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Genetic variation in CYP4A11 and blood pressure response to mineralocorticoid receptor antagonism or ENaC inhibition: an exploratory pilot study in African Americans.
Laffer CL, Elijovich F, Eckert GJ, Tu W, Pratt JH, Brown NJ
(2014) J Am Soc Hypertens 8: 475-80
MeSH Terms: Adolescent, Adult, African Americans, Aged, Blood Pressure, Cytochrome P-450 CYP4A, Cytochrome P-450 Enzyme System, DNA, Double-Blind Method, Female, Genetic Variation, Genotype, Humans, Hypertension, Male, Middle Aged, Mineralocorticoid Receptor Antagonists, Pilot Projects, Radioimmunoassay, United States, Young Adult
Show Abstract · Added February 19, 2015
An rs3890011 variant of CYP4A11, which is in linkage disequilibrium with the loss-of-function variant rs1126742, is associated with hypertension in humans. In mice, Cyp4a deficiency results in salt-sensitive hypertension through activation of ENaC. We tested the hypothesis that the rs3890011 variant is associated with blood pressure response to drugs acting via the ENaC pathway. African Americans with volume-dependent, resistant hypertension were randomized to treatment with placebo, spironolactone, amiloride, or combination. Blood pressure responses were analyzed by CYP4A11 genotypes. Rs3890011 (GG:GC:CC = 20:35:28) and rs1126742 (TT:TC:CC = 45:31:7) were in linkage disequilibrium (D' = 1, r = 0.561). Expected small number of rs1126742 CC homozygotes precluded analysis of the effect of this genotype on treatment responses. Spironolactone reduced blood pressure in rs3890011 GG and GC individuals, but not in CC homozygotes (P = .002), whereas amiloride reduced blood pressure similarly in all rs3890011 genotypes. The antihypertensive effects of spironolactone and amiloride were comparable in GG and GC participants, but only amiloride reduced pressure in CC homozygotes (-6.3 ± 7.3/-3.2 ± 4.0 vs. +6.8 ± 7.9/+4.8 ± 8.6 mm Hg, P < .01/<.05). The aldosterone response to spironolactone was also blunted in the CC genotype. In individuals homozygous for the CYP4A11 rs3890011 C allele, blood pressure is resistant to mineralocorticoid receptor antagonism, but sensitive to ENaC inhibition, consistent with ENaC activation. Studies in a larger population are needed to replicate these findings.
Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.
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21 MeSH Terms
Disassociation of muscle insulin signaling and insulin-stimulated glucose uptake during endotoxemia.
Mulligan KX, Morris RT, Otero YF, Wasserman DH, McGuinness OP
(2012) PLoS One 7: e30160
MeSH Terms: Animals, Biological Transport, Blood Pressure, Blotting, Western, Echocardiography, Endotoxemia, Glucose, Insulin, Interleukin-10, Interleukin-1beta, Interleukin-6, Lipopolysaccharides, Male, Mice, Mice, Inbred C57BL, Radioimmunoassay, Rats, Real-Time Polymerase Chain Reaction, Tumor Necrosis Factor-alpha
Show Abstract · Added December 10, 2013
Lipopolysaccharide (LPS) elicits a strong immune response, which leads to the release of inflammatory cytokines. Increased cytokine production has been shown to impair insulin-mediated glucose disposal. LPS can alter other factors, such as muscle blood flow and insulin signaling in the myocyte, that can influence glucose disposal. We hypothesize that LPS induced impairments in cardiovascular function contribute to the associated impairments in insulin action in vivo. Male wild-type C57BL/6J mice had a catheter implanted in the jugular vein for infusions and the carotid artery for sampling 5 days prior to the hyperinsulinemic-euglycemic clamp. Mice were treated with vehicle, low- (1 ug/gBW) or high-dose (10 ug/gBW) LPS 4 hours prior to the clamp. Muscle glucose uptake (MGU) was assessed using [2-(14)C] deoxyglucose. While both low- and high-dose LPS inhibited insulin-stimulated MGU compared to vehicle-treated mice, the impairment was more significant with the high-dose treatment (∼25% in soleus and ∼70% in both gastrocnemius and vastus lateralis). Interestingly, insulin signaling through the PI3-kinase pathway in the muscle was not affected by this treatment suggesting that the decrease in MGU is not directly due to impairments in muscle insulin action. Echocardiography demonstrated that high-dose LPS treatment significantly decreased stroke volume (∼30%), heart rate (∼35%), and cardiac output (∼50%). These observations were not seen with vehicle or low-dose LPS treatment. High-dose LPS treatment also significantly decreased muscle blood flow (∼70%) and whole body oxygen consumption (∼50%). Thus, in vivo acute endotoxemia does not impair insulin signaling through the PI3-kinase pathway in skeletal muscle and decreased tissue blood flow likely plays a central role in the impairment of glucose uptake in the muscle.
2 Communities
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19 MeSH Terms
Genetic, pharmacological and lesion analyses reveal a selective role for corticohippocampal GLUN2B in a novel repeated swim stress paradigm.
Kiselycznyk C, Svenningsson P, Delpire E, Holmes A
(2011) Neuroscience 193: 259-68
MeSH Terms: Analysis of Variance, Animals, Cerebral Cortex, Corticosterone, Dark Adaptation, Disease Models, Animal, Excitatory Amino Acid Antagonists, Exploratory Behavior, Feeding Behavior, Fever, Food Preferences, Hindlimb Suspension, Hippocampus, Immobility Response, Tonic, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neural Pathways, Phenols, Piperidines, Radioimmunoassay, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Stress, Psychological, Sucrose, Swimming, Time Factors
Show Abstract · Added November 25, 2014
Glutamate and N-methyl-d-aspartate receptor (NMDAR) dysfunction is strongly implicated in the pathophysiology of mood and anxiety disorders. Treatment with NMDAR antagonists has antidepressant efficacy in treatment-resistant depressives. In preclinical rodent models, NMDAR antagonist administration reduces anxiety- and stress-related behaviors in concert with increases in prefrontal cortical (PFC) dendritic spinogenesis and synaptic proteins. While these effects have been attributed to actions at the NMDAR GluN2B subunit, the precise role of cortical GluN2B in mediating emotional behaviors and stress-responsivity is not fully understood. Here, we employed a novel mutant model in which the GluN2B subunit is postnatally deleted in principal neurons in the cortex and the dorsal CA1 subregion of the hippocampus. GluN2BKO mice were phenotyped on a battery of tests for anxiety-related (light/dark exploration, stress-induced hyperthermia) and antidepressant-sensitive (sucrose preference, novelty-induced hypophagia, single-trial forced swim) behaviors. A novel repeated inescapable forced swim paradigm (riFS) was developed to assess behavioral responses to repeated stress in the GluN2BKO mice. For comparison, non-mutant C57BL/6J mice were tested for single-trial forced swim behavior after systemic Ro 25-6981 treatment and for riFS behavior after lesions of the ventromedial prefrontal cortex. riFS-induced alterations in corticolimbic GluN2B expression were also examined in C57BL/6J mice. We found that GluN2BKO mice reduced "despair-like" behavior in the riFS procedure, as compared to GluN2BFLOX controls. By contrast, GluN2BKO mice showed minimal alterations on anxiety-like or antidepressant-sensitive assays, including the single-trial forced swim test. In C57BL/6J mice, induction of "despair-like" responses in the riFS test was attenuated by vmPFC lesions, and was associated with changes in limbic GluN2B expression. Collectively, these data suggest that cortical GluN2B plays a major role in modulating adaptive responses to stress. Current findings provide further support for GluN2B as a key mechanism underlying stress responsivity, and a novel pharmacotherapeutic target for stress-related neuropsychiatric disorders.
Published by Elsevier Ltd.
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27 MeSH Terms
Endogenous anxiety and stress responses in water maze and Barnes maze spatial memory tasks.
Harrison FE, Hosseini AH, McDonald MP
(2009) Behav Brain Res 198: 247-51
MeSH Terms: Analysis of Variance, Animals, Anxiety, Cognition, Corticosterone, Exploratory Behavior, Male, Maze Learning, Memory, Mice, Mice, Inbred C57BL, Psychomotor Performance, Radioimmunoassay, Social Behavior, Space Perception, Spatial Behavior, Stress, Psychological, Swimming
Show Abstract · Added December 10, 2013
The effects of abnormally high or low stress on learning are well established. The Barnes maze and Morris water maze are two commonly used tests of spatial memory, of which the water maze is considered more stressful; however, until now this has not been demonstrated empirically. In the present study, mice matched for performance on commonly used anxiety tasks were trained on either the Barnes maze or water maze or received no cognitive testing. Water-maze training induced greater increases in plasma corticosterone than did Barnes maze training, assessed 30 min after the final session. Importantly, spatial learning was inversely correlated with corticosterone levels in the water maze but not the Barnes maze, suggesting that performance on the water maze may be more affected by test-induced stress even within wild-type subjects of the same age and gender. These findings are important when considering the appropriate cognitive tasks for any experiment in which stress responses may differ systematically across groups.
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18 MeSH Terms
A simple rapid immunoassay for S-adenosylhomocysteine in plasma.
Capdevila A, Burk RF, Freedman J, Frantzen F, Alfheim I, Wagner C
(2007) J Nutr Biochem 18: 827-31
MeSH Terms: Chromatography, High Pressure Liquid, Humans, Radioimmunoassay, Reference Values, Reproducibility of Results, S-Adenosylhomocysteine, Sensitivity and Specificity
Show Abstract · Added January 20, 2015
The measurement of plasma S-adenosylhomocysteine is a more sensitive indicator of the risk for vascular disease than is plasma homocysteine. Because the level of S-adenosylhomocysteine is normally in the nanomolar range, it has been difficult to measure and necessitated the development of complex fluorometric and mass-spectrophotometric methods. We have now adapted an existing immunoassay used for the measurement of homocysteine to the measurement of S-adenosylhomocysteine in plasma. This assay is sensitive down to the level of less than 0.1 pmol, and there is no interference by S-adenosylmethionine. The assay is carried out in microplates, allows the measurement of 12 samples per plate and can easily be carried out in a 4-h period. The method is applicable to plasma samples having S-adenosylhomocysteine concentrations ranging from 10 to 150 nM without dilution. The mean value for 16 normal subjects by this method was 18.9+/-1.4 nM (S.E.M.), compared with 17.8+/-1.4 nM obtained by a previously described method using two high-performance liquid chromatography columns with fluorescence derivatization. Mean values for seven cirrhotic patients were 46.5+/-3.3 nM by this new method compared with 44.6+/-5.3 by the former method. The ease and speed of this method should allow the widespread measurement of this important metabolite in laboratories without access to sophisticated equipment.
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7 MeSH Terms
Effects of hypoglycemia on human brain activation measured with fMRI.
Anderson AW, Heptulla RA, Driesen N, Flanagan D, Goldberg PA, Jones TW, Rife F, Sarofin H, Tamborlane W, Sherwin R, Gore JC
(2006) Magn Reson Imaging 24: 693-7
MeSH Terms: Adult, Blood Glucose, Brain Mapping, Chromatography, High Pressure Liquid, Epinephrine, Glucagon, Humans, Hydrocortisone, Hypoglycemia, Insulin, Magnetic Resonance Imaging, Norepinephrine, Photic Stimulation, Radioimmunoassay, Visual Cortex
Show Abstract · Added December 10, 2013
Functional magnetic resonance imaging (fMRI) was used to measure the effects of acute hypoglycemia caused by passive sensory stimulation on brain activation. Visual stimulation was used to generate blood-oxygen-level-dependent (BOLD) contrast, which was monitored during hyperinsulinemic hypoglycemic and euglycemic clamp studies. Hypoglycemia (50 +/- 1 mg glucose/dl) decreased the fMRI signal relative to euglycemia in 10 healthy human subjects: the fractional signal change was reduced by 28 +/- 12% (P < .05). These changes were reversed when euglycemia was restored. These data provide a basis of comparison for studies that quantify hypoglycemia-related changes in fMRI activity during cognitive tasks based on visual stimuli and demonstrate that variations in blood glucose levels may modulate BOLD signals in the healthy brain.
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15 MeSH Terms
Bone turnover across the menopause transition: correlations with inhibins and follicle-stimulating hormone.
Perrien DS, Achenbach SJ, Bledsoe SE, Walser B, Suva LJ, Khosla S, Gaddy D
(2006) J Clin Endocrinol Metab 91: 1848-54
MeSH Terms: Adult, Aged, Aged, 80 and over, Aging, Alkaline Phosphatase, Biomarkers, Bone Resorption, Bone and Bones, Calcification, Physiologic, Carrier Proteins, Cell Separation, Cells, Cultured, Collagen Type I, Estradiol, Female, Follicle Stimulating Hormone, Humans, Inhibins, Membrane Glycoproteins, Menopause, Middle Aged, RANK Ligand, Radioimmunoassay, Receptor Activator of Nuclear Factor-kappa B
Show Abstract · Added April 25, 2013
CONTEXT - Longitudinal clinical studies demonstrate that increases in bone turnover that occur in perimenopausal women correlate better with elevated serum FSH than with changes in serum estradiol (E2). This perimenopausal rise in FSH is due to a selective decrease in ovarian inhibin B (InhB). Our previous demonstration that inhibins suppress both osteoblast and osteoclast development suggests that changes in serum inhibins may regulate osteoblast and osteoclast differentiation and thereby bone turnover, independent of changes in sex steroids.
OBJECTIVE - The objective of this study was to determine whether decreased serum inhibin A (InhA) and InhB levels correlate with increases in markers of bone turnover in women across the menopause transition and to evaluate serum inhibins as better predictors of bone turnover markers across the menopause transition than FSH or bioavailable E2.
DESIGN - We studied a cross-sectional age-stratified population sample of 188 pre- and postmenopausal women not using oral contraceptives or hormone replacement therapy (age, 21-85 yr).
RESULTS - Serum InhA and InhB levels significantly correlated inversely with markers of bone formation and bone resorption in pre- and perimenopausal women and with markers of bone formation in postmenopausal women (InhA only). FSH was not significantly correlated with bone turnover in either pre- or postmenopausal women; however, FSH was significantly correlated with bone resorption (C-terminal collagen I cross-link) in perimenopausal women (age, 45-54 yr). Using multivariate analyses, serum InhA better predicted bone formation and resorption markers in premenopausal women than either FSH or bioavailable E2.
CONCLUSIONS - Decreases in inhibin levels across the menopause transition are associated with increasing bone turnover, regardless of changes in sex steroids or FSH.
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24 MeSH Terms
Ligand-dependent activation of the epidermal growth factor receptor by secondary bile acids in polarizing colon cancer cells.
Merchant NB, Rogers CM, Trivedi B, Morrow J, Coffey RJ
(2005) Surgery 138: 415-21
MeSH Terms: Amphiregulin, Bile Acids and Salts, Cell Line, Tumor, Cell Membrane, Cell Polarity, Cholic Acid, Colonic Neoplasms, Deoxycholic Acid, EGF Family of Proteins, ErbB Receptors, Glycoproteins, Humans, Intercellular Signaling Peptides and Proteins, Ligands, Radioimmunoassay
Show Abstract · Added August 12, 2010
BACKGROUND - Secondary bile acids such as deoxycholic acid (DCA) are known to promote colorectal cancer (CRC). Increasing evidence suggests that DCA-induced signaling is mediated by activation of the epidermal growth factor receptor (EGFR). We have shown that activation of the EGFR induces up-regulation of cyclooxygenase 2, basolateral release of prostaglandins (PGs), and mitogenesis in a polarizing human colon cancer cell line, HCA-7. The purpose of this study was to determine the mechanism by which DCA activates EGFR in human polarizing CRC cell lines HCA-7 and HCT-8.
METHODS - A primary, non-tumor-promoting bile acid (cholic acid [CA]) and a secondary, tumor-promoting bile acid, DCA, were added to the apical and basolateral compartment of polarized HCA-7 and HCT-8 cells. These cells were pretreated with monoclonal antibody 528, a monoclonal antibody that inhibits ligand binding to EGFR, or with WAY-022, a selective inhibitor of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloprotease-17 (TACE/ADAM-17), which cleaves amphiregulin (AR) to its mature, soluble form from the basolateral cell membrane. AR levels were measured in the apical and basolateral medium and cell lysates by radioimmunoassay. PGs were measured in the apical and basolateral medium by gas chromatography/mass spectrometry.
RESULTS - Basolateral delivery of DCA, but not CA, preferentially stimulated release of AR into the basolateral medium compared with cell lysates of polarized HCA-7 and HCT-8 cells. Basolateral delivery of DCA resulted in increased basolateral PGE2 levels (P < .05), and this effect was attenuated by pretreatment with monoclonal antibody 528 (P < .05). Inhibiting cell surface cleavage of AR with WAY-022 before DCA treatment reduced AR (P < .05) and PGE2 (P < .05) levels in the basolateral medium.
CONCLUSION - DCA, but not CA, results in compartment-specific, ligand-dependent activation of EGFR and subsequent increased basolateral PGE2 levels. The mechanism of DCA-induced EGFR activation is ligand-dependent and is controlled, at least in part, at the level of AR release from the basolateral cell membrane.
1 Communities
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15 MeSH Terms
Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention.
Zhang H, Zhang A, Kohan DE, Nelson RD, Gonzalez FJ, Yang T
(2005) Proc Natl Acad Sci U S A 102: 9406-11
MeSH Terms: Aldosterone, Animals, Biological Transport, Body Weight, Coloring Agents, Diabetes Mellitus, Type 2, Evans Blue, Gene Deletion, Genotype, Heterozygote, Hypoglycemic Agents, Immunohistochemistry, Integrases, Kidney, Kidney Tubules, Collecting, Mice, Mice, Knockout, Mice, Transgenic, Microscopy, Fluorescence, Microscopy, Phase-Contrast, Nephrons, PPAR gamma, Promoter Regions, Genetic, Radioimmunoassay, Rosiglitazone, Sodium, Thiazolidinediones
Show Abstract · Added September 9, 2013
The peroxisome proliferator-activated receptor subtype gamma (PPARgamma) ligands, namely the synthetic insulin-sensitizing thiazolidinedione (TZD) compounds, have demonstrated great potential in the treatment of type II diabetes. However, their clinical applicability is limited by a common and serious side effect of edema. To address the mechanism of TZD-induced edema, we generated mice with collecting duct (CD)-specific disruption of the PPARgamma gene. We found that mice with CD knockout of this receptor were resistant to the rosiglitazone- (RGZ) induced increases in body weight and plasma volume expansion found in control mice expressing PPARgamma in the CD. RGZ reduced urinary sodium excretion in control and not in conditional knockout mice. Furthermore, RGZ stimulated sodium transport in primary cultures of CD cells expressing PPARgamma and not in cells lacking this receptor. These findings demonstrate a PPARgamma-dependent pathway in regulation of sodium transport in the CD that underlies TZD-induced fluid retention.
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27 MeSH Terms
Decreased bone formation and osteopenia in mice lacking alpha-calcitonin gene-related peptide.
Schinke T, Liese S, Priemel M, Haberland M, Schilling AF, Catala-Lehnen P, Blicharski D, Rueger JM, Gagel RF, Emeson RB, Amling M
(2004) J Bone Miner Res 19: 2049-56
MeSH Terms: Alternative Splicing, Animals, Bone Diseases, Metabolic, Bone and Bones, Calcitonin, Calcitonin Gene-Related Peptide, Gene Deletion, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Transgenic, Osteoblasts, Osteogenesis, Peptides, Phenotype, Radioimmunoassay, Reverse Transcriptase Polymerase Chain Reaction, Tomography, X-Ray Computed
Show Abstract · Added July 12, 2010
UNLABELLED - We recently described an unexpected high bone mass phenotype in mice lacking the Calca gene that encodes CT and alphaCGRP. Here we show that mice specifically lacking alphaCGRP expression display an osteopenia caused by a decreased bone formation. These results show that alphaCGRP is a physiological activator of bone formation and that the high bone mass phenotype of the Calca-deficient mice is caused by the absence of CT.
INTRODUCTION - Calcitonin (CT) and alpha-calcitonin gene-related peptide (alphaCGRP) are two polypeptides without completely defined physiologic functions that are both derived from the Calca gene by alternative splicing. We have recently described an unexpected high bone mass phenotype in mice carrying a targeted deletion of the Calca gene. To uncover whether this phenotype is caused by the absence of CT or by the absence of alphaCGRP, we analyzed a mouse model, where the production of alphaCGRP is selectively abolished.
MATERIALS AND METHODS - Bones from Calca(-/-) mice, alphaCGRP(-/-) mice, and their corresponding wildtype controls were analyzed using radiography, muCT imaging, and undecalcified histology. Cellular activities were assessed using dynamic histomorphometry and by measuring the urinary collagen degradation products. CT expression was determined using radioimmunoassay and RT-PCR. Immunohistochemistry was performed using an anti-CGRP antibody on decalcified bone sections.
RESULTS - Unlike the Calca-deficient mice, the alphaCGRP-deficient mice do not display a high bone mass phenotype. In contrast, they develop an osteopenia that is caused by a reduced bone formation rate. Serum levels and thyroid expression of CT are not elevated in alphaCGRP-deficient mice. While CGRP expression is detectable in neuronal cell close to trabecular bone structures, the components of the CGRP receptor are expressed in differentiated osteoblast cultures.
CONCLUSION - The discrepancy between the bone phenotypes of Calca(-/-) mice and alphaCGRP(-/-) mice show that the high bone mass phenotype of the Calca(-/-) mice is caused by the absence of CT. The osteopenia observed in the alphaCGRP(-/-) mice that have normal levels of CT further show that alphaCGRP is a physiologic activator of bone formation.
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18 MeSH Terms