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Effects of raloxifene and estradiol on hippocampal acetylcholine release and spatial learning in the rat.

Gibbs RB, Gabor R, Cox T, Johnson DA.

Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, 1004 Salk Hall, Pittsburgh, PA 15261, USA. gibbsr pitt.edu

The effects of raloxifene on acquisition of a delayed matching to position (DMP) T-maze task and on hippocampal acetylcholine release were evaluated and compared with estradiol, to determine whether raloxifene has estrogenic effects on cognitive performance and hippocampal cholinergic activity. Ovariectomized rats received continuous treatment with raloxifene (one of two doses), estradiol, or vehicle for 30 days, followed by behavioral training, and then in vivo microdialysis assessment of basal and potassium-stimulated acetylcholine release. The data show that estradiol significantly enhanced DMP acquisition, whereas raloxifene did not. In contrast, both estradiol and the higher dose of raloxifene significantly increased potassium-stimulated acetylcholine release in the hippocampus. These data suggest that, despite increasing evidence for estrogenic effects of raloxifene in brain, raloxifene does not mimic the effects of estrogen on cognitive performance as assessed by acquisition of a simple spatial memory task in ovariectomized rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15110923&dopt=Abstract raloxifene Evista



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The effects of estrogen and raloxifene treatment on the antioxidant enzymes and nitrite-nitrate levels in brain cortex of ovariectomized rats.

Oge A, Sezer ED, Ozgonul M, Bayraktar F, Sozmen EY.

Department of Endocrinology, Adnan Menderes University Faculty of Medicine, Biyokimya Anabilim Dali, Bornova-Izmir, Turkey.

Number of studies indicate that the female gonadal hormone estrogen protects women against several neurodegenerative diseases and cerebral ischemia via various mechanisms. The possible protective effects of estrogen are mediated mainly by three ways; the activation of steroid receptors and/or modulation of a neurotransmitter and/or direct antioxidative action. Therefore we aimed to investigate the effects of estradiol and raloxifene on levels of nitric oxide (NO) and antioxidant enzymes in brain cortex of ovariectomized female rats. Ten Sprague-Dawley rats were used as naive controls while 32 rats were ovariectomized at 120-140 days of age. Twelve weeks after ovariectomy: (1). Ovariectomized Placebo group (n=11), was given physiologic saline. (2). Estrogen group (n=10) was given Ethynyl estradiol, 0.1 mg/kg sc. (3). Raloxifene group (n=10) was given raloxifene, 1 mg/kg sc. At the end of the treatment period (8 weeks), rats were decapitated and cortex samples were dissected. Results showed that ovariectomy caused a decrease in total nitrite-nitrate levels. The NO levels of both the estrogen and the raloxifene group were higher than the placebo group. Catalase activities did not show any significant difference between the groups, while superoxide dismutase (SOD) activities were elevated via ovariectomy. Estradiol and Raloxifene treatment had no statistically significant effect on SOD activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12581835&dopt=Abstract raloxifene Evista



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Cardiovascular effects of raloxifene: the arterial and venous systems.

Blumenthal RS, Baranowski B, Dowsett SA.

The John Hopkins Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Baltimore, Md 21287, USA. rblument jhmi.edu

BACKGROUND: Cardiovascular disease caused by atherosclerosis is the largest single killer of women. Prior observational data had suggested that hormone therapy may have cardioprotective effects. METHODS: Data from clinical trials and basic science studies were evaluated to assess the cardiovascular effects of hormone therapy and selective estrogen replacement modulators. RESULTS: Hormone therapy does not appear to lower the risk of cardiovascular events in older postmenopausal women. Selective estrogen receptor modulators (SERMS) have been approved for human use; tamoxifen is used for treatment and prevention of breast cancer and raloxifene is used for the treatment and prevention of osteoporosis. Raloxifene is the only SERM being specifically studied for its effects on coronary heart disease events in a prospective, randomized, controlled trial. CONCLUSIONS: Although raloxifene does increase venous thromboembolic events, there is suggestive data that it may have favorable effects on the arterial systems in women. Only compelling positive data from the Raloxifene Use for The Heart (RUTH) trial will lead to greater use of SERMS to potentially lower the risk of atherosclerotic vascular disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15131531&dopt=Abstract raloxifene Evista



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Differential effects of estradiol, raloxifene and tamoxifen on estrogen receptor expression in cultured human skin fibroblasts.

Haczynski J, Tarkowski R, Jarzabek K, Wolczynski S, Magoffin DA, Czarnocki KJ, Ziegert M, Jakowicki J, Jakimiuk AJ.

Second Department of Gynaecology, University School of Medicine in Lublin, Lublin, Poland.

The balance between ER-alpha and ER-beta in fibroblasts may be crucial in the physiological response to ligands. Up- or down-regulation of the ERs in response to different compounds could mediate the reversal of certain age-related changes in skin and connective tissue. The time-dependent effects of 17-beta estradiol, raloxifene and tamoxifen on ER-alpha and ER-beta mRNA expression in the skin fibroblast cultures were performed. Experiments were carried out in primary cultures of human skin fibroblasts obtained from postmenopausal women. The cells were cultured in medium containing: 2 micromol/l estradiol (E2), 4 micromol/l tamoxifen (Tx) or 4 micromol/l raloxifene (Rx) for 7, 24 and 32 h. ER-alpha and ER-beta mRNAs were measured by quantitative assays based on reverse transcription (RT) of the mRNA and polymerase chain reaction (PCR) amplification of the cDNA. We suggest that ER-alpha and ER-beta are co-expressed in human postmenopausal skin fibroblast and documented that the level of mRNA expression of ERs in this tissue is estradiol, raloxifene or tamoxifen regulated as a mechanism to control the action of those ligands on the cell. On the basis of ER mRNA expression levels, fibroblast response to estradiol appears to be modulated by up-regulation of ER-beta rather than ER-alpha. Two of the examined SERMs appear to have different response to modulation of ERs: response of raloxifen is modulated by up-regulation of ER-beta, and no changes in expression of ER-alpha and tamoxifen response seem to be modulated by ER down-regulation in short-term or up-regulation during longer treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15138633&dopt=Abstract raloxifene Evista



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Raloxifene relaxes rat cerebral arteries in vitro and inhibits L-type voltage-sensitive Ca2+ channels.

Tsang SY, Yao X, Essin K, Wong CM, Chan FL, Gollasch M, Huang Y.

Department of Physiology, Faculty of Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.

BACKGROUND AND PURPOSE: Because of their mixed estrogen-agonist and estrogen-antagonist properties, selective estrogen receptor modulators (SERMs) are considered promising substitutes for hormone replacement therapy. Raloxifene and other SERMs confer estrogen-like cardiovascular protective effects but lack the carcinogenic activity of exogenous estrogen. However, little is known about the cerebrovascular action of raloxifene. Therefore, we studied the effects of raloxifene on the mechanisms regulating rat cerebral artery tone. METHODS: Ring segments of the isolated rat posterior communicating cerebral arteries were mounted in a microvessel myograph for measurement of isometric tension. Whole-cell L-type voltage-sensitive Ca2+ currents were recorded using the perforated patch-clamp technique. Raloxifene (0.1 to 10 micromol/L) reduced the contractile responses to U46619, phenylephrine, and endothelin-1 in normal Krebs solution or to CaCl2 in Ca2+-free, high K+-containing solution. Raloxifene-induced relaxation was identical in endothelium-intact and endothelium-denuded rings. ICI 182780 had no effect on raloxifene-induced relaxation. Raloxifene reduced L-type Ca2+ currents with a pD2 of 5.98+/-0.06, close to that (6.44+/-0.09) for raloxifene-induced relaxation of 60 mmol/L K+-contracted rings. CONCLUSIONS: This study demonstrates that raloxifene acutely relaxes rat cerebral arteries largely via an endothelium-independent mechanism, involving inhibition of Ca2+ influx through L-type Ca2+ channels.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15155963&dopt=Abstract raloxifene Evista



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Raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism in the ischemic heart: role of phosphatidylinositol 3-kinase/Akt pathway.

Ogita H, Node K, Asanuma H, Sanada S, Kim J, Takashima S, Minamino T, Hori M, Kitakaze M.

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan.

The purpose of this study is to examine whether raloxifene, one of the selective estrogen receptor modulators, could improve myocardial ischemia and to assess the mechanisms involved. In open-chest beagle dogs anesthetized by intravenous infusion of sodium pentobarbital, the left anterior descending coronary artery (LAD) was perfused from the left carotid artery through an extracorporeal bypass tube. Raloxifene was infused into the LAD through the bypass tube under either ischemic or non-ischemic conditions. In the non-ischemic heart, raloxifene had no effect on coronary blood flow, fractional shortening, and myocardial metabolism. However, raloxifene caused an acute increase in both coronary blood flow and fractional shortening, and also improved myocardial anaerobic metabolism in the ischemic heart. These effects were partially attenuated by pretreatment with either L-NAME or wortmannin and were completely abolished by ICI182780 (an estrogen receptor antagonist) or L-NAME plus charybdotoxin (a blocker of Ca-activated K channels). Raloxifene also increased both Akt activity and the NO level, with these changes being completely abrogated by pretreatment with wortmannin. These results demonstrated that raloxifene improves coronary perfusion, cardiac contractility, and myocardial metabolism by release of NO and opening of Ca-activated K channels in the ischemic heart, and that NO production is mediated by the phosphatidylinositol 3-kinase/Akt pathway.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15167276&dopt=Abstract raloxifene Evista