of inducible NO synthase (iNOS) is responsible for a component of the estrogen-induced increase in coronary blood flow. Twenty-two ewes were instrumented with Doppler flow probes on their left circumflex coronary and pulmonary arteries. Nine ewes received 17beta-estradiol (1 microg/kg), and the coronary vascular response was followed for 16 h. Estradiol significantly increased coronary blood flow by 22 +/- 4% over baseline and the peak response occurred at 2 h (P < 0.01). To examine the effect of estrogen on NOS expression in the ovine coronary artery, 17 noninstrumented animals were killed 2 h after administration of estradiol or vehicle. Coronary arteries were analyzed for ovine iNOS and endothelial NOS (eNOS) expression by semiquantitative RT-PCR. PCR primers were based on partial cDNA clones for ovine eNOS and iNOS isolated as part of this study. The expression of iNOS was significantly increased (27-fold) by the administration of estradiol, whereas the expression of eNOS was much weaker (2-fold). To confirm these effects in vivo, additional instrumented animals received either the estrogen receptor (ER) antagonist ICI-182,780 (n = 5), the iNOS antagonist dexamethasone (n = 5), or pyrrolidine dithiocarbamic acid, an inhibitor of nuclear factor-kappaB (n = 5). All three antagonists inhibited estrogen-induced increases in coronary blood flow and increases in cardiac output by over 85%. These results strongly support the hypothesis that 17beta-estradiol increases coronary blood flow in the unanesthetized nonpregnant e
The effects of beta-estradiol on SHSY5Y neuroblastoma cells during heavy metal induced oxidative stress, neurotoxicity and beta-amyloid secretion.
Olivieri G, Novakovic M, Savaskan E, Meier F, Baysang G, Brockhaus M, Muller-Spahn F.
Neurobiology Laboratory, Psychiatric University Hospital, CH-4025 Basel, Switzerland. gianfranco.olivierharma.novartis.com
The role of estrogen as a neurotrophic/neuroprotective agent in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases is increasingly being shown. In this study we examine the neuroprotective effects of beta-estradiol on SHSY5Y neuroblastoma cells which have been exposed to the heavy metals cobalt and mercury. The results show that cobalt and mercury are able to induce oxidative stress and cell cytotoxicity and increase the secretion of beta-amyloid 1-40 and 1-42. These deleterious effects are reversed by the pretreatment of cells with beta-estradiol. It is further shown that beta-estradiol exerts its neuroprotective action through mechanisms which reduce oxidative stress and reduce beta-amyloid secretion. Pre-treatment of the cells with alpha-estradiol did not alleviate the toxic effects of the heavy metals. Our results are significant as they contribute to a better understanding of the mode of action of estrogen with relevance to its use in the treatment of neurodegenerative disorders. Copyright 2002 IBRO
J Endocrinol. 2003 Mar;176(3):359-66.
Effects of the Japanese herbal medicine Keishi-bukuryo-gan and 17beta-estradiol on calcitonin gene-related peptide-induced elevation of skin temperature in ovariectomized rats.
Noguchi M, Ikarashi Y, Yuzurihara M, Kase Y, Chen JT, Takeda S, Aburada M, Ishige A.
Tsumura Research Institute Medical Evaluation Laboratory, 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan. noguchi_masamichail.tsumura.co.jp
The effects of a Japanese herbal medicine, Keishi-bukuryo-gan, and 17beta-estradiol on calcitonin gene-related peptide (CGRP)-induced elevation of skin temperature were investigated in ovariectomized (OVX) rats. Ovariectomy not only potentiated CGRP-induced elevation of skin temperature and arterial vasorelaxation but also induced a lower concentration of endogenous CGRP in plasma and up-regulation of arterial CGRP receptors, suggesting that lowered CGRP in plasma due to ovarian hormone deficiency increases the number of CGRP receptors and consequently amplifies the stimulatory effects of CGRP to elevate skin temperature. Oral Keishi-bukuryo-gan (100-1000 mg/kg, once a day for 7 days) restored a series of CGRP-related responses observed in OVX rats by normalizing plasma CGRP levels in a dose-dependent manner as effectively as s.c. injection. 17Beta-estradiol (0.010 mg/kg, once a day for 7 days). However, Keishi-bukuryo-gan did not affect the lower concentration of plasma estradiol and the decreased uterine weight due to ovariectomy, although the hormone replacement of 17beta-estradiol restored them. These results suggest that Keishi-bukuryo-gan, which does not confer estrogen activity on plasma, may be useful for the treatment of hot flashes in patients for whom estrogen replacement therapy is contraindicated, as well as menopausal women.
J Pediatr Gastroenterol Nutr. 2002 Aug;35(2):185-91.
Effect of Ursodeoxycholic Acid on the Expression of the Hepatocellular Bile Acid Transporters (Ntcp and bsep) in Rats With Estrogen-Induced Cholestasis.
Micheline D, Emmanuel J, Serge E.
Unite de Recherche des Mecanismes et Traitement des Meladies du Goie (Inserm U 481), Hopital Beaujon, Clichy, France. dumonichat.inserm.fr
OBJECTIVES: Rats with ethinyl estradiol-induced cholestasis have a decreased bile flow and a decreased expression of basolateral and canalicular hepatocyte membrane transporters. The bile acid ursodeoxycholic acid improves bile flow in these animals. The purpose of this study was to examine the effect of ursodeoxycholic acid on the expression of hepatocellular bile acid carriers. METHODS: Rats received either ethinyl estradiol (5 mg.kg body wt. for 10 days) or ethinyl estradiol associated with ursodeoxycholic acid (1% in the diet). A third group of rats received ursodeoxycholic acid alone. Bile flow, bile acid, and glutathione biliary outputs were measured. Messenger RNA levels and protein expression of Na -dependent taurocholate co-transporting polypeptide, and bile salt export pump were determined in basolateral and canalicular membrane preparations by Northern and Western blot analysis. RESULTS: Ursodeoxycholic acid restored bile flow in ethinyl estradiol-treated rats by increasing bile acid secretion. It did not improve glutathione output nor bile acid-independent flow. Na -dependent taurocholate co-transporting polypeptide mRNA and protein were decreased by ethinyl estradiol and not restored by ursodeoxycholic acid. In contrast, canalicular bile salt export pump protein expression was decreased by ethinyl estradiol and fully restored to control levels by ursodeoxycholic acid. CONCLUSIONS: Ursodeoxycholic acid increases bile flow in ethinyl estradiol-treated rats by increasing bile acid secretion. This increase is possibly mediated by a normalization of the expression of the canalicular bile salt export pump.
Exp Dermatol. 2002 Aug;11(4):376-80.
17alpha-estradiol induces aromatase activity in intact human anagen hair follicles ex vivo.
Hoffmann R, Niiyama S, Huth A, Kissling S, Happle R.
Department of Dermatology, Philipp University, Deutschhausstrasse 9, D-35033 Marburg, Germany.
For topical treatment of androgenetic alopecia (AGA) in women, solutions containing either estradiol benzoate, estradiol valerate, 17beta- or 17alpha-estradiol are commercially available in Europe and some studies show an increased anagen and decreased telogen rate after treatment as compared with placebo. At present it is not precisely known how estrogens mediate their beneficial effect on AGA-affected hair follicles. We have shown recently that 17alpha-estradiol is able to diminish the amount of dihydrotestosterone (DHT) formed by human hair follicles after incubation with testosterone, while increasing the concentration of weaker steroids such as estrogens. Because aromatase is involved in the conversion of testosterone to estrogens and because there is some clinical evidence that aromatase activity may be involved in the pathogenesis of AGA, we addressed the question whether aromatase is expressed in human hair follicles and whether 17alpha-estradiol is able to modify the aromatase activity. Herewith we were able to demonstrate that intact, microdissected hair follicles from female donors express considerably more aromatase activity than hair follicles from male donors. Using immunohistochemistry, we detected the aromatase mainly in the epithelial parts of the hair follicle and not in the dermal papilla. Furthermore, we show that in comparison to the controls, we noticed in 17alpha-estradiol-incubated (1 nM) female hair follicles a concentration- and time-dependent increase of aromatase activity (at 24 h: 1 nM = +18%, 100 nM = +25%, 1 micro M = +57%; 24 h: 1 nM = +18%, 48 h: 1 nM = +25%). In conclusion, our ex vivo experiments suggest that under the influence of 17alpha-estradiol an increased conversion of testo
Brain Res Mol Brain Res. 2002 Jun 15;102(1-2):48-54.
Estradiol enhances Akt activation in cortical explant cultures following neuronal injury.
Wilson ME, Liu Y, Wise PM.
Department of Physiology, College of Medicine, University of Kentucky, MS 508, 800 Rose Street, Lexington, KY 40536, USA. mewilsky.edu
We have previously demonstrated that estradiol reduces cell death in cortical explant cultures following injury induced by metabolic inhibition in a receptor-dependent fashion. In this study, we examined whether cell death involves apoptosis and assessed the potential mediators of estradiol's actions. Cortical explant cultures were generated from postnatal day 3 rat pups. On day 7 in vitro, explants were injured by exposure to 1 mM 2-DG/2 mM KCN for 2 h to model the metabolic inhibition observed during ischemia. Explants were fixed in 4% paraformaldehyde at 2, 6, 10 and 24 h following the injury period and 18-microm thick sections were cut on a cryostat and stained with cresyl violet to assess cell death. The same sections were also labeled by TUNEL to determine whether cell death occurred by apoptosis. Other sections were used for immunohistochemistry to determine whether cells that stained positive for activated caspase 3 were also immunopositive for NeuN, a neuronal marker, or GFAP, an astrocyte marker. Protein was extracted for Western blot analysis from a separate set of explants collected at 0, 0.5, 1, 2 and 4 h following the conclusion of the injury. Estradiol treatment significantly reduced the number of cells undergoing apoptotic cell death as indicated by nuclear condensation visualized by cresyl violet staining (P<0.05). TUNEL staining revealed that the majority of pyknotic and fragmented nuclei were also TUNEL positive. Furthermore, caspase 3 activation appeared to be restricted to neurons. To examine a possible mechanism by which estradiol prevents apoptosis, we examined the level of activation of Akt kinase, which mediates antiapoptotic signals. Potential activation was measured by ph
J Clin Endocrinol Metab. 2003 Apr;88(4):1766-71.
Control of follicle-stimulating hormone by estradiol and the inhibins: critical role of estradiol at the hypothalamus during the luteal-follicular transition.
Welt CK, Pagan YL, Smith PC, Rado KB, Hall JE.
Reproductive Endocrine Unit and National Center for Infertility Research, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. cwelartners.org
To test the hypothesis that estradiol, inhibin A, and inhibin B contribute differentially to FSH negative feedback in specific phases of the menstrual cycle, daily blood samples were obtained across a control cycle and after selective estrogen blockade with tamoxifen. To examine the site of estradiol-negative feedback in control and tamoxifen treatment cycles, early follicular phase GnRH (free alpha-subunit) pulse frequency was assessed in normal women, and FSH levels were examined in GnRH-deficient women in whom hypothalamic output was fixed with GnRH administration. FSH was higher in the early follicular phase in the presence of estrogen receptor blockade (15.7 +/- 3.1 vs. 13.2 +/- 1.9 IU/liter; P < 0.05) but was not increased in the late follicular phase. In the luteal phase, FSH was elevated (10.1 +/- 0.7 vs. 7.3 +/- 0.6 IU/liter; P < 0.01). In normal women, free alpha-subunit pulse frequency increased (7.3 +/- 0.4 vs. 4.8 +/- 0.4 pulses per 8 h; P < 0.003), but in GnRH-deficient women, there was no FSH increase (11.1 +/- 1.6 vs. 12.5 +/- 3.6 IU/liter) in the early follicular phase in the presence of estrogen blockade. In conclusion, estradiol exerts a greater role over inhibin in FSH-negative feedback regulation during the luteal phase and the luteal-follicular transition. In contrast, inhibin A and/or B plays a more critical role as the follicular phase progresses. In addition, these studies support a primary if not exclusive hypothalamic site of estrogen-negative feedback in the early follicular phase.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12679471&dopt=Abstract estradiol [PubMed - indexed for MEDLINE]
Clin Sci (Lond). 2002 Aug;103 Suppl 48:434S-437S.
Oestrogen protects against ischaemic acute renal failure in rats by suppressing renal endothelin-1 overproduction.
Takaoka M, Yuba M, Fujii T, Ohkita M, Matsumura Y.
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. takaokups.ac.jp
We investigated whether the treatment with 17 beta-oestradiol has renal protective effects in male rats with ischaemic acute renal failure (ARF). We also examined if the effect of 17 beta-oestradiol is accompanied by suppression of enhanced endothelin-1 production in postischaemic kidneys. Ischaemic ARF was induced by clamping the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function parameters such as blood urea nitrogen, plasma creatinine and creatinine clearance were measured to test the effectiveness of the steroid hormone. Renal function in ARF rats markedly decreased 24 h after reperfusion. The ischaemia/reperfusion-induced renal dysfunction was dose-dependently improved by pretreatment with 17 beta-oestradiol (20 or 100 microg/kg, intravenously). Histopathological examination of the kidney of untreated ARF rats revealed severe lesions, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were markedly improved by the higher dose of 17 beta-oestradiol. In addition, endothelin-1 content in the kidney after the ischaemia/reperfusion increased significantly by approx. 2-fold over sham-operated rats, and this elevation was dose-dependently suppressed by the 17 beta-oestradiol treatment. These results suggest that oestrogen exhibits protective effects against renal dysfunction and tissue injury induced by ischaemia/reperfusion, possibly through the suppression of endothelin-1 overproduction in postischaemic kidneys.
Clin Sci (Lond). 2002 Aug;103 Suppl 48:438S-441S.
Acute effects of 17 beta-oestradiol on functional activity of endothelin-converting enzymes in human arteries and veins.
Heigl A, Lachat M, Lattmann T, Luscher T, Barton M.
Medical Policlinic and Clinical Atherosclerosis Research Laboratory, Medical Policlinic, Department of Internal Medicine, University Hospital, Ramistrasse 100, CH-8091 Zurich, Switzerland.
In this study, we investigated the short-term effect of 17 beta-oestradiol on functional enzyme activity (FEA) of endothelin-converting enzymes in vitro using human internal mammary arteries (n=7-8) and human saphenous veins (n=16-17) obtained from patients undergoing coronary artery bypass graft surgery. Vascular rings were preincubated with either solvent control (0.2% ethanol) or 17 beta-oestradiol (1 microM) for 30 min and concentration-response curves to big ET-1 (0.1-100 nM) or ET-1 (0.1-100 nM) were performed. FEA for each concentration was calculated as the percentage activity [(contraction to big ET-1/contraction to ET-1)x100] normalized to KCl (100 mM). In control experiments, at low concentrations FEA was lower in internal mammary arteries than in saphenous veins (P<0.05). While FEA was suppressed in saphenous veins by 10 nM (4+/-1 versus 22+/-5%, P<0.01) and 30 nM (26+/-4 versus 48+/-7%, P<0.05) 17 beta-oestradiol, FEA was markedly enhanced in internal mammary arteries by 10 nM (33+/-12 versus 1+/-1%, P<0.001) and 30 nM (44+/-12 versus 8+/-3%, P<0.01) 17 beta-oestradiol. FEA was not affected by 100 nM 17 beta-oestradiol. These results demonstrate for the first time that short-term exposure to 17 beta-oestradiol affects FEA in vitro. Human internal mammary arteries have lower FEA than the saphenous veins, but FEA is differentially affected by acute exposure to 17 beta-oestradiol in human arteries and veins. Whether changes in FEA play a role in the vascular effects of 17 beta-oestradiol in vivo remains to be determined.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12193140&dopt=Abstract estradiol [PubMed - indexed for MEDLINE
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