piperidines and Hypertrophy

A high-fat diet (HFD) causes obesity-associated morbidities involved in macroautophagy and chaperone-mediated autophagy (CMA). AMPK, the mediator of macroautophage, has been reported to be inactivated in HFD-caused renal injury. However, PAX2, the mediator for CMA, has not been reported in HFD-caused renal injury. Here we report that HFD-caused renal injury involved the inactivation of Pax2 and Ampk, and the activation of soluble epoxide hydrolase (sEH), in a murine model. Specifically, mice fed on an HFD for 2, 4, and 8 wk showed time-dependent renal injury, the significant decrease in renal Pax2 and Ampk at both mRNA and protein levels, and a significant increase in renal sEH at mRNA, protein, and molecular levels. Also, administration of an sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea, significantly attenuated the HFD-caused renal injury, decreased renal sEH consistently at mRNA and protein levels, modified the renal levels of sEH-mediated epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) as expected, and increased renal Pax2 and Ampk at mRNA and/or protein levels. Furthermore, palmitic acid (PA) treatment caused significant increase in

Topics: Adenylate Kinase; Animals; Cytochrome P-450 Enzyme System; Diet, High-Fat; Disease Models, Animal; Eicosanoids; Enzyme Inhibitors; Epoxide Hydrolases; Hypertrophy; Kidney; Mesangial Cells; Mice; Palmitic Acid; PAX2 Transcription Factor; Phenylurea Compounds; Piperidines; Solubility; Time Factors; Weight Gain

The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren), a novel, orally effective direct renin inhibitor (DRI), and compared its efficacy with that of aliskiren, a DRI that is already available in the market. TAK-272 was administered to calsequestrin transgenic (CSQ-tg) heart failure mouse model that show severe symptoms and high mortality. The CSQ-tg mice treated with 300 mg/kg, the highest dose tested, of TAK-272 showed significantly reduced plasma renin activity (PRA), cardiac hypertrophy, and lung congestion. Further, TAK-272 reduced cardiomyocyte injury accompanied by an attenuation of the increase in NADPH oxidase 4 and nitric oxide synthase 3 expressions. TAK-272 also prolonged the survival of CSQ-tg mice in a dose-dependent manner (30 mg/kg: P = 0.42, 100 mg/kg: P = 0.12, 300 mg/kg: P < 0.01). Additionally, when compared at the same dose level (300 mg/kg), TAK-272 showed strong and sustained PRA inhibition and reduced the heart weight and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, a heart failure biomarker, while aliskiren showed a significant weaker PRA inhibition and failed to demonstrate any cardioprotective effects. Our results showed that TAK-272 is an orally active and persistent renin inhibitor, which reduced the mortality of CSQ-tg mice and conferred protection against cardiac hypertrophy and injury. Thus, TAK-272 treatment could provide a new therapeutic approach for heart failure.

Topics: Amides; Animals; Benzimidazoles; Cardiovascular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fumarates; Heart; Heart Failure; Hypertrophy; Lung Diseases; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Morpholines; Piperidines; Protective Agents; Random Allocation; Renin

The signaling cascades of the mitogen activated protein kinase (MAPK) family, calcineurin/NFATc4, and PI3K/Akt/GSK3, are believed to participate in endothelin-1 (ET-1)-induced cardiac hypertrophy. The aim of this study was to investigate whether KMUP-1, a synthetic xanthine-based derivative, prevents cardiomyocyte hypertrophy induced by ET-1 and to elucidate the underlying mechanisms. We found that in H9c2 cardiomyocytes, stimulation with ET-1 (100 nM) for 4 days induced cell hypertrophy and enhanced expressions of hypertrophic markers, including atrial natriuretic peptide and brain natriuretic peptide, which were all inhibited by KMUP-1 in a dose-dependent manner. In addition, KMUP-1 prevented ET-1-induced intracellular reactive oxygen species generation determined by the DCFH-DA assay in cardiomyocytes. KMUP-1 also attenuated phosphorylation of ERK1/2 and Akt/GSK-3β, and activation of calcineurin/NFATc4 and RhoA/ROCK pathways induced by ET-1. Furthermore, we found that the expression of heme oxygenase-1 (HO-1), a stress-response enzyme implicated in cardio-protection, was up-regulated by KMUP-1. Finally, KMUP-1 attenuated ET-1-stimulated activator protein-1 DNA binding activity. In conclusion, KMUP-1 attenuates cardiomyocyte hypertrophy induced by ET-1 through inhibiting ERK1/2, calcineurin/NFATc4 and RhoA/ROCK pathways, with associated cardioprotective effects via HO-1 activation. Therefore, KMUP-1 may have a role in pharmacological therapy of cardiac hypertrophy.

Topics: Animals; Calcineurin; Endothelin-1; Enzyme Activation; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heme Oxygenase-1; Hypertrophy; Mitogen-Activated Protein Kinases; Models, Biological; Myocytes, Cardiac; NFATC Transcription Factors; Piperidines; Protein Binding; Proto-Oncogene Proteins c-akt; Rats; Reactive Oxygen Species; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Transcription Factor AP-1; Xanthines

Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprost; Disease Progression; Female; Glomerular Mesangium; Hypercholesterolemia; Hypertriglyceridemia; Hypertrophy; Hypoglycemic Agents; Hypolipidemic Agents; Insulin Resistance; Kidney; Mice; Mice, Inbred Strains; Mice, Obese; Obesity; Piperidines; PPAR alpha; Propionates

Mesangial cell growth is a key feature of several glomerular diseases. Vascular endothelial growth factor (VEGF) is a potent mitogen of vascular endothelial cells and promoter of vascular permeability. Here, we examined the ability of vasopressin (AVP), which causes mesangial cell proliferation and hypertrophy, to stimulate VEGF secretion from cultured rat mesangial cells. AVP potently induced a time- and concentration-dependent increase in VEGF secretion in these cells, which was then inhibited by a V(1A) receptor-selective antagonist, confirming this is a V(1A) receptor-mediated event. VEGF also induced hyperplasia and hypertrophy in mesangial cells, which was completely abolished by an anti-VEGF antibody. In addition, AVP-induced hyperplasia and hypertrophy were completely inhibited by the V(1A) receptor-selective antagonist and partially abolished by the anti-VEGF antibody. These results indicate that AVP increases VEGF secretion in rat mesangial cells via V(1A) receptors and modulates mesangial cell growth not only by direct action but also through stimulation of VEGF secretion. This autocrine mechanism might contribute to glomerulosclerosis in renal diseases such as diabetic nephropathy.

Topics: Animals; Antibodies; Antidiuretic Hormone Receptor Antagonists; Autocrine Communication; Benzazepines; Cell Proliferation; Cells, Cultured; Collagen Type IV; Hyperplasia; Hypertrophy; Male; Mesangial Cells; Piperidines; Rats; Rats, Wistar; Receptors, Vasopressin; Vascular Endothelial Growth Factor A; Vasopressins

1 The M3 muscarinic receptor subtype is widely accepted as the receptor on smooth muscle cells that mediates cholinergic contraction of the normal urinary bladder and other smooth muscle tissues, however, we have found that the M2 receptor participates in contraction under certain abnormal conditions. The aim of this study was to determine the effects of various experimental pathologies on the muscarinic receptor subtype mediating urinary bladder contraction. 2 Experimental pathologies resulting in bladder hypertrophy (denervation and outlet obstruction) result in an up-regulation of bladder M2 receptors and a change in the receptor subtype mediating contraction from M3 towards M2. Preventing the denervation-induced bladder hypertrophy by urinary diversion prevents this shift in contractile phenotype indicating that hypertrophy is responsible as opposed to denervation per se. 3 The hypertrophy-induced increase in M2 receptor density and contractile response is accompanied by an increase in the tissue concentrations of mRNA coding for the M2 receptor subtype, however, M3 receptor protein density does not correlate with changes in M3 receptor tissue mRNA concentrations across different experimental pathologies. 4 This shift in contractile phenotype from M3 towards M2 subtype is also observed in aged male Sprague-Dawley rats but not females or either sex of the Fisher344 strain of rats. 5 Four repeated, sequential agonist concentration response curves also cause this shift in contractile phenotype in normal rat bladder strips in vitro, as evidenced by a decrease in the affinity of the M3 selective antagonist p-fluoro-hexahydro-sila-diphenidol (p-F-HHSiD). 6 A similar decrease in the contractile affinity of M3 selective antagonists (darifenacin and p-F-HHSiD) is also observed in bladder specimens from patients with neurogenic bladder as well as certain organ transplant donors. 7 It is concluded that although the M3 receptor subtype predominantly mediates contraction under normal circumstances, the M2 receptor subtype can take over a contractile role when the M3 subtype becomes inactivated by, for example, repeated agonist exposures or bladder hypertrophy. This finding has substantial implications for the clinical treatment of abnormal bladder contractions.

Topics: Age Factors; Animals; Benzofurans; Carbachol; Denervation; Disease Models, Animal; Electric Stimulation; Female; Gene Expression Regulation; Humans; Hypertrophy; Male; Muscarinic Agonists; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; Piperidines; Pyrrolidines; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Receptor, Muscarinic M2; Receptor, Muscarinic M3; RNA, Messenger; Urinary Bladder; Urinary Bladder Neck Obstruction; Urinary Bladder, Neurogenic

Our objective was to determine the effects of SCH 57068 alone and with 17 beta-estradiol (E(2)) on bone, lipids and uteri in ovariectomized (OVX) rats. In OVX animals lumbar vertebral and femoral bone mineral density (BMD) were significantly higher after 12 weeks of treatment with SCH 57068 than in untreated OVX controls. Similarly BMD was superior in OVX + E(2) + SCH 57068 treated animals than in OVX + E(2) controls. SCH 57068 also significantly reduced the increase in bone turnover markers, serum pyridinoline and serum osteocalcin levels, induced by OVX, and increased mechanical bone strength. SCH 57068 also significantly reduced the rise in serum cholesterol and low-density lipoprotein cholesterol induced by OVX. SCH 57068 had no stimulatory effect on uterine epithelium when given alone in OVX rats. SCH 57068 (1 and 2.5 mg/kg) reduced uterine weight and blocked endometrial stimulation induced by E(2). In summary, SCH 57068 adds to the positive effects of E(2) on bone and lipid metabolism but blocks the stimulatory effects of E(2) on the uterus. Potentially, E(2) + SCH 57068 could be combined for the treatment and prevention of breast cancer or as a novel hormone replacement therapy.

Topics: Animals; Biomarkers; Biomechanical Phenomena; Bone Density; Cholesterol; Disease Models, Animal; Estrogen Antagonists; Estrogens; Female; Femur; Hypertrophy; Lumbar Vertebrae; Molecular Structure; Organ Size; Osteoporosis; Ovariectomy; Piperidines; Rats; Rats, Sprague-Dawley; Selective Estrogen Receptor Modulators; Uterus; Weight Gain

To investigate the effects of YM471, a non-peptide arginine vasopressin (AVP) V1A and V2 receptor antagonist, on the AVP-induced growth responses in human vascular smooth muscle cells (VSMCs).. Binding of YM471 to V1A receptors on VSMCs was measured using [3H]AVP. Intracellular free Ca2+ concentration was measured by fura 2 fluorescence. Mitogen-activated protein (MAP) kinase activity was determined using the p42/p44 MAP kinase specific peptide and [gamma- 32P]ATP as substrates. The effect of AVP on hyperplasia and hypertrophy of VSMCs was determined by cell number and protein content measurements.. YM471 potently and concentration-dependently inhibited the specific binding of [ 3H]AVP to V1A receptors on VSMCs, exhibiting an inhibition constant (Ki ) of 0.35 nmol/l. YM471 inhibited the AVP-induced increase in intracellular free Ca concentration with an 50% inhibition concentration (IC50 ) of 2.01 nmol/l and inhibited the activation of MAP kinase with an IC50 of 6.11 nmol/l. In addition, AVP concentration-dependently induced hyperplasia and hypertrophy in VSMCs, but YM471 prevented these AVP-induced growth effects, exhibiting IC50 values of 2.31 and 0.23 nmol/l, respectively.. These results indicate that YM471 has high affinity for V receptors on, and potently inhibits AVP-induced physiologic responses of, human VSMCs.

Topics: Antidiuretic Hormone Receptor Antagonists; Aorta; Arginine Vasopressin; Azepines; Cells, Cultured; Enzyme Activation; Humans; Hyperplasia; Hypertrophy; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; Piperidines; Receptors, Vasopressin

In vitro bladder contractions in response to cumulative carbachol doses were measured in the presence of selective muscarinic antagonists from rats which had their major pelvic ganglion bilaterally removed (denervation, DEN) or from rats in which the spinal cord was injured (SCI) via compression. DEN induced both hypertrophy (505+/-51 mg bladder weight) and a supersensitivity of the bladders to carbachol (EC50=0.7+/-0.1 uM). Some of the SCI rats regained the ability to void spontaneously (SPV). The bladders of these animals weighed 184+/-17 mg, significantly less than the bladders of non voiding rats (NV, 644+/-92 mg). The potency of carbachol was greater in bladder strips from NV SCI animals (EC50=0.54+/-0.1 uM) than either bladder strips from SPV SCI (EC50=0.93+/-0.3 microM), DEN or control (EC50=1.2+/-0.1 microM) animals. Antagonist affinities in control bladders for antagonism of carbachol induced contractions were consistent with M3 mediated contractions. Antagonist affinities in DEN bladders for 4-diphenlacetoxy-N-methylpiperidine methiodide (4-DAMP, 8.5) and para fluoro hexahydrosilodifenidol (p-F-HHSiD, 6.6); were consistent with M2 mediated contractions, although the methoctramine affinity (6.5) was consistent with M3 mediated contractions. p-F-HHSiD inhibited carbachol induced contraction with an affinity consistent with M2 receptors in bladders from NV SCI (pKb=6.4) animals and M3 receptors in bladders from SPV SCI animals (pKb=7.9). Subtype selective immunoprecipitation of muscarinic receptors revealed an increase in total and an increase in M2 receptor density with no change in M3 receptor density in bladders from DEN and NV SCI animals compared to normal or sham operated controls. M3 receptor density was lower in bladders from SPV SCI animals while the M2 receptor density was not different from control. This increase in M2 receptor density is consistent with the change in affinity of the antagonists for inhibition of carbachol induced contractions and may indicate that M2 receptors or a combination of M2 and M3 receptors directly mediate smooth muscle contraction in bladders from DEN and NV SCI rats.

Topics: Animals; Binding Sites; Carbachol; Diamines; Dose-Response Relationship, Drug; Female; Hypertrophy; Muscarinic Agonists; Muscarinic Antagonists; Muscle Contraction; Muscle Denervation; Muscle, Smooth; Organ Size; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M2; Receptors, Muscarinic; Spinal Cord Injuries; Urinary Bladder; Urinary Bladder, Neurogenic

The uterotrophic responses of ovariectomized CD1 mice to tamoxifen, toremifene, and raloxifene have been compared to 17beta-estradiol after a treatment period of 72 h. Uterine and vaginal weight, luminal epithelial thickening, and 5-bromodeoxyuridine (BrdU) labeling index in the endometrial stroma were examined. All three pharmaceuticals, as well as 17beta-estradiol, produced increases in the classic estrogen-dependent variables of uterine and vaginal weights after the 3-day treatment period. Tamoxifen, toremifene, raloxifene, and estradiol all increased luminal epithelial thickness, and increased the BrdU labeling index in the endometrial stroma of the uterus. Although the dose response for the uterotrophic effect and the vaginal weight increases for toremifene differed from tamoxifen and raloxifene, in that there was no dose at which these effects were maximal, the stimulation of BrdU labeling index in the endometrial stroma was dose dependent and very similar for all three, at the clinically relevant doses. Treatment-related hypertrophic effects were estimated by examination of the nuclear profile density in the endometrial stroma. Estradiol and tamoxifen caused a greater hypertrophic effect than toremifene and raloxifene, indicating that factors other than an increase in cell number contribute to the overall uterotrophic effect. This demonstrates that the use of uterine weight to estimate the relative estrogenicity of drugs could give a misleading impression of the response of the uterus to estrogen agonists. Variables, such as increased DNA replication, which may be more important to a subsequent potential carcinogenic process in the uterus, for a particular drug, requires separate evaluation.

Topics: Animals; Anticarcinogenic Agents; Bromodeoxyuridine; Cell Division; Cell Nucleus; Dose-Response Relationship, Drug; Endometrium; Epithelium; Estradiol; Estrogens; Female; Hypertrophy; Mice; Organ Size; Ovariectomy; Piperidines; Raloxifene Hydrochloride; Tamoxifen; Toremifene; Uterus; Vagina

We have recently reported that endothelin-1 (ET-1) mediates angiotensin II-induced hypertrophy of cardiomyocytes as an autocrine/paracrine factor. In the present study, we examined whether endothelin-3 (ET-3) induces hypertrophy of cultured neonatal rat cardiomyocytes and whether endogenous ET-1 mediates this effect. ET-3 (10(-7) M) increased the cell surface area of cardiomyocytes after 48 h. ET-3 dose dependently (10(-9)-10(-7) M) stimulated protein synthesis as evaluated by [3H]leucine incorporation; the maximum response was 1.4-fold increase over the control at 10(-7) M. Since the response of cardiac hypertrophy is characterized by enhanced expression of fetal isoforms of muscle specific genes, the effect of ET-3 on steady state levels of mRNA for skeletal alpha-actin was evaluated by Northern blot analysis. ET-3 (10(-9)-10(-7) M) increased mRNA level for skeletal alpha-actin with a maximum response after 6 h. ET-3-induced [3H]leucine incorporation, skeletal alpha-actin mRNA and cell surface area were inhibited by a synthetic ETB receptor antagonist (BQ788). Interestingly, ET-3-induced skeletal alpha-actin gene expression and [3H]leucine incorporation were inhibited by a synthetic ETA receptor antagonist (BQ123) as well as by antisense oligonucleotides against peproET-1 mRNA. ET-3 (10(-7) M) transiently increased mRNA levels for ET-1 peaking at 30 min and stimulated the release of immunoreactive ET-1 from cardiomyocytes. These results suggest that endogenous ET-1 locally generated and secreted by cardiomyocytes may contribute to ET-3-induced cardiac hypertrophy as an autocrine/paracrine factor.

Topics: Actins; Animals; Animals, Newborn; Base Sequence; Binding, Competitive; Cells, Cultured; Endothelin Receptor Antagonists; Endothelins; Gene Expression; Hypertrophy; Molecular Sequence Data; Muscle Proteins; Myocardium; Oligonucleotides, Antisense; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptors, Endothelin; RNA, Messenger

1. The effects on micturition of RP 67,580, a selective NK1 receptor antagonist, and SR 48,968, a highly, potent antagonist at NK2 receptor sites, given intrathecally (i.t.) or intra-arterially (i.a.) near the bladder, were investigated in unanaesthetized rats with and without bladder outlet obstruction. 2. In normal rats, RP 67,580, given i.t. in doses of 2 and 20 nmol per rat, decreased micturition pressure, but did not change other cystometric parameters. After 20 nmol of RP 67,580, dribbling incontinence due to retention was observed in 1 out of 7 animals. This effect was reversible. I.t. RP 67,580 in a dose of 2 nmol, had no effect on hyperactivity induced by intravesically instilled capsaicin. 3. In animals with bladder hypertrophy secondary to outflow obstruction, RP 67,580, given i.t. in a dose of 2 nmol per rat, decreased the micturition pressure, but had no effect on other cystometric parameters. After 20 nmol, dribbling incontinence due to retention was observed in 5 out of 7 animals. 4. RP 67,580, given i.a. in a dose of 4 nmol, had little effect on the cystometric parameters investigated, both in normal animals and rats with bladder hypertrophy. 5. SR 48,968, given i.t. in doses of 2 and 20 nmol per rat, had no clear-cut effects on the micturition pattern in normal rats, or rats with bladder hypertrophy. However, the drug reduced capsaicin-induced bladder hyperactivity. When given i.a. in a dose of 4 nmol, SR 48,968 had no effect on cystometric parameters in normal rats or rats with bladder hypertrophy. 6. The effects of both RP 67,580 and SR 48,968 were stereoselective, their enantiomers (RP 68,651 and SR 48,965) being inactive.7. These results thus suggest that at the spinal level there is a tachykinin involvement (via NK,receptors) in the micturition reflex induced by bladder filling, both in normal rats, and, more clearly, in animals with bladder hypertrophy secondary to outflow obstruction. The bladder response to filling was not influenced by blockade of vesical NKI and NK2 receptors. On the other hand, the bladder hyperactivity evoked by intravesical capsaicin seems to involve NK2 receptors both at the bladder and spinal levels.

Topics: Analgesics; Animals; Benzamides; Cystoscopy; Female; Hypertrophy; Indoles; Injections, Intra-Arterial; Injections, Spinal; Isoindoles; Neurokinin-1 Receptor Antagonists; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-2; Tachykinins; Urinary Bladder; Urinary Bladder Neck Obstruction; Urinary Catheterization; Urination

There is a medical need for an agent with the positive effects of estrogen on bone and the cardiovascular system, but without the negative effects on reproductive tissue. Raloxifene (LY139481 HCI) is a benzothiophene derivative that binds to the estrogen receptor and inhibits the effects of estrogen on the uterus. In an ovariectomized (OVX) rat model we investigated the effects of raloxifene on bone loss (induced by estrogen deficiency), serum lipids, and uterine tissue. After oral administration of raloxifene for 5 wk (0.1-10 mg/kg per d) to OVX rats, bone mineral density in the distal femur and proximal tibia was significantly greater than that observed in OVX controls (ED50 of 0.03-0.3 mg/kg). Serum cholesterol was lower in the raloxifene-treated animals, which had a minimal effective dose of 0.1 mg/kg and an approximate oral ED50 of 0.2 mg/kg. The effects of raloxifene on bone and serum cholesterol were comparable to those of a 0.1-mg/kg per d oral dose of ethynyl estradiol. Raloxifene diverged dramatically from estrogen in its lack of significant estrogenic effects on uterine tissue. Ethynyl estradiol produced a marked elevation in a number of uterine histologic parameters (e.g., epithelial cell height, stromal eosinophilia). These data suggest that raloxifene has promise as an agent with beneficial bone and cardiovascular effects in the absence of significant uterine effects.

Topics: Administration, Oral; Alkaline Phosphatase; Animals; Body Weight; Bone Density; Bone Resorption; Calcium; Cholesterol; Dose-Response Relationship, Drug; Epithelial Cells; Epithelium; Estrogen Antagonists; Ethinyl Estradiol; Female; Hypertrophy; Ovariectomy; Phosphorus; Piperidines; Raloxifene Hydrochloride; Rats; Rats, Sprague-Dawley; Triglycerides; Uterus

A new benzothiophene derived antiestrogen, LY139481, inhibited the uterotropic action of estradiol in a dose related fashion, and at 1 mg per day suppressed more than 90 percent of estradiol's activity in immature rats. LY139481 induced minimal uterotropic activity, and that activity declined in relation to dose. The relative binding affinity of LY139481 for rat uterine cytosol estrogen receptors was greater than that of estradiol in competitive assays and increased in relation to temperature (2.9 +/- 0.5 x estradiol at 30 degrees C). LY139481 caused estradiol-induced uterine hypertrophy to regress in a manner similar to that which resulted from withdrawal of estradiol treatment. Three successive daily injections of LY139481 slightly increased uterine weight, and blocked additional uterotropic action in response to estradiol and LY139481 administration on subsequent days. Furthermore, ten daily injections of estradiol alone did not increase uterine weight in animals pretreated with LY139481 for three days. In contrast, LY139481 did not prevent the partial uterotropic action of tamoxifen administration.

Topics: Animals; Estradiol; Estrogen Antagonists; Female; Hypertrophy; Piperidines; Raloxifene Hydrochloride; Rats; Receptors, Estrogen; Tamoxifen; Uterus