Sample records for adrenergic pathway polymorphism

  1. Renal albumin excretion: twin studies identify influences of heredity, environment, and adrenergic pathway polymorphism

    DEFF Research Database (Denmark)

    Rao, Fangwen; Wessel, Jennifer; Wen, Gen;


    Albumin excretion marks early glomerular injury in hypertension. This study investigated heritability of albumin excretion in twin pairs and its genetic determination by adrenergic pathway polymorphism. Genetic associations used single nucleotide polymorphisms at adrenergic pathway loci spanning...... biosynthesis (tyrosine hydroxylase), catabolism (monoamine oxidase A), storage/release (chromogranin A), receptor target (dopamine D1 receptor), and postreceptor signal transduction (sorting nexin 13 and rho kinase). Epistasis (gene-by-gene interaction) occurred between alleles at rho kinase, tyrosine...... hydroxylase, chromogranin A, and sorting nexin 13. Dopamine D1 receptor polymorphism showed pleiotropic effects on both albumin and dopamine excretion. These studies establish new roles for heredity and environment in albumin excretion. Urinary excretions of albumin and catecholamines are highly heritable...

  2. β2-adrenergic receptor Thr164Ile polymorphism, obesity, and diabetes

    DEFF Research Database (Denmark)

    Thomsen, Mette; Dahl, Morten; Tybjærg-Hansen, Anne;


    The β(2)-adrenergic receptor (ADRB2) influences regulation of energy balance by stimulating catecholamine-induced lipolysis in adipose tissue. The rare functional ADRB2rs1800888(Thr164Ile) polymorphism could therefore influence risk of obesity and subsequently diabetes.......The β(2)-adrenergic receptor (ADRB2) influences regulation of energy balance by stimulating catecholamine-induced lipolysis in adipose tissue. The rare functional ADRB2rs1800888(Thr164Ile) polymorphism could therefore influence risk of obesity and subsequently diabetes....

  3. Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density

    NARCIS (Netherlands)

    Veldhuis-Vlug, A G; Oei, L; Souverein, P C; Tanck, M W T; Rivadeneira, F; Zillikens, M C; Kamphuisen, P W; Maitland-van der Zee, A H; de Groot, M C H; Hofman, A; Uitterlinden, A G; Fliers, E; de Boer, A; Bisschop, P H


    Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Stu

  4. Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density

    NARCIS (Netherlands)

    A.G. Veldhuis-Vlug; L. Oei (Ling); P. Souverein (Patrick); M.W.T. Tanck (Michael); F. Rivadeneira Ramirez (Fernando); M.C. Zillikens (Carola); P.W. Kamphuisen; A-H. Maitland-van der Zee (Anke-Hilse); M.C.H. de Groot; A. Hofman (Albert); A.G. Uitterlinden (André); E. Fliers (Eric); A.C. de Boer (Anthonius); P.H. Bisschop


    textabstractSummary: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in t

  5. Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density

    NARCIS (Netherlands)

    Veldhuis-Vlug, A. G.; Oei, L.; Souverein, P. C.; Tanck, M. W T; Rivadeneira, F.; Zillikens, M. C.; Kamphuisen, P. W.; Maitland - van der Zee, A. H.; de Groot, M. C H; Hofman, A.; Uitterlinden, A. G.; Fliers, E.; de Boer, A.; Bisschop, P. H.


    Summary: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rott

  6. ß2-adrenergic receptor polymorphisms, asthma and COPD

    DEFF Research Database (Denmark)

    Thomsen, M; Nordestgaard, B G; Sethi, A A


    (COPD). We first genotyped 8,971 individuals from the Copenhagen City Heart Study for all three polymorphisms. To validate our findings, we genotyped an additional 53,777 individuals from the Copenhagen General Population Study for the Thr164Ile polymorphism. We identified 60,910 Thr164Ile noncarriers......) % pred and FEV(1)/FVC, respectively, compared with noncarriers. The odds ratio for COPD in Thr164Ile heterozygotes was 1.46 (95% CI 1.05-2.02). In the Copenhagen General Population Study, the Thr164 genotype associated with reduced FEV(1) % pred (p = 0.04) and FEV(1)/FVC (p ... and heterozygotes had 7% and 1% reduced FEV(1) % pred and 6% and 1% reduced FEV(1)/FVC, respectively, compared with noncarriers. The odds ratios for COPD in Thr164Ile homozygotes and heterozygotes were 4.53 (95% CI 1.54-13.3) and 1.07 (95% CI 0.92-1.25), respectively. Our results suggest that ADRB2 Thr164Ile...

  7. Adrenergic receptor polymorphisms and autonomic nervous system function in human obesity. (United States)

    Yasuda, Koichiro; Matsunaga, Tetsuro; Adachi, Tetsuya; Aoki, Norihiko; Tsujimoto, Gozoh; Tsuda, Kinsuke


    Adrenergic receptors (ARs) are cell-surface G-protein-coupled receptors for catecholamines. They are essential components of the sympathetic nervous system, organized within the autonomic nervous system (ANS), which controls various physiological functions, including energy homeostasis and metabolism of glucose and lipids. An impairment of ANS function in metabolism is considered to be one of the pathological states associated with human obesity and related metabolic diseases; thus, alterations in AR function might be implicated in the pathophysiology of these diseases. Several studies have suggested an association between obesity phenotypes and some AR polymorphisms. In vitro and human clinical studies indicate that some of these polymorphisms have functional and pathophysiological significance, including the linkage to ANS function. This review summarizes present knowledge of AR polymorphisms related to human obesity, and their association with ANS function.

  8. The impact of β 2 adrenergic receptor polymorphisms on the outcomes in cardiovascular diseases

    Directory of Open Access Journals (Sweden)

    Ersilia Cipolletta


    Full Text Available Cardiovascular diseases (CVD include a heterogeneous group of multifactorial conditions and represent the major health problem in the western society. Many studies have evidenced that inter-individual variability affects the prognosis and the response to pharmacological treatment in patients with CVD. The identification of genetic markers to select patients more susceptible to develop cardiovascular complications has a therapeutic interest for undertaking individualized therapeutic approach. The sympathetic nervous system acts through adrenergic receptor subtypes and plays a key role in the development and prognosis of CVD. In particular, β-2 adrenergic receptors (β2AR, expressed in a wide variety of tissues, are critical regulators of cardiac output, peripheral vascular resistance and metabolism. Several variations with multiple single-nucleotide polymorphisms have been identified in β2AR gene. There are 3 common β2AR polymorphisms characterized in more detail for their influence on functional receptor activity. In particular, the changing an arginine for a glycine at position 16 of the receptor protein (Arg16Gly is associated with increased agonist-induced down-regulation; the substitution of glutamine with glutamic acid at position 27 (Gln27Glu leads to resistance to down-regulation; the substitution of threonine with isoleucine (Thr164Ile at position 164 causes receptor uncoupling from the G protein. Many studies have indicated the association of β2AR polymorphisms with various cardiovascular and metabolic diseases and have contributed to indicate the β2AR gene variants an appropriate target for investigating possible links between receptor polymorphisms, drug responses and susceptibility to CVD. However, the reports on the association of β2AR polymorphisms with clinical outcomes of CVD have been contradictory. In this review, we will illustrate the effects of β2ARs genetic variability on the management of CVD.

  9. N-terminal {beta}{sub 2}-adrenergic receptor polymorphisms do not correlate with bronchodilator response in asthma families

    Energy Technology Data Exchange (ETDEWEB)

    Holyroyd, K.J.; Dragwa, C.; Xu, J. [Johns Hopkins Medical Institutions, Baltimore, MD (United States)] [and others


    Family and twin studies have suggested that susceptibility to asthma is inherited. One clinically relevant phenotype in asthma is the bronchodilator response to beta adrenergic therapy (reversibility) which may also be inherited and vary among asthmatics. Two polymorphisms of the {beta}{sub 2}-adrenergic receptor common to both asthmatic and normal individuals have been reported. One polymorphism, an amino acid polymorphism at position 16, correlated in one study with the need for long-term corticosteriod use in a population of asthmatics. It is conceivable that the increased use of corticosteroids needed to control symptoms in these patients may be explained by a decreased responsiveness to brochodilators mediated through this amino acid polymorphism in the {beta}{sub 2}-adrenergic receptor. However, the response to {beta}{sub 2} bronchodilators was not tested in these patients. In our Dutch asthma families, DNA sequencing of the {beta}{sub 2}-adrenergic receptor has been performed for N-terminal polymorphisms at amino acid positions 16 and 27 in over 100 individuals, and no correlation was found with the increase of FEV{sub 1} in response to bronchodilator. Linkage analysis between bronchodilator response and marker D5S412 near the {beta}{sub 2}-adrenergic receptor gene was performed in 286 sibpairs from these families. Using a bronchodilator response of >10% in FEV{sub 1} as a qualitative definition of affected individuals, there were 145 unaffected sibpairs, 121 sibpairs where one was affected, and 20 in which both were affected. Linear regression analysis of these sibpair data suggested possible linkage (p=0.007). This supports further examination of the {beta}{sub 2}-adrenergic receptor and its regulatory regions for polymorphisms that correlate with the bronchodilator response in asthma families.

  10. High-throughput chemiluminometric genotyping of single nucleotide polymorphisms of histamine, serotonin, and adrenergic receptor genes. (United States)

    Toubanaki, Dimitra K; Christopoulos, Theodore K; Ioannou, Penelope C; Flordellis, Christodoulos S


    Several pharmacogenetic studies are focused on the investigation of the relation between the efficacy of various antipsychotic agents (e.g., clozapine) and the genetic profile of the patient with an emphasis on genes that code for neurotransmitter receptors such as histamine, serotonin, and adrenergic receptors. We report a high-throughput method for genotyping of single nucleotide polymorphisms (SNPs) within the genes of histamine H2 receptor (HRH2), serotonin receptor (HTR2A1 and HTR2A2), and beta(3) adrenergic receptor (ADRB3). The method combines the high specificity of allele discrimination by oligonucleotide ligation reaction (OLR) and the superior sensitivity and simplicity of chemiluminometric detection in a microtiter well assay configuration. The genomic region that spans the locus of interest is first amplified by polymerase chain reaction (PCR). Subsequently, an oligonucleotide ligation reaction is performed using a biotinylated common probe and two allele-specific probes that are labeled at the 3' end with digoxigenin and fluorescein. The ligation products are immobilized in polystyrene wells via biotin-streptavidin interaction, and the hybrids are denatured. Detection is accomplished by the addition of alkaline phosphatase-conjugated anti-digoxigenin or anti-fluorescein antibodies in combination with a chemiluminogenic substrate. The ratio of the luminescence signals obtained from digoxigenin and fluorescein indicates the genotype of the sample. The method was applied successfully to the genotyping of 23 blood samples for all four SNPs. The results were in concordance with both PCR-restriction fragment length polymorphism analysis and sequencing.

  11. Differential coupling of Arg- and Gly389 polymorphic forms of the β1-adrenergic receptor leads to pathogenic cardiac gene regulatory programs



    The β1-adrenergic receptor (β1AR; ADRB1) polymorphism Arg389Gly is located in an intracellular loop and is associated with distinct human and mouse cardiovascular phenotypes. To test the hypothesis that β1-Arg389 and β1-Gly389 alleles could differentially couple to pathways beyond that of classic Gs-adenylyl cyclase (AC)/cAMP signaling, we performed comparative gene expression profile analyses on hearts from wild-type and transgenic mice that expressed either human β1-Arg389 or β1-Gly389 rece...

  12. Family-based association analysis of beta(2)-adrenergic receptor polymorphisms in the Childhood Asthma Management Program

    NARCIS (Netherlands)

    Silverman, EK; Kwiatkowski, DJ; Sylvia, JS; Lazarus, R; Drazen, JM; Lange, C; Laird, NM; Weiss, ST


    Background: beta(2)-Adrenergic receptor (B2AR) polymorphisms have been associated with a variety of asthma-related phenotypes, but association results have been inconsistent across different studies. Objective: We sought to apply family-based association methods to individual single nucleotide polym

  13. Association of beta 2 -adrenergic receptor gene polymorphisms and nocturnal asthma in Saudi patients

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    Al-Rubaish Abdullah


    Full Text Available Background and Objectives : Two polymorphisms of beta 2 -adrenergic receptor (β2 -AR gene, namely the substitution from arginine (Arg to glycine (Gly at codon 16 and from glutamine (Gln to glutamic (Glu at codon 27, are linked with functional changes in the β2 -AR in the respiratory system even though they are not deemed to be susceptibility genes for asthma per se. The objective of this study was to investigate this association in a subset of asthmatic patients, namely those with nocturnal asthma. Methods : The β2 -AR gene polymorphisms at codon 16 and 27 were assessed in 40 patients clinically diagnosed with nocturnal asthma and 96 normal controls. Genomic DNA was obtained from whole blood and genotyping was carried out by a PCR based restriction fragment length polymorphism technique. Results : There was a statistically significant difference in genotype frequencies at codon 16 (Arg/Gly between nocturnal asthmatic patients and normal control subjects (P < 0.05. However, there was no statistically significant difference in allele frequencies between the two groups. In addition, there was a significant association between Arg16-Gly genotype with nocturnal asthma compared to homozygous Gly16 (codominant model P = 0.0033, OR = 3.69: 95% CI: 1.49-9.12. However, there were no statistically significant differences in genotype and allele frequencies at codon 27 (Gln/Glu between the normal control and nocturnal asthmatic groups (χ2 = 1.81, P = 0.41. The results also indicate that linkage disequilibrium existed between the β2 -AR codon 16 and β2 -AR codon 27 polymorphism (/ D΄/ = 0.577. The data for all haplotypes did not show a statistically significant association. Conclusion : We present the genotype and allele frequencies of β2 -AR gene polymorphisms in normal Saudi subjects and nocturnal asthmatic patients. There was a significant difference in genotype frequencies at codon 16 (Arg/Gly. However, our study indicates a poor association of

  14. ß2 -adrenergic receptor Thr164IIe polymorphism, blood pressure and ischaemic heart disease in 66¿750 individuals

    DEFF Research Database (Denmark)

    Thomsen, M; Dahl, Morten; Tybjaerg-Hansen, A;


    The ß(2) -adrenergic receptor (ADRB2) is located on smooth muscle cells and is an important regulator of smooth muscle tone. The Thr164Ile polymorphism (rs1800888) in the ADRB2 gene is rare but has profound functional consequences on receptor function and could cause lifelong elevated smooth musc...... tone. We tested the hypothesis that Thr164Ile is associated with increased blood pressure, increased frequency of hypertension and increased risk of cardiovascular disease (CVD)....

  15. Polymorphisms in α- and β-Adrenergic Receptor Genes, Hypertension, and Obstructive Sleep Apnea: The Skaraborg Sleep Study

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    Kristina Bengtsson Boström


    Full Text Available The sympathetic nervous system and the adrenergic receptors play an important role in regulation of blood pressure. This study explored the associations between functional polymorphisms of the α2B-, β1-, and β2-adrenergic receptor genes and obstructive sleep apnea (OSA in hypertensive patients and hypertension in patients with OSA in a populationbased sample of 157 hypertensive patients and 181 healthy control subjects. Only the Arg389Gly polymorphism of the β1-adrenergic receptor gene was associated with increased risk for mild OSA in hypertensive patients (Arg/Arg versus Gly/Arg/Gly/Gly, 2.1, 95% CI, 1.02–4.7. Hypertensive men carrying the Arg389Arg genotype had higher crude and age-adjusted AHI than carriers of the Arg389Gly/Gly389Gly genotypes. When adjusted also for BMI this difference became borderline significant. This difference was not observed in women. The risk of hypertension in mild OSA was associated with increasing number of Arg-alleles (Arg/Arg OR 5.4, 95% CI 1.4–21.2.

  16. The Polymorphisms of Ser49Gly and Gly389Arg in Beta-1-Adrenergic Receptor Gene in Major Depression (United States)

    KOKUT, Süleyman; ATAY, İnci Meltem; UZ, Efkan; AKPINAR, Abdullah; DEMİRDAŞ, Arif


    Introduction It was reported that the genetic susceptibility of major depressive disorder (MDD) is related with genetic polymorphisms. The aim of this study was to investigate the possible association of the genotype and allele frequencies of Ser49Gly and Arg389Gly polymorphisms in MDD by comparing them with healthy subjects. Methods A total of 144 patients with MDD diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria and 105 healthy controls were included in the study. Polymerase chain reaction (PCR) with restriction fragment length polymorphism (RFLP) was used for genotyping. Results Of the 144 participants in the MDD group, 77 (53.5%) had homozygous wild type (AA), 57 (39.6%) had heterozygous type (AG), and 10 (6.9%) had mutant (GG) genotype for Ser49Gly, whereas 75 (52.1%) had homozygous wild type (GG), 59 (41.0%) had heterozygous (GC) type, and 10 (6.9%) had mutant homozygous (CC) genotype for Gly386Arg. There were no significant difference in the allele and genotype frequencies of the beta-1-adrenergic receptor (ADRB1) gene for Ser49Gly and Arg389Gly polymorphisms after comparing with healthy controls (p=0.626; p=0.863 and p=0.625; p=0.914). Conclusion The results of our study did not reveal a major effect of the polymorphism of Ser49Gly and Gly389Arg in the ADRB1 gene in MDD. Further studies with larger sample size are required to elucidate the role of other beta-1 adrenergic gene polymorphisms in MDD.

  17. Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and Metastasis (United States)


    1 AWARD NUMBER: W81XWH-13-1-0439 TITLE: Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and...treatment of breast cancer often experience severe and chronic psychological stress. The sympathetic nervous system (SNS) is an important pathway by which...Sephton SE, McDonald PG, et al. The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer . 2006;6:240-8. 3

  18. Environmental factors and beta2-adrenergic receptor polymorphism: influence on the energy expenditure and nutritional status of obese women. (United States)

    Rosado, Eliane Lopes; Bressan, Josefina; Martínez, J Alfredo


    Our aim was to evaluate the influence of the Gln27Glu polymorphism of the β2-adrenergic receptor (ADRβ2) gene, fat intake and physical activity on the energy expenditure (EE) and nutritional status of obese women. Sixty obese women (30-46 years) participated in the study and were assigned to three groups depending on the genotypes: Gln27Gln, Gln27Glu and Glu27Glu. At baseline and after nutritional intervention, the anthropometric and body composition (bioelectrical impedance), dietary, EE (indirect calorimetry) and biochemical variables were measured. All women received a high-fat test meal to determine the postprandial EE (short-term) and an energy-restricted diet for 10 weeks (long term). The frequencies of Gln27Gln, Gln27Glu and Glu27Glu were 36.67, 40.0 and 23.33 %, respectively. Anthropometric and biochemical variables and EE did not differ between groups, although women who had no polymorphism demonstrated decreased carbohydrate oxidation. On the other hand, the Glu27Glu genotype showed a positive relation with EE in physical activity and fat oxidation. The environmental factors and Gln27Glu polymorphism did not influence the nutritional status and EE of obese women, but physical activity in obese women with the polymorphism in the ADRβ2 gene can promote fat oxidation. The results suggest that encouraging the practice of physical exercise is important considering the high frequency of this polymorphism in obese subjects.

  19. β3-Adrenergic receptor gene polymorphism and type 2 diabetes in a Caucasian population

    NARCIS (Netherlands)

    Oeveren van-Dybicz, A.M.; Vonkeman, H.E.; Bon, M.A.M.; Bergh, van den F.A.J.T.M.; Vermes, I.


    Aim: The β3-adrenergic receptor (β3-AR) is suspected to play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. A mutation in the β3-AR gene (Trp64Arg) has been associated with the capacity of weight gain and with early onset of noninsulin dependent diabetes me

  20. Lack of associations between serum leptin, a polymorphism in the gene for the beta(3)-adrenergic receptor and glucose tolerance in the Dutch population.

    NARCIS (Netherlands)

    Janssen, JAMJL; Koper, JW; Stolk, RP; Englaro, P; Uitterlinden, AG; Huang, Q; van Leeuwen, JPTM; Blum, WF; Attanasio, AMF; Pols, HAP; Grobbee, DE; de Jong, FH; Lamberts, SWJ


    BACKGROUND The associations between leptin levels and the prevalence of a polymorphism in the beta(3)-adrenergic receptor were studied in a cross-sectional analysis of 600 participants in a population-based study, which were stratified for glucose tolerance by an oral glucose tolerance test. METHODS

  1. Beta-adrenergic signals regulate cardiac differentiation of mouse embryonic stem cells via mitogen-activated protein kinase pathways. (United States)

    Yan, Lihui; Jia, Zhuqing; Cui, Jingjing; Yang, Hongtao; Yang, Huangtian; Zhang, Yongzhen; Zhou, Chunyan


    As embryonic stem cell-derived cardiomyocytes (ESC-CMs) have the potential to be used in cell replacement therapy, an understanding of the signaling mechanisms that regulate their terminal differentiation is imperative. In previous studies, we discovered the presence of adrenergic and muscarinic receptors in mouse embryonic stem cells (ESCs). However, little is known about the role of these receptors in cardiac differentiation and development, which is critically important in cardiac physiology and pharmacology. Here, we demonstrated that a β-adrenergic receptor (β-AR) agonist significantly enhanced cardiac differentiation as indicated by a higher percentage of beating embryoid bodies and a higher expression level of cardiac markers. Application of β1-AR and β2-AR antagonists partly abolished the effect of the β-AR agonist. In addition, by administering selective inhibitors we found that the effect of β-AR was driven via p38 mitogen-activated protein kinase and extracellular-signal regulated kinase pathway. These findings suggest that ESCs are also a target for β-adrenergic regulation and β-adrenergic signaling plays a role in ESC cardiac differentiation.

  2. Polymorphism of starch pathway genes in cassava. (United States)

    Vasconcelos, L M; Brito, A C; Carmo, C D; Oliveira, E J


    The distribution and frequency of single nucleotide polymorphisms (SNPs) can help to understand changes associated with characteristics of interest. We aimed to evaluate nucleotide diversity in six genes involved in starch biosynthesis in cassava using a panel of 96 unrelated accessions. The genes were sequenced, aligned, and used to obtain values for nucleotide diversity (π), segregating sites (θ), Tajima's D test, and neighbor-joining (NJ) clustering. On average, one SNP per 147 and 171 bp was identified in exon and intron regions, respectively. Thirteen heterozygous loci were found. Three of seven SNPs in the exon region resulted in non-synonymous replacement or four synonymous substitutions. However, no associations were noted between SNPs and root dry-matter content. The parameter π ranged from 0.0001 (granule bound starch synthase I) to 0.0033 (α-amylase), averaging 0.0011, while θ ranged from 0.00014 (starch branching enzyme) to 0.00584 (starch synthase I), averaging 0.002353. The θ diversity value was typically double that of the π. Results of the D test did not suggest any evidence of deviance of neutrality in these genes. Among the evaluated accession, 82/96 were clustered using the NJ method but without a clear separation of the root dry-matter content, root pulp coloration, and classification of the cyanogenic compound content. High variation in genes of the starch biosynthetic pathway can be used to identify associations with the functional properties of starch for the use of polymorphisms for selection purposes.

  3. Polymorphism at the ovine beta3-adrenergic receptor locus: associations with birth weight, growth rate, carcass composition and cold survival. (United States)

    Forrest, R H; Hickford, J G H; Hogan, A; Frampton, C


    The beta3-adrenergic receptors (ADRB3s) are predominantly found on the surface of adipocytes and are the major mediators of the lipolytic and thermogenic effects of high catecholamine concentrations. Polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis of part of the ovine beta3-adrenergic receptor gene (ADRB3) intron was used to screen 12 large Merino half-sib families for sequence variation. Six different alleles that segregated in a Mendelian fashion were observed. The genetic basis for the allelic differences were identified by sequencing the ADRB3 (coding and non-coding regions) from animals that were homozygous for each of the alleles. Five sire lines (two Merino x Merino, two Merino x Coopworth, one Dorset Down x Coopworth) provided phenotypic and genotypic data used to ascertain the effects of allelic variation at the ADRB3 locus on birth weight, weaning weight, growth rate (up until weaning), carcass composition at 63 days post-weaning and cold survival. Statistical analyses within each half-sib family showed that in some sire lines (S13, S15, and S17) the inheritance of a particular allele was associated with increased birth weights and/or increased growth rates up until weaning. The inheritance of a particular sire allele was associated with fatter carcasses in sire line S16. Chi-squared analysis revealed the association of the E allele with cold survival and the D allele with cold-related mortality in sire line S14. Such associations support the hypothesis that ADRB3s are involved in energy homeostasis. With more research, the variation detected at the ADRB3 locus may assist in the genetic selection for desirable animal production traits.

  4. Energy expenditure, body composition and insulin response to glucose in male twins discordant for the Trp64Arg polymorphism of the beta3-adrenergic receptor gene

    DEFF Research Database (Denmark)

    Højlund, K; Christiansen, C; Bjørnsbo, K S;


    and environmental background, the Trp64Arg polymorphism of the beta3AR gene is associated with lower fat mass, fasting insulin levels and an appropriate insulin response to glucose. Thus, heterozygosity for the Trp64Arg variant is unlikely to increase the risk of obesity, insulin resistance or type 2 diabetes.......AIM: The tryptophan to arginine change in position 64 (Trp64Arg) polymorphism of the beta3-adrenergic receptor (beta3AR) gene has been associated with an increased prevalence of obesity, insulin resistance and type 2 diabetes. In this, decreased rates of energy expenditure and impaired insulin......-ray absorptiometry scanning and energy expenditure by indirect and direct calorimetry. RESULTS: Twins heterozygous for the Trp64Arg polymorphism showed significantly lower fat mass independent of the method used, and significantly lower fasting insulin and glucose concentrations compared with their homozygous wild...

  5. Differential regulation of atrial natriuretic peptide- and adrenergic receptor-dependent lipolytic pathways in human adipose tissue. (United States)

    Moro, Cédric; Polak, Jan; Richterova, Blanka; Sengenès, Coralie; Pelikanova, Terezie; Galitzky, Jean; Stich, Vladimir; Lafontan, Max; Berlan, Michel


    The aim of the study was to investigate the regulation affecting the recently described atrial natriuretic peptide (ANP)-dependent lipolytic pathway in comparison with the adrenergic lipolytic cascade. We studied in vivo the effect of a euglycemic-hyperinsulinemic clamp on the changes occurring in the extracellular glycerol concentration (EGC) of subcutaneous adipose tissue (SCAT) during ANP or epinephrine perfusion in a microdialysis probe. Homologous desensitization and the incidence of hyperinsulinemia on the ANP- and catecholaminergic-dependent control of lipolysis were also investigated in vitro on fat cells from SCAT. When perfused in SCAT, epinephrine and ANP promoted an increase in EGC; the EGC increase was significantly lower during the clamp. The reduction of epinephrine-induced lipolysis was limited (18%) when phentolamine (an alpha(2)-adrenergic receptor [AR] antagonist) was perfused together with epinephrine. Unlike the effect of epinephrine, the response to ANP observed during the second perfusion was reduced by 32%. The increase in extracellular guanosine 3',5' -cyclic monophosphate concentration, which reflects ANP activity, was also reduced during the second perfusion. Desensitization of the lipolytic effects of ANP was observed in vitro after a 2-hour period of recovery, while the effects of alpha(2)-AR agonist or of epinephrine were unchanged. Insulin was without any effect on ANP-induced lipolysis and alpha(2)-AR-mediated antilipolysis, while it reduced beta-AR-induced lipolysis. The ANP-dependent lipolytic pathway undergoes desensitization in vitro and in situ. Insulin had no inhibitory effect on either ANP- or alpha(2)-AR-dependent pathways, while it counteracted the beta-AR pathway.

  6. Association of Gln27Glu and Arg16Gly polymorphisms in Beta2-adrenergic receptor gene with obesity susceptibility: a meta-analysis.

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    Hongxiu Zhang

    Full Text Available BACKGROUND: The beta2-adrenergic receptor (ADRB2 gene polymorphism has been implicated in susceptibility to obesity, but study results are still controversial. OBJECTIVE: The present meta-analysis is performed to determine whether there are any associations between the Gln27Glu (rs1042714 or the Arg16Gly (rs1042713 polymorphisms in ADRB2 and obesity susceptibility. METHODS: The PubMed (1950-2014, Embase (1974-2014, and China National Knowledge Infrastructure (CNKI, 1994-2014 databases were searched using the search terms ("Beta2-adrenergic receptor", "β2-adrenergic receptor" or "ADRB2", "polymorphism," and "obesity". Fixed- or random-effects pooled measures were determined on the bias of heterogeneity tests across studies. Publication bias was examined by Egger's test and the modified Begg's test. RESULTS: Eighteen published articles were selected for meta-analysis. Overall analyses showed that rs1042714 (Gln27Glu was associated with significantly increased obesity risk in the heterozygote model (Gln/Glu vs. Gln/Gln: OR: 1.16, 95% CI: 1.04-1.30, I2 = 49%, P = 0.009 and the dominant model (Gln/Glu + Glu/Glu vs. Gln/Gln: OR: 1.2, 95% CI: 1.00-1.44, I2 = 55%, P = 0.04, whereas no significant association was found in the other models for rs1042714. Also, no significant association was found between the rs1042713 (Arg16Gly gene polymorphism and the risk of obesity in all genetic models. In addition, neither rs1042713 (Arg16Gly nor rs1042714 (Gln27Glu showed any significant association with obesity susceptibility when the population were stratified based on gender. CONCLUSION: Our meta-analysis revealed that the rs1042714 (Gln27Glu polymorphism is associated with obesity susceptibility. However, our results do not support an association between rs1042713 (Arg16Gly polymorphisms and obesity in the populations investigated. This conclusion warrants confirmation by more case-control and cohort studies.

  7. G16R single nucleotide polymorphism but not haplotypes of the ß2-adrenergic receptor gene alters cardiac output in humans

    DEFF Research Database (Denmark)

    Rokamp, Kim Z; Staalsø, Jonatan M; Gartmann, Martin


    Variation in genes encoding the ß2-adrenergic receptor (ADRB2) and angiotensin-converting enzyme (ACE) may influence Q¿ (cardiac output). The 46G>A (G16R) SNP (single nucleotide polymorphism) has been associated with ß2-mediated vasodilation, but the effect of ADRB2 haplotypes on Q¿ has not been...... studied. Five SNPs within ADRB2 (46G>A, 79C>G, 491C>T, 523C>A and 1053G>C by a pairwise tagging principle) and the I/D (insertion/deletion) polymorphism in ACE were genotyped in 143 subjects. Cardiovascular variables were evaluated by the Model flow method at rest and during incremental cycling exercise...

  8. Impaired desensitization of a human polymorphic α2B-adrenergic receptor variant enhances its sympatho-inhibitory activity in chromaffin cells

    Directory of Open Access Journals (Sweden)

    Lymperopoulos Anastasios


    Full Text Available Abstract Background α2-adrenergic receptors (ARs mediate many cellular actions of epinephrine and norepinephrine and inhibit their secretion from adrenal chromaffin cells. Like many other G-protein coupled receptors (GPCRs, they undergo agonist-dependent phopshorylation and desensitization by GPCR Kinases (GRKs, a phenomenon recently shown to play a major role in the sympathetic overdrive that accompanies and aggravates chronic heart failure. A deletion polymorphism in the human α2B-AR gene (Glu301-303 causes impaired agonist-promoted receptor phosphorylation and desensitization in heterologous cell lines. Given the importance of α2-ARs in regulation of catecholamine secretion from chromaffin cells, we sought to investigate, in the present study, the desensitization properties and the sympatho-inhibitory activity of this variant in a chromaffin cell line. For this purpose, we expressed this variant and its wild type counterpart in the well-established chromaffin cell line PC12, and performed receptor phosphorylation and desensitization studies, as well as in vitro catecholamine secretion assays. Results Both the agonist-induced phosphorylation and agonist-dependent desensitization of the human Glu301-303 deletion polymorphic α2B-AR are significantly impaired in PC12 cells, resulting in enhanced signaling to inhibition of cholinergic-induced catecholamine secretion in vitro. Conclusion This α2B-AR gene polymorphism (Glu301-303 deletion might confer better protection against conditions characterized and aggravated by sympathetic/catecholaminergic overstimulation in vivo.

  9. Effects of β2-Adrenergic Receptor Gene Polymorphisms on Ritodrine Therapy in Pregnant Women with Preterm Labor: Prospective Follow-Up Study

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    Jin Young Park


    Full Text Available This study aimed to evaluate the effects of β2-adrenergic receptor (ADRB2 gene polymorphisms on ritodrine therapy outcomes in patients with preterm labor. Genotyping analysis of ADRB2 gene (rs1042713, rs1042714, rs1042717, rs1042718, and rs1042719 was performed on 137 patients with preterm labor. Survival analysis was conducted for the effects of SNPs on the median time to delivery as a primary outcome. The median time to delivery in the study patients was 349.3 h. Gestational age at admission and modified Bishop scores revealed significant effects on time to delivery (p < 0.001. Among studied SNPs, rs1042717 and rs1042718 showed linkage disequilibrium in this population, and their effects on time to delivery were marginally significant (p < 0.1. Patients with variant-homozygotes in the rs1042713 showed considerably shortened time to delivery compared to wild-allele carriers. The rs1042719 polymorphism significantly affected time to delivery in both univariate and multivariate analysis; the GC and CC carriers showed 64% decrease in time to delivery compared to the wild-type homozygote carriers. Based on the results, it was concluded that the gene polymorphisms of ADRB2 could affect ritodrine therapy in patients with preterm labor. However, given the single-center and the relatively small sample size, our hypothesis requires further independent validation using multi-center and large sample size.

  10. Effect of polymorphisms in the β2-adrenergic receptor on the susceptibility and pulmonary function of patients with chronic obstructive pulmonary disease: a meta analysis

    Institute of Scientific and Technical Information of China (English)

    NIU Li-ming; LIANG Ying; XU Ming; ZHANG You-yi; ZHANG Yuan; HE Bei


    Background Chronic obstructive pulmonary disease (COPD) is a heterogeneous and complex disease of which the pathogenesis remains largely unknown.Many factors could influence COPD development and progression.One of them is the genetic risk factor.A severe hereditary deficiency of alpha-1 antitrypsin is the best genetic proof.Four single nucleotide polymorphisms (SNPs) of beta2-adrenergic receptor (β2AR) result in single amino acid substitution.Two loci had been extensively studied and found that they could change the function of β2AR.Two SNPs consist of substitutions of glycine for arginine at amino acid position 16,glutamic acid for glutamine at position 27.Many studies proved that polymorphisms at position 16 and 27 altered the lung function of COPD patients or the patient's susceptibility to the development of COPD.However,there was no exclusive conclusion.Therefore,a meta analysis was done to investigate the effect of polymorphisms in the β2-adrenergic receptor (ADRB2) gene on the risk of COPD and lung function.Methods Comprehensive searches of MEDLINE,Embase,Ovid,HighWire,Cochrane Library,and Chinese databases (CBMdisc,VIP,CNKI,and Wanfang data) from January 1980 to September 2011 were performed,using the keywords:COPD OR chronic obstructive pulmonary disease AND adrenoreceptor OR adrenergic receptor AND polymorphism OR mutation OR variation.Case-control research or cross sectional studies in which diagnosis of COPD met the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines; all the studies reported the ADRB2 genotype at position 16 or 27.Outcomes measured were genotype frequency and forced expiratory volume in the first second (FEV1%) in both the case and control.Results Twelve case-control studies and eight cross-sectional studies were included.Compared to the control (n=1225),neither Gly/Gly (n=527) nor Arg/Arg (n=422) homozygotes at position 16 demonstrated increased susceptibility to COPD,with odds ratios (ORs) of 0.95 (95% Cl

  11. α1A-adrenergic receptor induces activation of extracellular signal-regulated kinase 1/2 through endocytic pathway.

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    Fei Liu

    Full Text Available G protein-coupled receptors (GPCRs activate mitogen-activated protein kinases through a number of distinct pathways in cells. Increasing evidence has suggested that endosomal signaling has an important role in receptor signal transduction. Here we investigated the involvement of endocytosis in α(1A-adrenergic receptor (α(1A-AR-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2. Agonist-mediated endocytic traffic of α(1A-AR was assessed by real-time imaging of living, stably transfected human embryonic kidney 293A cells (HEK-293A. α(1A-AR was internalized dynamically in cells with agonist stimulation, and actin filaments regulated the initial trafficking of α(1A-AR. α(1A-AR-induced activation of ERK1/2 but not p38 MAPK was sensitive to disruption of endocytosis, as demonstrated by 4°C chilling, dynamin mutation and treatment with cytochalasin D (actin depolymerizing agent. Activation of protein kinase C (PKC and C-Raf by α(1A-AR was not affected by 4°C chilling or cytochalasin D treatment. U73122 (a phospholipase C [PLC] inhibitor and Ro 31-8220 (a PKC inhibitor inhibited α(1B-AR- but not α(1A-AR-induced ERK1/2 activation. These data suggest that the endocytic pathway is involved in α(1A-AR-induced ERK1/2 activation, which is independent of G(q/PLC/PKC signaling.

  12. β1-adrenergic receptor(Arg389Gly) polymorphism and response to bisoprolol in patients with chronic heart failure

    Institute of Scientific and Technical Information of China (English)



    Objective The purpose of this study was to investigate the relation between the Arg389Gly polymorphism of theβ1-AR gene and chronic heart failure (CHF) and to evaluate the effect of this polymorphism on clinical response toβ-adrenoceptor blockade (bisoprolol) in patients with CHF. Methods One hundred and ten patients with stable CHF receiving basic therapy for heart failure were included. Before initiation and 3 months af-

  13. Association of β3 Adrenergic Receptor and Peroxisome Proliferator-activated Receptor Gamma 2 Polymorphisms With Insulin Sensitivity: A Twin Study

    Institute of Scientific and Technical Information of China (English)



    Objective To study the effect of β3 adrenergic receptor (β3AR) Trp64Arg and peroxisome proliferator activated receptor gamma 2 (PPARγ2) Pro12Ala polymorphisms on insulin resistance. Methods One hundred and eight dizygotic twin pairs were enrolled in this study. Microsatellite polymorphism was used to diagnose zygosity of twins. Insulin sensitivity was estimated with logarithm transformed homeostasis model assessment (HOMA). PCR-RFLP analysis was performed to detect the variants. As a supplement to the sib-pair method, identity by state (IBS) was used to analyze the association of polymorphisms with insulin sensitivity. Results The genotype frequencies of Trp64Trg, Trp64Arg, and Arg64Arg were 72.3%, 23.8%, and 3.9%, respectively, while the genotype frequencies of Pro12Pro, Pro12Ala, and Ala12Ala were 89.9%, 9.6%,and 0.5%, respectively. For β3AR Trp64Arg the interclass co-twin correlations of Waist-to-hip ratio (WHR), blood glucose (GLU), and insulin (INS), homeostasis model assessment insulin resistance index (HOMA-IR) of the twin pairs sharing 2alleles of IBS were greater than those sharing 0-1 allele of IBS, and HOMA-IR had statistic significance. For PPARγ2 Pro12Ala most traits of twin pairs sharing 2 alleles of IBS had greater correlations and statistic significance in body mass index (BMI),WHR, percent of body fat (PBF) and GLU, but there were low correlations of either insulin or HOMA-IR of twin pairs sharing 1 or 2 alleles of IBS. The combined effects of the two variations showed less squared significant twin-pair differences of INS and HOMA-IR among twins sharing 4 alleles of IBS. Conclusions β3AR Trp64Arg and PPARγ2 Pro12Ala polymorphisms might be associated with insulin resistance and obesity, and there might be slight synergistic effects between this two gene loci,and further studies are necessary to confirm this finding.

  14. The beta2 adrenergic receptor Gln27Glu polymorphism affects insulin resistance in patients with heart failure: possible modulation by choice of beta blocker. (United States)

    Vardeny, Orly; Detry, Michelle A; Moran, John J M; Johnson, Maryl R; Sweitzer, Nancy K


    Insulin resistance is prevalent in heart failure (HF) patients, and beta2 adrenergic receptors (beta2-AR) are involved in glucose homeostasis. We hypothesized that beta2-AR Gln27Glu and Arg16Gly polymorphisms affect insulin resistance in HF patients, and we explored if effects of beta2-AR polymorphisms on glucose handling are modified by choice of beta blocker. We studied 30 nondiabetic adults with HF and a history of systolic dysfunction; 15 were receiving metoprolol succinate, and 15 were receiving carvedilol. We measured fasting glucose, insulin, and insulin resistance, and we determined beta2-AR genotypes at codons 27 and 16. The cohort was insulin resistant with a mean HOMA-IR score of 3.4 (95% CI, 2.3 to 4.5; normal value, 1.0). Patients with the Glu27Glu genotype exhibited higher insulin and HOMA-IR compared to individuals carrying a Gln allele (P = 0.019). Patients taking carvedilol demonstrated lower insulin resistance if also carrying a wild-type allele at codon 27 (fasting insulin, 9.8 +/- 10.5 versus 20.5 +/- 2.1 for variant, P = 0.072; HOMA-IR, 2.4 +/- 2.7 versus 5.1 +/- 0.6, P = 0.074); those on metoprolol succinate had high insulin resistance irrespective of genotype. The beta2-AR Glu27Glu genotype may be associated with higher insulin concentrations and insulin resistance in patients with HF. Future studies are needed to confirm whether treatment with carvedilol may be associated with decreased insulin and insulin resistance in beta2-AR codon 27 Gln carriers.


    Directory of Open Access Journals (Sweden)

    S. Iu. Nikulina


    Full Text Available Aim. To study the association of the hereditary sick sinus syndrome (SSS with gene α2B-adrenergic receptor (ADRA2B polymorphism.Material and methods. 29 families with hereditary primary SSS from the database of the Chair of Therapy № 1 of Krasnoyarsk State Medical University named after prof. V.F. Voyno-Yasenetsky were included in the study. Group 1 included probands (20 women and 9 men, 58±0.15 y.o., group 2 – proband relatives of I, II and III degree (65 males and 68 females, 39±0.13 y.o., group 3 (control — 89 healthy volunteers. Clinical examination (physical examination, ECG, bicycle ergometry, ECG monitoring, atropine test, electrophysiological study, echocardiography was performed in all probands and their relatives. The diagnosis of SSS was confirmed by transesophageal left atrium stimulation in 75 individuals. Genotypic examination of gene ADRA2B I/D polymorphism was performed in 213 individuals: 75 SSS-patients, 49 their healthy relatives, 89 healthy volunteers.Results. 3 types of ADRA2B genotypes (II — homozygous wild, ID — heterozygous, DD — homozygous mutant were founded by allele-specific polymerase chain reaction. Significant prevalence of the homozygous genotype of more rare alleles DD in SSS-patients (28±5.2% compared to the control group (8.99±3.0% was found.Conclusion. Study of the genetic marker can be used to identify predisposition to hereditary SSS in the population and individual-family level. SSS due to mutations in genes that regulate cell function of sinus node and the sinoatrial conduct occurs, apparently, extremely rarely.

  16. The Gln27Glu Polymorphism in β2-Adrenergic receptor gene is linked to hypertriglyceridemia, hyperinsulinemia and hyperleptinemia in Saudis

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    Daghestani Maha H


    Full Text Available Abstract Background β2-adrenoceptor (β2AR gene polymorphism glutamine 27 glutamic acid (Gln27Glu and Arg16Gly were reported to have an association with obesity and obesity related disorders in some population. We evaluated Gln27Glu polymorphism in the β2AR gene in obese Saudi populations to investigate the association of β2AR gene with obesity and other related metabolic parameters. Design We studied possible association of Gln27Glu in β2AR gene with body mass index (BMI, anthropometric measurements and other metabolic parameters. The β2AR gene polymorphism (Gln27Glu was identified by sequencing PCR products representing locus of interest. Based on BMI, the subjects were divided into three groups, normal weight, overweight and obese. The genotype and allele frequency were calculated separately for each group. Results The allelic frequency of Glu27 did not differ amongst the three groups, though the Glu27 homozygote (Glu/Glu were more in obese subjects and had higher concentration of triglyceride, leptin and insulin compared to in the Gln27 heterozygotes and Gln/Gln homozygotes. Conclusions In this study we were able to provide evidence on the influence of Gln27Glu genetic variant of β2AR gene on lipid phenotypes, insulin and leptin levels in the Saudi populations.

  17. Association analysis of the beta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urate and gout. (United States)

    Fatima, Tahzeeb; Altaf, Sara; Phipps-Green, Amanda; Topless, Ruth; Flynn, Tanya J; Stamp, Lisa K; Dalbeth, Nicola; Merriman, Tony R


    The Arg64 allele of variant rs4994 (Trp64Arg) in the β3-adrenergic receptor gene has been associated with increased serum urate and risk of gout. Our objective was to investigate the relationship of rs4994 with serum urate and gout in New Zealand European, Māori and Pacific subjects. A total of 1730 clinically ascertained gout cases and 2145 controls were genotyped for rs4994 by Taqman(®). Māori and Pacific subjects were subdivided into Eastern Polynesian (EP) and Western Polynesian (WP) sample sets. Publicly available genotype data from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study were utilized for serum urate association analysis. Multivariate logistic and linear regression adjusted for potential confounders was carried out using R version 2.15.2. No significant association of the minor Arg64 (G) allele of rs4994 with gout was found in the combined Polynesian cohorts (OR = 0.98, P = 0.88), although there was evidence, after adjustment for renal disease, for association in both the WP (OR = 0.53, P = 0.03) and the lower Polynesian ancestry EP sample sets (OR = 1.86, P = 0.05). There was no evidence for association with gout in the European sample set (OR = 1.11, P = 0.57). However, the Arg64 allele was positively associated with urate in the WP data set (β = 0.036, P = 0.004, P Corrected = 0.032). Association of the Arg64 variant with increased urate in the WP sample set was consistent with the previous literature, although the protective effect of this variant with gout in WP was inconsistent. This association provides an etiological link between metabolic syndrome components and urate homeostasis.

  18. Association of beta-adrenergic receptor polymorphisms and mortality in carvedilol-treated chronic heart-failure patients

    DEFF Research Database (Denmark)

    Petersen, Morten; Andersen, Jon T; Hjelvang, Brian R


    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Chronic heart failure (HF) is a syndrome with increasing prevalence. Though mortality is still high, the introduction of ß-adrenoceptor blockers for its treatment has improved survival considerably. • As is the case for all medical treatment, not all...... patients benefit from ß-adrenoceptor blocker treatment, and stratifying patients to different ß-adrenoceptor blockers by the use of pharmacogenomics might be of great value in improving HF therapy. • Previous studies have shown that the two single nucleotide polymorphisms (SNPs) ADRB1 Arg389Gly and ADRB2...... Gln27Glu interact with the ß-adrenoceptor blockers metoprolol and carvedilol, respectively. These interactions have led to stratified responses with regard to surrogate parameters, e.g. left ventricular ejection fraction (LVEF), pulse and blood pressure. • Several studies have failed to show...

  19. Association of β-adrenergic receptor genes polymorphisms with incidence of subsequent cardiovascular events in Han Chinese patients with coronary artery disease

    Institute of Scientific and Technical Information of China (English)

    LI Zhi-gen; WU Hong; ZHOU Ying-ling; CHEN Zhu-jun; MENG Jin-xiu; YANG Jun-qing; CHEN Ji-yan


    Background Sequence variants in the β-adrenergic receptor (ADRB) genes have a close relationship with the development of coronary artery disease (CAD) and the patient's prognosis.However,there is a lack of data on the role of the variants in ADRBs genes in Han Chinese patients with CAD.We aimed to investigate the association of genetic variants in the ADRB1 and ADRB2 genes with the incidence of major adverse cardiac event (MACE) in Han Chinese patients with CAD.Methods A total of 545 Han Chinese patients with CAD undergoing percutaneous coronary intervention (PCI) were recruited to the study and followed for one year.Three variant sites in ADRB1 (rs1801253) and ADRB2 (rs1042713 and rs1042714) were genotyped.The effect of the ADRB1 and ADRB2 genotypes on MACE within one year was assessed.Results There were 47 cases of MACE during follow-up.There was no significant difference in the incidence of MACE among patients carrying different genotypes of the three variants in ADRB1 and ADRB2 (Log-rank,all P >0.05).Cox regression analysis showed no association between three variants in ADRB1 and ADRB2 genes and the incidence of MACE during one-year follow-up,the adjusted hazard ratios (95% confidence interval) for rs1801253,rs1042713 and rs1042714 were 1.05 (0.54-2.02),1.24 (0.58-2.64) and 1.66 (0.81-3.42),respectively.Conclusion Our data did not support a relationship between the three polymorphisms of ADRB1 (rs1801253) and ADRB2 (rs1042713 and rs1042714) genes and risk of subsequent cardiovascular events after PCI in Han Chinese patients with CAD.

  20. Association of β1 and β3 adrenergic receptors gene polymorphisms with insulin resistance and high lipid profiles related to type 2 diabetes and metabolic syndrome

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    Ana I. Burguete-García


    Full Text Available Background: Among the diverse genes associated to type 2 diabetes (T2D, the β-adrenergic receptors are an excellent candidate to study in Mexican population. The objective of this work was to analyze the association of polymorphisms in ADRB1 (rs1801253 (Arg389Gly and ADRB3 (Trp64Arg genes with T2D and metabolic syndrome (MS. Methods: We studied 445 MS patients, 502 with T2D and 552 healthy controls. Anthropometric features and complete biochemical profile were evaluated, and Arg389Gly and Trp64Arg SNPs were determined by TaqMan assays. Data analysis was adjusted by African, Caucasian and Amerindian ancestral percentage. Results: The variant Arg389Gly of ADRB1 was statistically associated with an increase of LDL levels (P < 0.008, and the variant ADRB3 Trp64Arg was associated to larger HOMA-IR (P < 0.018 and with an increase of insulin levels (P < 0.001. A multiple logistic regression analysis was made in three grouping models: For ADRB3 in the codominant model Trp/Arg genotype, there was an OR of 1.53 (1.09-2.13, P < 0.003 which was increased up to OR 2.99 (1.44-6.22, P < 0.003 for the Arg/Arg genotype. Similar risk association was found under the dominant model Trp/Arg-Arg/Arg genotype with OR 1.67 (1.21-2.30; P < 0.002. In the recessive model (Arg/Arg genotype, there was also a high association OR 2.56 (1.24-5.26, P < 0.01. Conclusions: The ADRB3 Trp64Arg variant is a susceptibility gene polymorphism for T2D and the ADRB1 Gly389Arg for lipid metabolism disruption. These results show that these variants are potential biomarkers for predicting metabolic alterations and evolution in diabetic and metabolic syndrome patients.

  1. Adrenergic pathways in dopamine modulation of K+ transport in cortex slices after low dose X-Rays

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    Kulikova, I.A.; Dvoretsky, A.I. [Laboratoire of Radiobiology et Radioecology, Science Research Institute of Biology, Dnipropetrovsk State University (Ukraine)


    Using the method of surviving brain cortex slices it has been shown that prolonged whole body acute or chronic 25 cGy X-irradiation (1 cGy/day at dose rate of 2.22 mGy/min) essentially modified dopamine (DA) modulating influence upon Na, K-pump in nervous tissue. Obtained results pointed to that normally DA had the defined biphasic effect upon active K{sup +} transport with lower level activation (by 24.0 %) and higher level inhibition (by 42.1 %). The patterns of the Na,K-pump reaction to DA was not changed after irradiation, but percentage of the total DA suppression was increased by 15.1 % in average after single X-ray exposure and by 34.5 % after chronic one. The decisive role of {beta}-adrenergic mechanisms in realization of postirradiation interaction between systems of catecholamine and active K{sup +} transfer across neuronal membrane has been determined. Experimental data obtained with the use of 10 {mu}M phentolamine and 10 {mu}M propranolol, respectively {alpha}- and {beta}-adrenergic antagonists, supported that metabolic DA effect was mediated via {alpha}-AR normally, and via {beta}-AR after low dose-rate irradiation. (authors)

  2. Moxonidine, an antihypertensive agent, is permissive to alpha1-adrenergic receptor pathway in the rat-tail artery. (United States)

    George, Oommen K; Gonzalez, Ramon R; Edwards, Lincoln P


    To investigate whether alpha1-adrenergic receptors were involved in the contractile response of tail arteries to moxonidine, isolated ring segments of tail arteries from male adult Sprague-Dawley rats were studied. Moxonidine (EC50 = 1.3 microM) and the alpha1-agonist phenylephrine (EC50 = 2.5 microM) increased tension development in the rat-tail artery similarly. The response to moxonidine (1 microM) could be blocked by both alpha1-adrenoceptor blockers prazosin (IC50 = 1 nM), and urapidil (IC50 = 14 nM), and also by alpha2-adrenoceptor blockers, yohimbine (IC50 = 49 nM) and efaroxan (IC50 = 49 nM). Combination drug treatment (urapidil and yohimbine, or yohimbine and prazosin) was more effective in blocking the contractile response to moxonidine, than treatment with prazosin or urapidil alone. Comparison of pA2 values for prazosin in the presence of moxonidine (9.35) or phenylephrine (10.2) confirm that alpha1-adrenergic receptors are involved in the contractile response of rat-tail artery to moxonidine.

  3. Studies of associations between the Arg389Gly polymorphism of the beta1-adrenergic receptor gene (ADRB1) and hypertension and obesity in 7677 Danish white subjects

    DEFF Research Database (Denmark)

    Gjesing, A P; Andersen, G; Albrechtsen, A;


    Activation of the beta(1)-adrenergic receptor (ADRB1) causes increased lipolysis in adipose tissue and enhances cardiac output. Analysis of the association of the functional ADRB1 Arg389Gly variant with obesity and hypertension has given ambiguous results. To clarify the potential impact...

  4. Exercise does not activate the β3 adrenergic receptor-eNOS pathway, but reduces inducible NOS expression to protect the heart of obese diabetic mice. (United States)

    Kleindienst, Adrien; Battault, Sylvain; Belaidi, Elise; Tanguy, Stephane; Rosselin, Marie; Boulghobra, Doria; Meyer, Gregory; Gayrard, Sandrine; Walther, Guillaume; Geny, Bernard; Durand, Gregory; Cazorla, Olivier; Reboul, Cyril


    Obesity and diabetes are associated with higher cardiac vulnerability to ischemia-reperfusion (IR). The cardioprotective effect of regular exercise has been attributed to β3-adrenergic receptor (β3AR) stimulation and increased endothelial nitric oxide synthase (eNOS) activation. Here, we evaluated the role of the β3AR-eNOS pathway and NOS isoforms in exercise-induced cardioprotection of C57Bl6 mice fed with high fat and sucrose diet (HFS) for 12 weeks and subjected or not to exercise training during the last 4 weeks (HFS-Ex). HFS animals were more sensitive to in vivo and ex vivo IR injuries than control (normal diet) and HFS-Ex mice. Cardioprotection in HFS-Ex mice was not associated with increased myocardial eNOS activation and NO metabolites storage, possibly due to the β3AR-eNOS pathway functional loss in their heart. Indeed, a selective β3AR agonist (BRL37344) increased eNOS activation and had a protective effect against IR in control, but not in HFS hearts. Moreover, iNOS expression, nitro-oxidative stress (protein s-nitrosylation and nitrotyrosination) and ROS production during early reperfusion were increased in HFS, but not in control mice. Exercise normalized iNOS level and reduced protein s-nitrosylation, nitrotyrosination and ROS production in HFS-Ex hearts during early reperfusion. The iNOS inhibitor 1400 W reduced in vivo infarct size in HFS mice to control levels, supporting the potential role of iNOS normalization in the cardioprotective effects of exercise training in HFS-Ex mice. Although the β3AR-eNOS pathway is defective in the heart of HFS mice, regular exercise can protect their heart against IR by reducing iNOS expression and nitro-oxidative stress.

  5. [Research advances in gene polymorphisms in biological pathways of drugs for asthma]. (United States)

    Guo, Dan-Dan; Zheng, Xiang-Rong


    The studies on gene polymorphisms in biological pathways of the drugs for the treatment of asthma refer to the studies in which pharmacogenetic methods, such as genome-wide association studies, candidate gene studies, genome sequencing, admixture mapping analysis, and linkage disequilibrium, are used to identify, determine, and repeatedly validate the effect of one or more single nucleotide polymorphisms on the efficacy of drugs. This can provide therapeutic strategies with optimal benefits, least side effects, and lowest costs to patients with asthma, and thus realize individualized medicine. The common drugs for asthma are β2 receptor agonists, glucocorticoids, and leukotriene modifiers. This article reviews the research achievements in polymorphisms in biological pathways of the common drugs for asthma, hoping to provide guidance for pharmacogenetic studies on asthma in future and realize individualized medicine for patients with asthma soon.

  6. An association study between polymorphisms in five genes in glutamate and GABA pathway and paranoid schizophrenia. (United States)

    Zhang, Boyu; Yuan, Yanbo; Jia, Yanbin; Yu, Xin; Xu, Qi; Shen, Yucun; Shen, Yan


    Dysfunctions of glutamatergic and GABAergic neurotransmission are two important hypotheses for the pathogenesis of schizophrenia. Thus, genes in the pathway are candidates for schizophrenia susceptibility. Phosphate-activated glutaminase (GLS), glutamine synthetase (GLUL), glutamic acid decarboxylase (GAD), GABA transaminase (ABAT) and succinic semialdehyde dehydrogenase (ALDH5A1) are five primary enzymes in glutamate and GABA synthetic and degradative pathway. In order to investigate the possible involvement of these genes in the development of paranoid schizophrenia, we genotyped 80 paranoid schizophrenics from northern China and 108 matched controls by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) methods or directly sequencing of PCR product. Seven SNPs were found to be polymorphic in the population investigated. No significant differences in the genotype distributions or allele frequencies between patients and controls were found. Therefore, we conclude the polymorphisms studied in the five genes do not play major roles in pathogenesis of paranoid schizophrenia in the population investigated.

  7. Association between essential hypertension and polymorphisms of beta 1 adrenergic receptor gene G1165C (Gly389Arg) in Chinese Mongolian population

    Institute of Scientific and Technical Information of China (English)

    Rile Hu; Shigang Zhao; Guangming Niu; Chunyu Zhang; Zhiguang Wang; Mingfang Jiang


    BACKGROUND: The prevalences of hypertension, cerebrovascular diseases, etc. are higher in Mongolian population because of the influence of various factors including genetics, geography, diet, etc. Therefore, it is helpful to develop researches on the genetics of various diseases including hypertension in Mongolian population.OBJECTIVE: To analyze the association between the polymorphism of beta1 adrenergic receptor (β1-AR)gene G1165C (Arg389Gly), an important candidate gene for various diseases of cardiovascular system, and essential hypertension in Mongolian population.DESIGN: A cross-sectional study.SETTINGS: Department of Neurology, the First Affiliated Hospital of Inner Mongolia Medical College; Wulate Houqi Red Cross Society.PARTICIPANTS: The survey was carried out from February 2003 to March 2005. Totally 239 Mongolian residents, whose blood relations of 3 generations were all Mongolians, were selected from Wulate Houqi, Inner Mongolia, and they were all informed with the survey and detected items. Based on the diagnostic standard of hypertension set by WHO in 1999, the subjects were divided into two groups according to the level blood pressure: ① Normal blood pressure group (n=117): systolic blood pressure (SBP) < 140 mm Hg (1 mm Hg =0.133 kPa), diastolic blood pressure (DBP) < 90 mm Hg, and those having histories of cerebrovascular disease, heart disease, diseases of liver, kidney and tiroides, and diabetes mellitus were excluded. ② Essential hypertension group (n=122): including 51 patients with simple high SBP. All the enrolled subjects had no blood relationship with each other, and had no history of miscegenation.METHODS: The body height, body mass, waist circumference and blood lipids were measured routinely, and their habits of smoking and drinking were also investigated. Peripheral venous blood (5 mL) was drawn, the genome DNA was extracted, and the polymorphisms of the β1-AR G1165C (Gly389Arg) genotype were detected with the Sequenom system

  8. β3 肾上腺能受体基因多态性分析及其初步应用%β3- adrenergic receptor gene polymorphism analysis and application

    Institute of Scientific and Technical Information of China (English)


    Objective: To investigate the effect of β3- adrenergic receptor gene polymorphism on obesity and insulin resistance. Methods: With PCR - RFLP and PCR - dideoxy - chain - termination method of DNA sequencing, we investigated the influence of the β3- adrenergic receptor gene polymorphism on obesity, insulin resistance and lipid profile in native Chinese. Results: β3- AR 190 T→C mutation was detected among 48 diabetic patients and 32 volunteers. Conclusion:This genetic variation is likely to be involved in early onset of Type 2 diabetes. But it's not the major factor affecting on obesity and dyslipidemia.%建立 β3- 肾上腺能受体基因多态性检测方法,了解其表型特征。方法:应用 PCR-限制性片段长度多态性和 PCR-双脱氧链终止法测序技术分析 β3- 肾上腺能受体(β3-AR)基因型。结果:48 例北方汉族糖尿病人和 32 例正常对照者中均存在 β3-AR 基因 190 位 T→C 的单碱基变异,两组人群中基因型的构成比例无显著差异。结论:Arg64Arg 纯合子可能具有糖尿病早发的特点,但 β3-AR 基因不是造成肥胖、脂质紊乱的主要决定因素。

  9. Relation between sonic hedgehog pathway gene polymorphisms and basal cell carcinoma development in the Polish population. (United States)

    Lesiak, Aleksandra; Sobolewska-Sztychny, Dorota; Majak, Paweł; Sobjanek, Michał; Wodz, Karolina; Sygut, Karolina Przybyłowska-; Majsterek, Ireneusz; Wozniacka, Anna; Narbutt, Joanna


    In recent decades, increases have been observed in the incidence of nonmelanoma skin cancers, including basal cell carcinoma (BCC) and squamous cell carcinoma. BCC is the most common neoplasm in Caucasian populations. Sonic hedgehog (Shh) pathway impairment plays a key role in BCC pathogenesis, and there is evidence that Shh pathway genetic variations may predispose to BCC development. We genotyped 22 single-nucleotide polymorphisms (SNPs) in 4 Shh pathway genes: SHH, GLI, SMO, and PTCH. The study group consisted of 142 BCC patients and 142 age-matched, sex-matched healthy subjects (controls). SNPs were assessed using the PCR-RFLP method. The genotype distribution for the polymorphisms in the rs104894049 331 A/T SHH, rs104894040 349 T/C SHH, and rs41303402 385 G/A SMO genes differed significantly between the BCC patients and the controls. The presence of CC genotype in the SHH rs104894040 349 T/C polymorphism was linked to the highest risk of BCC development (OR 87.9, p < 0.001). Other genotypes, such as the TT in SHH rs104894049 331 A/T and the GG in SMO rs41303402 385 G/A also statistically raised the risk of BCC, but these associations were weaker. Other investigated polymorphisms showed no statistical differences between patients and controls. The results obtained testify to the importance of the SHH and SMO gene polymorphisms in skin cancerogenesis. These results mainly underline the potential role of SHH3 rs104894040 349 T/C gene polymorphism in the development of skin basal cell carcinomas in patients of Polish origin.

  10. Validation of microRNA pathway polymorphisms in esophageal adenocarcinoma survival. (United States)

    Faluyi, Olusola O; Eng, Lawson; Qiu, Xin; Che, Jiahua; Zhang, Qihuang; Cheng, Dangxiao; Ying, Nanjiao; Tse, Alvina; Kuang, Qin; Dodbiba, Lorin; Renouf, Daniel J; Marsh, Sharon; Savas, Sevtap; Mackay, Helen J; Knox, Jennifer J; Darling, Gail E; Wong, Rebecca K S; Xu, Wei; Azad, Abul Kalam; Liu, Geoffrey


    Polymorphisms in miRNA and miRNA pathway genes have been previously associated with cancer risk and outcome, but have not been studied in esophageal adenocarcinoma outcomes. Here, we evaluate candidate miRNA pathway polymorphisms in esophageal adenocarcinoma prognosis and attempt to validate them in an independent cohort of esophageal adenocarcinoma patients. Among 231 esophageal adenocarcinoma patients of all stages/treatment plans, 38 candidate genetic polymorphisms (17 biogenesis, 9 miRNA targets, 5 pri-miRNA, 7 pre-miRNA) were genotyped and analyzed. Cox proportional hazard models adjusted for sociodemographic and clinicopathological covariates helped assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then evaluated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis, and median OS and PFS were 20 and 12 months, respectively. GEMIN3 rs197412 (aHR = 1.37, 95%CI: [1.04-1.80]; P = 0.02), hsa-mir-124-1 rs531564 (aHR = 0.60, 95% CI: [0.53-0.90]; P = 0.05), and KIAA0423 rs1053667 (aHR = 0.51, 95% CI: [0.28-0.96]; P = 0.04) were found associated with OS. Furthermore, GEMIN3 rs197412 (aHR = 1.33, 95% CI: [1.03-1.74]; P = 0.03) and KRT81 rs3660 (aHR = 1.29, 95% CI: [1.01-1.64]; P = 0.04) were found associated with PFS. Although none of these polymorphisms were significant in the second cohort, hsa-mir-124-1 rs531564 and KIAA0423 rs1053667 had trends in the same direction; when both cohorts were combined together, GEMIN3 rs197412, hsa-mir-124-1 rs531564, and KIAA0423 rs1053667 remained significantly associated with OS. We demonstrate the association of multiple miRNA pathway polymorphisms with esophageal adenocarcinoma prognosis in a discovery cohort of patients, which did not validate in a separate cohort

  11. Discovery and validation of vascular endothelial growth factor (VEGF) pathway polymorphisms in esophageal adenocarcinoma outcome. (United States)

    Eng, Lawson; Azad, Abul Kalam; Qiu, Xin; Kong, Qin Quinn; Cheng, Dangxiao; Ying, Nanjiao; Tse, Alvina; Kuang, Qin; Dodbiba, Lorin; Renouf, Daniel J; Marsh, Sharon; Savas, Sevtap; Mackay, Helen J; Knox, Jennifer J; Darling, Gail E; Wong, Rebecca K S; Xu, Wei; Liu, Geoffrey; Faluyi, Olusola O


    Polymorphisms in the vascular endothelial growth factor (VEGF)/angiogenesis pathway have been implicated previously in cancer risk, prognosis and response to therapy including in esophageal adenocarcinoma. Prior esophageal adenocarcinoma studies focused on using candidate polymorphisms, limiting the discovery of novel polymorphisms. Here, we applied the tagSNP (single nucleotide polymorphism) approach to identify new VEGF pathway polymorphisms associated with esophageal adenocarcinoma prognosis and validated them in an independent cohort of esophageal adenocarcinoma patients. In 231 esophageal adenocarcinoma patients of all stages/treatment plans, 58 genetic polymorphisms (18 KDR, 7 VEGFA and 33 FLT1) selected through tagging and assessment of predicted function were genotyped. Cox-proportional hazard models adjusted for important socio-demographic and clinico-pathological factors were applied to assess the association of genetic polymorphisms with overall survival (OS) and progression-free survival (PFS). Significantly associated polymorphisms were then validated in an independent cohort of 137 esophageal adenocarcinoma patients. Among the 231 discovery cohort patients, 86% were male, median diagnosis age was 64 years, 34% were metastatic at diagnosis and median OS and PFS were 20 and 12 months, respectively. KDR rs17709898 was found significantly associated with PFS (adjusted hazard ratio, aHR = 0.69, 95% confidence interval (CI): 0.53-0.90; P = 5.9E-3). FLT1 rs3794405 and rs678714 were significantly associated with OS (aHR = 1.44, 95% CI: 1.04-1.99; P = 0.03 and aHR = 1.50, 95% CI: 1.01-2.24; P = 0.045, respectively). No VEGFA polymorphisms were found significantly associated with either outcome. Upon validation, FLT1 rs3794405 remained strongly associated with OS (aHR = 1.59, 95% CI: 1.04-2.44; P = 0.03). FLT1 rs3794405 is significantly associated with OS in esophageal adenocarcinoma, whereby each variant allele confers a 45-60% increased risk of mortality

  12. Evidence for activation of both adrenergic and cholinergic nervous pathways by yohimbine, an alpha 2-adrenoceptor antagonist. (United States)

    Bagheri, H; Chale, J J; Guyen, L N; Tran, M A; Berlan, M; Montastruc, J L


    Adrenoceptors are involved in the control of the activity of the autonomic nervous system and especially the sympathetic nervous system. Activation of alpha 2-adrenoceptors decreases sympathetic tone whereas their blockade has an opposite effect. However, previous investigations have shown that yohimbine (a potent alpha 2-adrenoceptor antagonist) increases salivary secretion through activation of cholinergic pathways. The aim of the present experiment was to investigate the involvement of both the sympathetic and the parasympathetic system in several pharmacological effects of yohimbine. For this purpose, salivary secretion and various endocrino-metabolic parameters (noradrenaline and insulin secretions, lipomobilization) were evaluated in conscious fasting dogs before and after blockade of either the sympathetic (with the beta-adrenoceptor antagonist agent nadolol) or the parasympathetic (with the anticholinergic agent atropine) systems. Yohimbine alone (0.4, i.v.) increased within 5-15 minutes, plasma noradrenaline (600%), insulin levels (300%), free-fatty acids (79%) and salivary secretion (143%). Atropine (0.2, i.v.) suppressed yohimbine-induced salivary secretion (90%) but did not significantly modify the yohimbine induced changes in noradrenaline (312%), insulin (277%) and free-fatty acids (102%) plasma levels. Administration of nadolol (1, i.v.) did not change the magnitude of the increase in both noradrenaline plasma levels (550%) and salivary secretion (300%) induced by yohimbine. However, nadolol totally blunted the increase in insulin (15%) and free-fatty acids (4%) plasma levels. These results show that yohimbine-induced increase in salivary secretion is a cholinergic effect whereas the increase in insulin and free fatty acids can be explained by an increase in sympathetic tone.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Polymorphisms in serotonergic pathways influence the outcome of antidepressant therapy in psychiatric inpatients. (United States)

    Staeker, Julia; Leucht, Stefan; Laika, Barbara; Steimer, Werner


    Serotonergic pathways are known to play an essential role in the effects generated by antidepressants. Polymorphisms in serotonin receptor and transporter genes have been identified as an important factor. To investigate which of these polymorphisms may be useful to predict clinical outcome, we assessed their effect in a naturalistic clinical study. We studied the influence of the 5-hydroxytryptamine transporter (5-HTT) variable number of tandem repeats (VNTR), 5-HTTLPR/rs25531 and a 5-HTR2A intron 2 SNP with regard to response and side effects in 273 psychiatric inpatients. Main clinical assessments included Clinical Global Impressions ratings, paranoid depression scale self-rating scale and Dosage Record, and Treatment Emergent Symptoms (DOTES) Scale. We found significant associations between 5-HTTLPR/rs25531 S/L(G) alleles and response and side effects in 100 patients with selective serotonin reuptake inhibitor (SSRI) treatment (p = 0.037, CGI-I ≤ 2: 0% vs. 19% and p = 0.0005, DOTES cluster c: 0.76 vs. 0.19). 5-HTT VNTR and 5-HTR2A intron 2 polymorphisms were associated significantly with adverse effects in patients with selective and nonselective SRI (5-HTT VNTR 12/12: n = 170, p = 0.0001, side effect rates: 51% vs. 19% and rs7997012 [A/A]: n = 50, p = 0.020, side effects rates: 43% vs. 11%). No impact of the polymorphisms on mirtazapine treatment was found. Our study confirms the influence of serotonergic polymorphisms at the receptor and transporter level on SSRI response and side effects, supporting previous reports based on various study designs. The effects were strong enough to be noticed clinically in this naturalistic setting. However, randomized controlled trials are warranted to provide unequivocal evidence of the clinical usefulness of pretherapeutic screening for these polymorphisms.

  14. [Polymorphisms of 2B-adrenergic receptor and endothelial NO-Synthase genes in genesis of the hereditary sick sinus node syndrome]. (United States)

    Chernova, A A; Nikulina, S Iu; Shul'man, V A; Kukushkina, T S; Voevoda, M I; Maksimov, V N


    In this work we have demonstrated for the first time on the clinico-genetic material association between hereditary sick sinus node syndrome (SSNS) ADRA2B and eNOS genes polymorphisms. We have established predominance of homozygote genotype of more rare DD allele in patients with SSNS (28%) compared with subjects of control group (8.99%). We have found predominance of heterozygote genotype 4a/4b in patients with SSNS compared with subjects of control group (41.8 and 25.39%, respectively). The data obtained allow to suggest that eNOS gene polymorphism might be associated with SSNS.

  15. Association of polymorphism in cell death pathway gene FASLG withhuman male infertility

    Institute of Scientific and Technical Information of China (English)

    Deepika Jaiswal; Sameer Trivedi; Neeraj K Agrawal; Kiran Singh


    Objective: To investigate –844C>T single nucleotide polymorphism (SNP) present in the promoter of cell death pathway gene FASLG with male infertile phenotype. Methods:Genotyping for SNP FASLG (rs763110) was done by polymerase chain reaction followed by analysis with specific endonuclease (PCR-RFLP). DNA sequencing was used to ascertain PCR-RFLP results. Results: FASLG –844C>T polymorphism, allele and genotype distribution did not differ significantly between patients and controls (OR: 1.03, 95% CI= 0.7638 to 1.3952, P=0.83). Thus SNP-844C>T of the FASLG gene is not associated with male infertility risk in the analyzed patients. Conclusion: Human male infertility is a complex disorder and thus other genetic or environmental factors may be contributing to the complex etiology, and further study in other region of Indian populations will verify whether it is associated with male infertility risk.

  16. Association of the beta3-adrenergic receptor Trp64Arg polymorphism with common metabolic traits: studies of 7605 middle-aged white people

    DEFF Research Database (Denmark)

    Gjesing, A. P.; Andersen, G; Borch-Johnsen, K;


    of type 2 diabetes and obesity in a relatively large, homogenous study population. METHODS: The Trp64Arg polymorphism was genotyped in 7605 Danish subjects using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Association was examined in case-control studies of obesity (1529...... cases and 6049 controls) and type 2 diabetes (1373 cases and 4742 controls) and quantitative trait analyses among 5822 individuals. Furthermore, the association of Trp64Arg with type 2 diabetes was examined in a meta-analysis. RESULTS: The Trp64Arg polymorphism was not associated with obesity. However...... (p=0.02). After sex stratification these associations were only present among women. Furthermore, the Arg-allele was borderline associated with type 2 diabetes in a meta-analysis of the present and 26 previous studies (p=0.06, OR1.27 (CI: 0.99-1.63)) (n=18891). CONCLUSION/INTERPRETATION: Trp64Arg...

  17. Polymorphisms of catechol estrogens metabolism pathway genes and breast cancer risk in Mexican women. (United States)

    Martínez-Ramírez, O C; Pérez-Morales, R; Castro, C; Flores-Díaz, A; Soto-Cruz, K E; Astorga-Ramos, A; Gonsebatt, M E; Casas, L; Valdés-Flores, M; Rubio, J


    Breast cancer is associated to estrogen exposure. Allelic variants involved in estrogen metabolism might change the risk of developing this neoplasia. We examined the potential association of breast cancer risk in Mexican women with the polymorphisms CYP1A1 rs1048943, CYP1B1 rs1056836, COMT rs4680, GSTP1 rs1695, GSTT1 null and GSTM1 null which are involved in estrogen metabolism pathway. This study included 150 cases and 150 controls. A significant association was observed between, CYP1A1 rs1048943 (OR = 1.95, C.I. 1.13-3.36) and GSTP1 rs1695 (OR = 2.39, C.I. 1.24-4.24) polymorphisms with the risk of breast cancer. This risk was increased when the women were stratified according to their menopausal status. The results show that breast cancer risk significantly increases in women with 3-6 risk polymorphisms (OR = 3.75, C.I. 1.44-9.74).

  18. Effect of genetic polymorphisms in the folate pathway on methotrexate therapy in rheumatic diseases. (United States)

    Stamp, Lisa K; Roberts, Rebecca L


    Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis and is frequently used in the management of other forms of inflammatory arthritis. It is currently challenging to predict which patients will achieve adequate disease control and which patients will develop adverse effects while taking MTX. As an analog of dihydrofolic acid, MTX enters cells through the reduced folate carrier-1 protein, and is polyglutamated. MTX polyglutamates inhibit key enzymes in the folate pathway to produce an anti-inflammatory effect. It has been suggested that genetic polymorphisms in the folate pathway may influence intracellular folate and MTX polyglutamates pools, and thus MTX response. However, studies to identify genetic predictors have yielded inconclusive results. Nonreplication across studies has been attributed to insufficient statistical power as well as pharmacological and clinical confounders. Prospective studies, standardizing the definitions of response and toxicity, and application of genome-wide approaches may advance the search for genetic predictors of MTX response.

  19. Association of Polymorphisms of β3—Adrenergic Receptor,Angiotensinogen and Angiotensin—Converting Enzyme Gene with Hypertension in type 2 DM

    Institute of Scientific and Technical Information of China (English)

    丁国宪; 沈捷; 等


    Objective To explore the relationship between the mutant genes of ACE,ATN,β3-AR and hypertension in patients with type 2DM.Methods 281 recruited Chinese subjects were divided into two groups according to the oral glucose tolerance test (OGTT):(1)non-diabetes group including normal and impaired glucose tolerance(NGT,IGT):169cases;(2)Type 2 diabetes mellitus(DM):112 cases.The subjects were genotyped for the ACE gene,the ATN gene and the codon 64 of β3-AR gene polymorphisms by applying polymerase chain reaction(PCR),PCR restriction fragment-length polymorphisms screening with the use of endonuclease.Results Our study found that the frequency of D/D genotype and D allele of ACE gene,a/a genotype and an allele of ATN gene in HT patients without DM were increased (P all<0.05);that the frequency of codon 64 mutation of β3-AR gene also increased in HT patients with NGT(P<0.05).In the model of multiple factors non-condition-al Logistic regression analyses,HT had relationship with history of hypertension,age and glucose tolerance(OR=10.7457,1.7804,2.0346;P=0.0004,0.0000,0.0246;respectively),with polymorphism of ATN gene,β3AR gene,ACE gene(OR=2.2736,1.9353,1.8309;P=0.0543,0.0287,0.0432;resceptively).Conclusion These results suggest that variants of ACE gene,β3AR gene,ATN gene were associated with HT in type 2 DM.

  20. Association of Polymorphisms of β3-Adrenergic Receptor,Angiotensinogen and Angiotensin-Converting Enzyme Gene with Hypertension in type 2 DM

    Institute of Scientific and Technical Information of China (English)

    丁国宪; 沈捷; 陈家伟


    ObjectiveTo explore the relationship between the mutant genes of ACE,ATN,β3-AR and hypertension in patients with type 2 DM.Methods281 recruited Chinese subjects were divided into two groups according to the mellitus (DM):112 cases.The subjects were genotyped for the ACE gene,the ATN gene and the codon 64 of β3-AR gene polymorphisms by applying polymerase chain reaction (PCR),PCR restriction fragment-length polymorphisms screening with the use of endonuclease.ResultsOur study found that the frequency of D/D genotype and D allele of ACE gene,a/a genotype and an allele of ATN gene in HT patients without DM were increased (P all <0.05);that the frequency of codon 64 mutation of β3-AR gene also increased in HT patients with NGT (P <0.05).In the model of multiple factors non-condition-al Logistic regression analyses,HT had relationship with history of hypertension,age and glucose tolerance (OR=10.745 7,1.780 4,2.034 6;P=0.000 4,0.000 0,0.024 6;respectively),with polymorphism of ATN gene,β3AR gene,ACE gene (OR=2.273 6,1.935 3,1.830 9;P=0.054 3,0.028 7,0.043 2;resceptively).ConclusionThese results suggest that variants of ACE gene,β3AR gene,ATN gene were associated with HT in type 2 DM.``

  1. Association of polymorphisms in genes involved in the dopaminergic pathway with blood pressure and uric acid levels in Chinese females. (United States)

    Yeh, Ting-Kuang; Yeh, Ting-Chi; Weng, Chi-Feng; Shih, Bing-Fu; Tsao, Hsueh-Jen; Hsiao, Chien-Hua; Chuang, Fu-Tai; Hu, Chung-Yi; Chang, Chun-Yen


    Since the high degree of heritability of physiological traits was demonstrated by twin and adoption studies, contemporary researchers in the fields of clinical medicine, behavioral science, and genetics have acknowledged the crucial role of genetic factors in human physiology. The study described herein explores the association between physiological parameters and the dopaminergic system using molecular genetic techniques. A total of 558 Taiwanese female volunteers, ranging from 16 to 17 years, were recruited. Single nucleotide polymorphisms in genes involved in the dopaminergic pathway were selected for analysis. Systolic blood pressure and diastolic blood pressure were associated significantly with the catechol-O-methyltransferase (COMT) Val158Met polymorphism and the dopamine β-hydroxylase (DBH) C1021T polymorphism. Furthermore, plasma uric acid was associated significantly with the COMT Val158Met polymorphism. Our study suggests the possible involvement of genetic polymorphisms in COMT and DBH in the regulation of blood pressure and plasma uric acid.

  2. Neurohumoral activation in heart failure: the role of adrenergic receptors

    Directory of Open Access Journals (Sweden)

    Patricia C. Brum


    Full Text Available Heart failure (HF is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.A insuficiência cardíaca (IC é a via final comum da maioria das doenças cardiovasculares e uma das maiores causas de morbi-mortalidade. O desenvolvimento do estágio final da IC freqüentemente envolve um insulto inicial do miocárdio, reduzindo o débito cardíaco e levando ao aumento compensatório da atividade do sistema nervoso simpático (SNS. Existem evidências de que apesar da exposição aguda ser benéfica, exposições crônicas a elevadas concentra

  3. Genetic polymorphisms in the nucleotide excision repair pathway and lung cancer risk: A meta-analysis

    Directory of Open Access Journals (Sweden)

    Chikako Kiyohara, Kouichi Yoshimasu


    Full Text Available Various DNA alterations can be caused by exposure to environmental and endogenous carcinogens. Most of these alterations, if not repaired, can result in genetic instability, mutagenesis and cell death. DNA repair mechanisms are important for maintaining DNA integrity and preventing carcinogenesis. Recent lung cancer studies have focused on identifying the effects of single nucleotide polymorphisms (SNPs in candidate genes, among which DNA repair genes are increasingly being studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. We identified a sufficient number of epidemiologic studies on lung cancer to conduct a meta-analysis for genetic polymorphisms in nucleotide excision repair pathway genes, focusing on xeroderma pigmentosum group A (XPA, excision repair cross complementing group 1 (ERCC1, ERCC2/XPD, ERCC4/XPF and ERCC5/XPG. We found an increased risk of lung cancer among subjects carrying the ERCC2 751Gln/Gln genotype (odds ratio (OR = 1.30, 95% confidence interval (CI = 1.14 - 1.49. We found a protective effect of the XPA 23G/G genotype (OR = 0.75, 95% CI = 0.59 - 0.95. Considering the data available, it can be conjectured that if there is any risk association between a single SNP and lung cancer, the risk fluctuation will probably be minimal. Advances in the identification of new polymorphisms and in high-throughput genotyping techniques will facilitate the analysis of multiple genes in multiple DNA repair pathways. Therefore, it is likely that the defining feature of future epidemiologic studies will be the simultaneous analysis of large samples.

  4. Relationship between human evolution and neurally mediated syncope disclosed by the polymorphic sites of the adrenergic receptor gene α2B-AR.

    Directory of Open Access Journals (Sweden)

    Tomoyoshi Komiyama

    Full Text Available The objective of this study was to clarify the effects of disease on neurally mediated syncope (NMS during an acute stress reaction. We analyzed the mechanism of the molecular interaction and the polymorphisms of the alpha-2 adrenoreceptor (α2B-AR gene as the potential psychiatric cause of incentive stress. We focused on the following three genotypes of the repeat polymorphism site at Glu 301-303 in the α2B-AR gene: Glu12/12, Glu12/9, and Glu9/9. On the basis of our clinical research, NMS is likely to occur in people with the Glu12/9 heterotype. To verify this, we assessed this relationship with the interaction of Gi protein and adenylate cyclase by in silico analysis of the Glu12/9 heterotype. By measuring the difference in the dissociation time of the Gi-α subunit twice, we found that the Glu12/9 heterotype suppressed the action of adenylate cyclase longer than the Glu homotypes. As this difference in the Glu repeat number effect is thought to be one of the causes of NMS, we investigated the evolutionary significance of the Glu repeat number. Glu8 was originally repeated in simians, while the Glu12 repeats occurred over time during the evolution of bipedalism in humans. Taken with the Glu12 numbers, NMS would likely become a defensive measure to prevent significant blood flow to the human brain.

  5. Polymorphisms of Insulin-Like Growth Factor 1 Pathway Genes and Breast Cancer Risk. (United States)

    Shi, Joy; Aronson, Kristan J; Grundy, Anne; Kobayashi, Lindsay C; Burstyn, Igor; Schuetz, Johanna M; Lohrisch, Caroline A; SenGupta, Sandip K; Lai, Agnes S; Brooks-Wilson, Angela; Spinelli, John J; Richardson, Harriet


    Genetic variants of insulin-like growth factor 1 (IGF1) pathway genes have been shown to be associated with breast density and IGF1 levels and, therefore, may also influence breast cancer risk via pro-survival signaling cascades. The aim of this study was to investigate associations between IGF1 pathway single nucleotide polymorphisms (SNPs) and breast cancer risk among European and East Asian women, and potential interactions with menopausal status and breast tumor subtype. Stratified analyses of 1,037 cases and 1,050 controls from a population-based case-control study were conducted to assess associations with breast cancer for 22 SNPs across 5 IGF1 pathway genes in European and East Asian women. Odds ratios were calculated using logistic regression in additive genetic models. Polytomous logistic regression was used to assess heterogeneity by breast tumor subtype. Two SNPs of the IGF1 gene (rs1019731 and rs12821878) were associated with breast cancer risk among European women. Four highly linked IGF1 SNPs (rs2288378, rs17727841, rs7136446, and rs7956547) were modified by menopausal status among East Asian women only and associated with postmenopausal breast cancers. The association between rs2288378 and breast cancer risk was also modified by breast tumor subtype among East Asian women. Several IGF1 polymorphisms were found to be associated with breast cancer risk and some of these associations were modified by menopausal status or breast tumor subtype. Such interactions should be considered when assessing the role of these variants in breast cancer etiology.

  6. Polymorphisms in genes involved in the estrogen pathway and mammographic density

    Directory of Open Access Journals (Sweden)

    Dumas Isabelle


    Full Text Available Abstract Background Single nucleotide polymorphisms (SNPs in genes involved in the estrogen pathway appear to be associated with breast cancer risk and possibly with mammographic density (MD, but little is known of these associations among premenopausal women. This study examines the association of 11 polymorphisms in five estrogen-related genes (estrogen receptors alpha and beta (ERα, ERβ, 17β-hydroxysteroid dehydrogenase 1 (HSD17B1, catechol-O-methyltransferase (COMT, cytochrome P450 1B1 (CYP1B1 with premenopausal MD. Effect modification of four estrogen-related factors (parity, age at menarche, hormonal derivatives use and body mass index (BMI on this relation is also assessed. Methods Polymorphisms were genotyped in 741 premenopausal Caucasian women whose MD was measured in absolute density (AD, cm2 and percent density using a computer-assisted method. Multivariate linear models were used to examine the associations (Ptrend and interactions (Pi. Results None of the SNPs showed a statistically significant association with AD. However, each additional rare allele of rs1056836 CYP1B1 was associated with a reduction in AD among nulliparous women (Ptrend = 0.004, while no association was observed among parous women (Ptrend = 0.62; Pi = 0.02. An increase in the number of rare alleles of the HSD17B1 SNP (rs598126 and rs2010750 was associated with an increase in AD among women who never used hormonal derivatives (Ptrend = 0.06 and Ptrend = 0.04, respectively, but with a decrease in AD among past hormonal derivatives users (Ptrend = 0.04; Pi = 0.02 and Ptrend = 0.08; Pi = 0.01, respectively. Moreover, a negative association of rs598126 HSD17B1 SNP with AD was observed among women with higher BMI (>median (Ptrend = 0.01; Pi = 0.02. A negative association between an increased number of rare alleles of COMT rs4680 SNP and AD was limited to women who never used hormonal derivatives (Ptrend = 0.02; Pi = 0.03 or with late age at menarche (>median

  7. 中国肥胖患者β_2 肾上腺素受体基因多态性的研究%Polymorphism in β_2 Adrenergic Receptor Gene in Chinese Population with Obesity

    Institute of Scientific and Technical Information of China (English)

    吴红梅; 白怀; 范平; 刘瑞; 刘宇; 刘秉文


    Objective To investigate the variation of β_2 adrenergic receptor (β_2AR) gene and its association with obesity in Chinese population. Methods The allele of β_2AR gene at Argl6Gly and Gln27Glu sites were analysed with polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) in 396 people with Han nationality in Chengdu, among whom 126 had obesity. Results The allele frequencies of Arg and Gly at Argl6Gly site were 0. 571 and 0. 429 for the obese people, and 0. 559 and 0. 441 for the non-obese people, respectively. The allele frequencies of Gin and Glu at Gln27Glu site were 0. 920 and 0. 080 for the obese people, and 0. 916 and 0. 084 for the non-obese people, respectively. No significant differences were found in the genotype frequencies of the two sites between non-obese and obese people. The non-obese females and obese males with genotype Arg/Arg at Argl6Gly site had elevated serum TC and LDL-C levels compared with those who carried Arg/ Gly or Gly/Gly (P0.05).在Arg16Gly位点,非肥胖组女性和肥胖组男性Arg/Arg基因型携带者血清 TC 和 LDLC 水平分别高于Arg/Gly和Gly/Gly基因型携带者(P0.05).结论 β_2AR基因Arg16Gly和Gln27Glu多态性与成都地区中国汉族人肥胖无关联,但Arg16Gly位点对特定性别非肥胖及肥胖人群血清TC、LDLC及部分载脂蛋白水平有一定影响.

  8. Genetic polymorphisms of human β-adrenergic receptor genes and their association with obesity%人类β-肾上腺素受体基因的遗传多态性及其与肥胖的关系

    Institute of Scientific and Technical Information of China (English)

    刘昭前; 莫玮; 黄琼; 周宏灏


    The prevalent rates of overweight and obesity are steadily increasing all over the world. Previous studies of some candidate genes have indicated that most of the genes are associated with obesity in human adipose tissue. As much as 40% of the variations in body mass could be attributed to genetic difference. The β-adrenergic receptor (β-AR) plays a major role in the regulation of energy balance in humans. A high sympathetic nervous system activity has been shown to be associated with obesity and is believed to have pathogenetic relevance. Several common single nucleotide polymorphisms (SNPs) including Gly389Arg in β1-AR, Gln27Glu in β2-AR, and Trp64Arg in β3-AR in humans could alter receptor function and these variations ofβ-ARs were shown to have certain association with obesity. Here we summarize the genetic polymorphisms of human β-ARs and their potential impacts to obesity.%在世界范围内,肥胖和超重的发生率正在稳步增长.过去有关候选基因的大量研究已经表明,大多数基因与人类脂肪组织中肥胖的发生相关.与人体体质量相关的40%以上的基因变异可以产生遗传差异.β-肾上腺素受体在人体能量平衡调节中扮演重要作用,交感神经系统的高度激活被认为与肥胖的发生密切相关.β-肾上腺素受体的单核苷酸多态性如β1-肾上腺素受体Gly389Arg,β2-肾上腺素受体Gln27Glu和β3-肾上腺素受体Trp64Arg已经被证明能够改变受体的功能,并与肥胖的发生有关.本文就β-肾上腺素受体的遗传多态性以及它们在肥胖发生中的作用作一综述.

  9. Investigation of single nucleotide polymorphisms and biological pathways associated with response to TNFα inhibitors in patients with rheumatoid arthritis

    DEFF Research Database (Denmark)

    Krintel, Sophine B; Palermo, Giuseppe; Johansen, Julia S;


    Recently, two genome-wide association studies identified single nucleotide polymorphisms (SNPs) significantly associated with the treatment response to tumor necrosis factor α (TNFα) inhibitors in patients with rheumatoid arthritis (RA). We aimed to replicate these results and identify SNPs...... and the possible biological pathways associated with the treatment response to TNFα inhibitors....

  10. Plasmodium falciparum field isolates from South America use an atypical red blood cell invasion pathway associated with invasion ligand polymorphisms

    DEFF Research Database (Denmark)

    Lopez-Perez, Mary; Villasis, Elizabeth; Machado, Ricardo L D;


    Studies of Plasmodium falciparum invasion pathways in field isolates have been limited. Red blood cell (RBC) invasion is a complex process involving two invasion protein families; Erythrocyte Binding-Like (EBL) and the Reticulocyte Binding-Like (PfRh) proteins, which are polymorphic and not fully...

  11. The Golgi apparatus is a functionally distinct Ca2+ store regulated by the PKA and Epac branches of the β1-adrenergic signaling pathway. (United States)

    Yang, Zhaokang; Kirton, Hannah M; MacDougall, David A; Boyle, John P; Deuchars, James; Frater, Brenda; Ponnambalam, Sreenivasan; Hardy, Matthew E; White, Edward; Calaghan, Sarah C; Peers, Chris; Steele, Derek S


    Ca(2+) release from the Golgi apparatus regulates key functions of the organelle, including vesicle trafficking. We found that the Golgi apparatus was the source of prolonged Ca(2+) release events that originated near the nuclei of primary cardiomyocytes. Golgi Ca(2+) release was unaffected by depletion of sarcoplasmic reticulum Ca(2+), and disruption of the Golgi apparatus abolished Golgi Ca(2+) release without affecting sarcoplasmic reticulum function, suggesting functional and spatial independence of Golgi and sarcoplasmic reticulum Ca(2+) stores. β1-Adrenoceptor stimulation triggers the production of the second messenger cAMP, which activates the Epac family of Rap guanine nucleotide exchange factors and the kinase PKA (protein kinase A). Phosphodiesterases (PDEs), including those in the PDE3 and PDE4 families, degrade cAMP. Activation of β1-adrenoceptors stimulated Golgi Ca(2+) release, an effect that required activation of Epac, PKA, and the kinase CaMKII. Inhibition of PDE3s or PDE4s potentiated β1-adrenergic-induced Golgi Ca(2+) release, which is consistent with compartmentalization of cAMP signaling near the Golgi apparatus. Interventions that stimulated Golgi Ca(2+) release appeared to increase the trafficking of vascular endothelial growth factor receptor-1 (VEGFR-1) from the Golgi apparatus to the surface membrane of cardiomyocytes. In cardiomyocytes from rats with heart failure, decreases in the abundance of PDE3s and PDE4s were associated with increased Golgi Ca(2+) release events. These data suggest that the Golgi apparatus is a focal point for β1-adrenergic-stimulated Ca(2+) signaling and that the Golgi Ca(2+) store functions independently from the sarcoplasmic reticulum and the global Ca(2+) transients that trigger contraction in cardiomyocytes.

  12. IGF and myostatin pathways are respectively induced during the earlier and the later stages of skeletal muscle hypertrophy induced by clenbuterol, a β₂-adrenergic agonist. (United States)

    Abo, Tokuhisa; Iida, Ryo-Hei; Kaneko, Syuhei; Suga, Takeo; Yamada, Hiroyuki; Hamada, Yoshiki; Yamane, Akira


    Clenbuterol, a β₂-adrenergic agonist, increases the hypertrophy of skeletal muscle. Insulin-like growth factor (IGF) is reported to work as a potent positive regulator in the clenbuterol-induced hypertrophy of skeletal muscles. However, the precise regulatory mechanism for the hypertrophy of skeletal muscle induced by clenbuterol is unknown. Myostatin, a member of the TGFβ super family, is a negative regulator of muscle growth. The aim of the present study is to elucidate the function of myostatin and IGF in the hypertrophy of rat masseter muscle induced by clenbuterol. To investigate the function of myostatin and IGF in regulatory mechanism for the clenbuterol-induced hypertrophy of skeletal muscles, we analysed the expression of myostatin and phosphorylation levels of myostatin and IGF signaling components in the masseter muscle of rat to which clenbuterol was orally administered for 21 days. Hypertrophy of the rat masseter muscle was induced between 3 and 14 days of oral administration of clenbuterol and was terminated at 21 days. The expression of myostatin and the phosphorylation of smad2/3 were elevated at 21 days. The phosphorylation of IGF receptor 1 (IGFR1) and akt1 was elevated at 3 and 7 days. These results suggest that myostatin functions as a negative regulator in the later stages in the hypertrophy of rat masseter muscle induced by clenbuterol, whereas IGF works as a positive regulator in the earlier stages.

  13. Common genetic polymorphisms of microRNA biogenesis pathway genes and breast cancer survival

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    Sung Hyuna


    Full Text Available Abstract Background Although the role of microRNA’s (miRNA’s biogenesis pathway genes in cancer development and progression has been well established, the association between genetic variants of this pathway genes and breast cancer survival is still unknown. Methods We used genotype data available from a previously conducted case–control study to investigate association between common genetic variations in miRNA biogenesis pathway genes and breast cancer survival. We investigated the possible associations between 41 germ-line single-nucleotide polymorphisms (SNPs and both disease free survival (DFS and overall survival (OS among 488 breast cancer patients. During the median follow-up of 6.24 years, 90 cases developed disease progression and 48 cases died. Results Seven SNPs were significantly associated with breast cancer survival. Two SNPs in AGO2 (rs11786030 and rs2292779 and DICER1 rs1057035 were associated with both DFS and OS. Two SNPs in HIWI (rs4759659 and rs11060845 and DGCR8 rs9606250 were associated with DFS, while DROSHA rs874332 and GEMIN4 rs4968104 were associated with only OS. The most significant association was observed in variant allele of AGO2 rs11786030 with 2.62-fold increased risk of disease progression (95% confidence interval (CI, 1.41-4.88 and in minor allele homozygote of AGO2 rs2292779 with 2.94-fold increased risk of death (95% CI, 1.52-5.69. We also found cumulative effects of SNPs on DFS and OS. Compared to the subjects carrying 0 to 2 high-risk genotypes, those carrying 3 or 4–6 high-risk genotypes had an increased risk of disease progression with a hazard ratio of 2.16 (95% CI, 1.18- 3.93 and 4.47 (95% CI, 2.45- 8.14, respectively (P for trend, 6.11E-07. Conclusions Our results suggest that genetic variants in miRNA biogenesis pathway genes may be associated with breast cancer survival. Further studies in larger sample size and functional characterizations are warranted to validate these results.

  14. The regulated secretory pathway and human disease: insights from gene variants and single nucleotide polymorphisms

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    Stephen eSalton


    Full Text Available The regulated secretory pathway provides critical control of peptide, growth factor, and hormone release from neuroendocrine and endocrine cells, and neurons, maintaining physiological homeostasis. Propeptides and prohormones are packaged into dense core granules (DCGs, where they frequently undergo tissue-specific processing as the DCG matures. Proteins of the granin family are DCG components, and although their function is not fully understood, data suggest they are involved in DCG formation and regulated protein/peptide secretion, in addition to their role as precursors of bioactive peptides. Association of gene variation, including single nucleotide polymorphisms (SNPs, with neuropsychiatric, endocrine and metabolic diseases, has implicated specific secreted proteins and peptides in disease pathogenesis. For example, a SNP at position 196 (G/A of the human brain-derived neurotrophic factor (BDNF gene dysregulates protein processing and secretion and leads to cognitive impairment. This suggests more generally that variants identified in genes encoding secreted growth factors, peptides, hormones, and proteins involved in DCG biogenesis, protein processing, and the secretory apparatus, could provide insight into the process of regulated secretion as well as disorders that result when it is impaired.

  15. [Beta 3 adrenergic receptor polymorphism and obesity]. (United States)

    Yoshida, T; Umekawa, T


    The beta 3-adrenoceptor plays a significant role in the control of lipolysis and thermogenesis in the brown adipose tissue of rodents and humans. In human beta 3-adrenoceptor, a Trp to Arg replacement has recently been discovered. This change which occurs at position 64, in the first coding exon, has been correlated with increased weight gain, difficulty in losing weight, insulin resistance syndrome, and worsened diabetic situation. Higher percentages of this mutation are observed in Pima Indians (over 30%) and Japanese (20%). The possible functional mechanism of Trp54Arg is reported using human HEK293 cell line stably expressing the wild type and the [Arg64] beta 3-adrenoceptor type. Beta 3-adrenoceptor agonists available for humans are been also developing. In this paper we describe these points up-to-date.

  16. Plasmodium falciparum field isolates from South America use an atypical red blood cell invasion pathway associated with invasion ligand polymorphisms.

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    Mary Lopez-Perez

    Full Text Available Studies of Plasmodium falciparum invasion pathways in field isolates have been limited. Red blood cell (RBC invasion is a complex process involving two invasion protein families; Erythrocyte Binding-Like (EBL and the Reticulocyte Binding-Like (PfRh proteins, which are polymorphic and not fully characterized in field isolates. To determine the various P. falciparum invasion pathways used by parasite isolates from South America, we studied the invasion phenotypes in three regions: Colombia, Peru and Brazil. Additionally, polymorphisms in three members of the EBL (EBA-181, EBA-175 and EBL-1 and five members of the PfRh (PfRh1, PfRh2a, PfRh2b, PfRh4, PfRh5 families were determined. We found that most P. falciparum field isolates from Colombia and Peru invade RBCs through an atypical invasion pathway phenotypically characterized as resistant to all enzyme treatments (NrTrCr. Moreover, the invasion pathways and the ligand polymorphisms differed substantially among the Colombian and Brazilian isolates while the Peruvian isolates represent an amalgam of those present in the Colombian and Brazilian field isolates. The NrTrCr invasion profile was associated with the presence of the PfRh2a pepC variant, the PfRh5 variant 1 and EBA-181 RVNKN variant. The ebl and Pfrh expression levels in a field isolate displaying the NrTrCr profile also pointed to PfRh2a, PfRh5 and EBA-181 as being possibly the major players in this invasion pathway. Notably, our studies demonstrate the uniqueness of the Peruvian P. falciparum field isolates in terms of their invasion profiles and ligand polymorphisms, and present a unique opportunity for studying the ability of P. falciparum parasites to expand their invasion repertoire after being reintroduced to human populations. The present study is directly relevant to asexual blood stage vaccine design focused on invasion pathway proteins, suggesting that regional invasion variants and global geographical variation are likely to

  17. Adrenergic receptors are a fallible index of adrenergic denervation hypersensitivity

    DEFF Research Database (Denmark)

    Dejgaard, Anders; Liggett, S B; Christensen, N J


    by measuring these in a group of subjects with well-documented adrenergic denervation hypersensitivity, patients with diabetic autonomic neuropathy. Mononuclear leukocyte beta 2-adrenergic receptor densities (and binding affinities), measured with 125I-labelled pindolol, and isoproterenol-stimulated cyclic AMP...... accumulation, in samples from patients with insulin-dependent diabetes mellitus (IDDM) with diabetic autonomic neuropathy (n = 8), were no different from those in samples from patients with IDDM without neuropathy (n = 8), or from non-diabetic subjects (n = 8). In addition, platelet alpha 2-adrenergic receptor...... to diabetic autonomic neuropathy. Regardless of the mechanism of adrenergic denervation hypersensitivity in such patients, these data provide further evidence that measurements of cellular adrenergic receptors (and adenylate cyclase) in vitro are a fallible index of sensitivity to catecholamines in vivo....

  18. The Impact of Gene Polymorphisms on the Success of Anticholinergic Treatment in Children with Overactive Bladder

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    Serhat Gurocak


    Full Text Available Aim. To determine the impact of gene polymorphisms on detrusor contraction-relaxation harmony in children with lower urinary tract symptoms (LUTS. Materials and Methods. Toilet trained children older than 5 years of age with LUTS and normal neurological examination underwent videourodynamic study. The control group was composed of age matched children with no voiding complaints. The study group who filled out the voiding dysfunction symptom score before and after the treatment received standard oxybutynin treatment and was reevaluated 1 year after treatment. Genomic DNA was isolated from all patients and subjected to PCR for amplification. Genotyping of ARGHEF10, ROCK2, ADRB3, and CYP3A4 was carried out with Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP method. Results. 34 (45% and 42 (55% patients were enrolled in the study and control group, respectively. ARGEF10 GG, ADRB3 TC, and CYP3A4 AG genotype patients displayed insignificant difference between pre- and posttreatment voiding dysfunction symptom score and bladder volumes. Conclusions. The polymorphism of genes in the cholinergic pathway did not significantly differ clinical parameters. On the other hand, polymorphic patients in the adrenergic pathway seemed to suffer from clinical disappointment. For this reason, we think that the neglected adrenergic pathway could be a new therapeutic target for the treatment of anticholinergic resistant LUTS in children.

  19. T-Cell Cytokine Gene Polymorphisms and Vitamin D Pathway Gene Polymorphisms in End-Stage Renal Disease due to Type 2 Diabetes Mellitus Nephropathy: Comparisons with Health Status and Other Main Causes of End-Stage Renal Disease

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    Alicja E. Grzegorzewska


    Full Text Available Background. T-cell cytokine gene polymorphisms and vitamin D pathway gene polymorphisms were evaluated as possibly associated with end-stage renal disease (ESRD resulting from type 2 diabetes mellitus (DM nephropathy. Methods. Studies were conducted among hemodialysis (HD patients with ESRD due to type 2 DM nephropathy, chronic glomerulonephritis, chronic infective tubulointerstitial nephritis, and hypertensive nephropathy as well as in healthy subjects. A frequency distribution of T-cell-related interleukin (IL genes (IL18 rs360719, IL12A rs568408, IL12B rs3212227, IL4R rs1805015, IL13 rs20541, IL28B rs8099917, IL28B, and rs12979860 and vitamin D pathway genes (GC genes: rs2298849, rs7041, and rs1155563; VDR genes: rs2228570, rs1544410; and RXRA genes: rs10776909, rs10881578, and rs749759 was compared between groups. Results. No significant differences in a frequency distribution of tested polymorphisms were shown between type 2 DM nephropathy patients and controls. A difference was found in IL18 rs360719 polymorphic distribution between the former group and chronic infective tubulointerstitial nephritic patients (Ptrend=0.033, which also differed in this polymorphism from controls (Ptrend=0.005. Conclusion. T-cell cytokine and vitamin D pathway gene polymorphisms are not associated with ESRD due to type 2 DM nephropathy in Polish HD patients. IL18 rs360719 is probably associated with the pathogenesis of chronic infective tubulointerstitial nephritis.

  20. Contribution of α- and β-Adrenergic Mechanisms to the Development of Pulmonary Edema

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    Beate Rassler


    Full Text Available Endogenous or exogenous catecholamines can induce pulmonary edema (PE. This may occur in human pathologic conditions such as in pheochromocytoma or in neurogenic pulmonary edema (NPE but can also be provoked after experimental administration of adrenergic agonists. PE can result from stimulation with different types of adrenergic stimulation. With -adrenergic treatment, it develops more rapidly, is more severe with abundant protein-rich fluid in the alveolar space, and is accompanied by strong generalized inflammation in the lung. Similar detrimental effects of -adrenergic stimulation have repeatedly been described and are considered to play a pivotal role in NPE or in PE in patients with pheochromocytoma. Although -adrenergic agonists have often been reported to prevent or attenuate PE by enhancing alveolar fluid clearance, PE may also be induced by -adrenergic treatment as can be observed in tocolysis. In experimental models, infusion of -adrenergic agonists induces less severe PE than -adrenergic stimulation. The present paper addresses the current understanding of the possible contribution of - and -adrenergic pathways to the development of PE.

  1. Pregnancy modifies the alpha2-beta-adrenergic receptor functional balance in rabbit fat cells. (United States)

    Bousquet-Mélou, A; Muñoz, C; Galitzky, J; Berlan, M; Lafontan, M


    The sympathetic nervous system controls lipolysis in fat by activation of four adrenergic receptors: beta1, beta2, beta3, and alpha2. During pregnancy, maternal metabolism presents anabolic and catabolic phases, characterized by modifications of fat responsiveness to catecholamines. The contributions of the four adrenergic receptors to adipocyte responsiveness during pregnancy have never been studied. Our aim was to evaluate the influence of pregnancy on adrenergic receptor-mediated lipolysis in rabbit white adipocytes. Functional studies were performed using subtype-selective and non-selective adrenergic receptor agonists. Overall adrenergic responsiveness was measured with the physiological agonist epinephrine. Non-adrenergic agents were used to evaluate different steps of the lipolytic cascade. The alpha2- and beta1/beta2-adrenergic receptor numbers were determined with selective radioligands. Non-adrenergic agents revealed that pregnancy induced an intracytoplasmic modification of the lipolytic cascade in inguinal but not in retroperitoneal adipocytes. Pregnancy induced an increase in beta1- and specially beta3-mediated lipolysis. The amounts of adipocyte beta1/beta2- and alpha2-adrenergic receptors were increased in pregnant rabbits. Epinephrine effects revealed an increased contribution of alpha2-adrenergic receptor-mediated antilipolysis in adipocytes from pregnant rabbits. These results indicate that pregnancy regulates adipocyte responsiveness to catecholamines mainly via the alpha2- and beta3-adrenergic pathways. Pregnancy induces an intracytoplasmic modification of the lipolytic cascade, probably via hormone-sensitive lipase, with differences according to fat location.-Bousquet-Mélou, A., C. Muñoz, J. Galitzky, M. Berlan, and M. Lafontan. Pregnancy modifies the alpha2-beta-adrenergic receptor functional balance in rabbit fat cells.

  2. The roles of beta-adrenergic receptors in tumorigenesis and the possible use of beta-adrenergic blockers for cancer treatment: possible genetic and cell-signaling mechanisms

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    Luong KV


    Full Text Available Khanh vinh quốc Lương, Lan Thi Hoàng NguyễnVietnamese American Medical Research Foundation, Westminster, California, USAAbstract: Cancer is the leading cause of death in the USA, and the incidence of cancer increases dramatically with age. Beta-adrenergic blockers appear to have a beneficial clinical effect in cancer patients. In this paper, we review the evidence of an association between β-adrenergic blockade and cancer. Genetic studies have provided the opportunity to determine which proteins link β-adrenergic blockade to cancer pathology. In particular, this link involves the major histocompatibility complex class II molecules, the renin–angiotensin system, transcription factor nuclear factor-kappa-light-chain-enhancer of activated B cells, poly(ADP-ribose polymerase-1, vascular endothelial growth factor, and the reduced form of nicotinamide adenine dinucleotide phosphate oxidase. Beta-adrenergic blockers also exert anticancer effects through non-genomic factors, including matrix metalloproteinase, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase-2, oxidative stress, and nitric oxide synthase. In conclusion, β-adrenergic blockade may play a beneficial role in cancer treatment. Additional investigations that examine β-adrenergic blockers as cancer therapeutics are required to further elucidate this role.Keywords: β-adrenergic blocker, neoplasm, β-adrenergic antagonism, non-genomic factor

  3. Folate Pathway Gene Methylenetetrahydrofolate Reductase C677T Polymorphism and Alzheimer Disease Risk in Asian Population. (United States)

    Rai, Vandana


    The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and susceptibility to Alzheimers disease (AD) was controversial in previous studies. The present meta-analysis was designed to investigate the association of MTHFR C677T polymorphism with AD. Nine studies were identified by search of PubMed, Google Scholar, Elsevier, Springer Link databases, up to January 2013. Odds ratios (ORs) with corresponding 95 % confidence interval (CI) were calculated using fixed effects model or random effects model. All statistical analysis was done by Mix version 1.7. MTHFR C677T polymorphism had a significant association with susceptibility to AD in all genetic models (for T vs C: OR 1.29, 95 % CI 1.15-1.44, p < 0.0001; for TT + CT vs CC: OR 1.38, 95 % CI 1.16-1.364, p = 0.0002; for TT vs CC: OR 1.60, 95 % CI 1.25-2.04, p = 0.0001; for CT vs CC: OR 1.28, 95 % CI 1.1-1.53, p < 0.008; for TT vs CT + CC: OR 1.37, 95 % CI 1.12-1.67, p = 0.002). Results from present meta-analysis supported that the MTHFR C677T polymorphism was associated with an increased risk of AD in Asian population.

  4. Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder

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    Mayor-Olea Alvaro


    Full Text Available Abstract Background Temporomandibular disorder (TMD is a multifactorial syndrome related to a critical period of human life. TMD has been associated with psychological dysfunctions, oxidative state and sexual dimorphism with coincidental occurrence along the pubertal development. In this work we study the association between TMD and genetic polymorphisms of folate metabolism, neurotransmission, oxidative and hormonal metabolism. Folate metabolism, which depends on genes variations and diet, is directly involved in genetic and epigenetic variations that can influence the changes of last growing period of development in human and the appearance of the TMD. Methods A case-control study was designed to evaluate the impact of genetic polymorphisms above described on TMD. A total of 229 individuals (69% women were included at the study; 86 were patients with TMD and 143 were healthy control subjects. Subjects underwent to a clinical examination following the guidelines by the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD. Genotyping of 20 Single Nucleotide Polymorphisms (SNPs, divided in two groups, was performed by multiplex minisequencing preceded by multiplex PCR. Other seven genetic polymorphisms different from SNPs (deletions, insertions, tandem repeat, null genotype were achieved by a multiplex-PCR. A chi-square test was performed to determine the differences in genotype and allelic frequencies between TMD patients and healthy subjects. To estimate TMD risk, in those polymorphisms that shown significant differences, odds ratio (OR with a 95% of confidence interval were calculated. Results Six of the polymorphisms showed statistical associations with TMD. Four of them are related to enzymes of folates metabolism: Allele G of Serine Hydoxymethyltransferase 1 (SHMT1 rs1979277 (OR = 3.99; 95%CI 1.72, 9.25; p = 0.002, allele G of SHMT1 rs638416 (OR = 2.80; 95%CI 1.51, 5.21; p = 0.013, allele T of Methylentetrahydrofolate

  5. Adrenergic Metabolic and Hemodynamic Effects of Octopamine in the Liver

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    Adelar Bracht


    Full Text Available The fruit extracts of Citrus aurantium (bitter orange are traditionally used as weight-loss products and as appetite suppressants. A component of these extracts is octopamine, which is an adrenergic agent. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of octopamine on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways and hemodynamics. Octopamine increased glycogenolysis, glycolysis, oxygen uptake, gluconeogenesis and the portal perfusion pressure. Octopamine also accelerated the oxidation of exogenous fatty acids (octanoate and oleate, as revealed by the increase in 14CO2 production derived from 14C labeled precursors. The changes in glycogenolysis, oxygen uptake and perfusion pressure were almost completely abolished by α1-adrenergic antagonists. The same changes were partly sensitive to the β-adrenergic antagonist propranolol. It can be concluded that octopamine accelerates both catabolic and anabolic processes in the liver via adrenergic stimulation. Acceleration of oxygen uptake under substrate-free perfusion conditions also means acceleration of the oxidation of endogenous fatty acids, which are derived from lipolysis. All these effects are compatible with an overall stimulating effect of octopamine on metabolism, which is compatible with its reported weight-loss effects in experimental animals.

  6. Molecular adaptation in flowering and symbiotic recognition pathways: insights from patterns of polymorphism in the legume Medicago truncatula

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    Ronfort Joëlle


    Full Text Available Abstract Background We studied patterns of molecular adaptation in the wild Mediterranean legume Medicago truncatula. We focused on two phenotypic traits that are not functionally linked: flowering time and perception of symbiotic microbes. Phenology is an important fitness component, especially for annual plants, and many instances of molecular adaptation have been reported for genes involved in flowering pathways. While perception of symbiotic microbes is also integral to adaptation in many plant species, very few reports of molecular adaptation exist for symbiotic genes. Here we used data from 57 individuals and 53 gene fragments to quantify the overall strength of both positive and purifying selection in M. truncatula and asked if footprints of positive selection can be detected at key genes of rhizobia recognition pathways. Results We examined nucleotide variation among 57 accessions from natural populations in 53 gene fragments: 5 genes involved in nitrogen-fixing bacteria recognition, 11 genes involved in flowering, and 37 genes used as control loci. We detected 1757 polymorphic sites yielding an average nucleotide diversity (pi of 0.003 per site. Non-synonymous variation is under sizable purifying selection with 90% of amino-acid changing mutations being strongly selected against. Accessions were structured in two groups consistent with geographical origins. Each of these two groups harboured an excess of rare alleles, relative to expectations of a constant-sized population, suggesting recent population expansion. Using coalescent simulations and an approximate Bayesian computation framework we detected several instances of genes departing from selective neutrality within each group and showed that the polymorphism of two nodulation and four flowering genes has probably been shaped by recent positive selection. Conclusion We quantify the intensity of purifying selection in the M. truncatula genome and show that putative footprints of

  7. Role of Genetic Polymorphisms in NFKB-Mediated Inflammatory Pathways in Response to Primary Chemoradiation Therapy for Rectal Cancer

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    Dzhugashvili, Maia [Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia (Spain); Department of Radiation Oncology, Madrid Oncology Institute (Group IMO), Murcia (Spain); Luengo-Gil, Ginés; García, Teresa; González-Conejero, Rocío [Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia (Spain); Conesa-Zamora, Pablo [Department of Pathology, University Hospital Santa Lucía, Cartagena (Spain); Escolar, Pedro Pablo [Department of Radiation Oncology, University Hospital Santa Lucía, Cartagena (Spain); Calvo, Felipe [Department of Radiation Oncology, University General Hospital Gregorio Marañón, Madrid (Spain); Vicente, Vicente [Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia (Spain); Ayala de la Peña, Francisco, E-mail: [Department of Hematology and Medical Oncology, University Hospital Morales Meseguer, Murcia (Spain)


    Purpose: To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). Methods and Materials: Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. Results: The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95% confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21-64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade ≥2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). Conclusions: Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment.

  8. Identification of gene-specific polymorphisms and association with capsaicin pathway metabolites in Capsicum annuum L. collections. (United States)

    Reddy, Umesh K; Almeida, Aldo; Abburi, Venkata L; Alaparthi, Suresh Babu; Unselt, Desiree; Hankins, Gerald; Park, Minkyu; Choi, Doil; Nimmakayala, Padma


    Pepper (Capsicum annuum L.) is an economically important crop with added nutritional value. Production of capsaicin is an important quantitative trait with high environmental variance, so the development of markers regulating capsaicinoid accumulation is important for pepper breeding programs. In this study, we performed association mapping at the gene level to identify single nucleotide polymorphisms (SNPs) associated with capsaicin pathway metabolites in a diverse Capsicum annuum collection during two seasons. The genes Pun1, CCR, KAS and HCT were sequenced and matched with the whole-genome sequence draft of pepper to identify SNP locations and for further characterization. The identified SNPs for each gene underwent candidate gene association mapping. Association mapping results revealed Pun1 as a key regulator of major metabolites in the capsaicin pathway mainly affecting capsaicinoids and precursors for acyl moieties of capsaicinoids. Six different SNPs in the promoter sequence of Pun1 were found associated with capsaicin in plants from both seasons. Our results support that CCR is an important control point for the flux of p-coumaric acid to specific biosynthesis pathways. KAS was found to regulate the major precursors for acyl moieties of capsaicinoids and may play a key role in capsaicinoid production. Candidate gene association mapping of Pun1 suggested that the accumulation of capsaicinoids depends on the expression of Pun1, as revealed by the most important associated SNPs found in the promoter region of Pun1.

  9. Interleukin 28B-related polymorphisms: A pathway for understanding hepatitis C virus infection? (United States)

    Garcia, Raquel Francine Liermann; Moreira, Simone; Ramos, Ana Lucia de Araújo; Ferreira, Leslie Ecker; de Mattos, Angelo Alves; Tovo, Cristiane Valle; Nader, Lysandro Alsina; Ramos, Juliene Antonio; Rondinelli, Edson; Dominici, Arnaldo de Jesus; Garcia, Christian Evangelista; Pinho, Mauro de Souza Leite; Brandão-Mello, Carlos Eduardo; Villela-Nogueira, Cristiane Alves; de França, Paulo Henrique Condeixa


    AIM: To analyze the role of rs12979860 and rs8099917 polymorphisms in hepatitis C virus (HCV) genotype 1 infection of Brazilians. METHODS: A total of 145 adult patients diagnosed with genotype 1 chronic hepatitis C (CHC) who had completed a 48-wk regimen of pegylated-interferon α-2a or -2b plus ribavirin combination therapy were recruited from six large urban healthcare centers and 199 healthy blood donors (controls) from a single site between January 2010 and January 2012. Data on the patients’ response to treatment was collected. Polymerase chain reaction-restriction fragment length polymorphism genotyping of the interleukin (IL)28B gene fragment encompassing the single nucleotide polymorphisms (SNPs) rs12979860 (C/T) and rs8099917 (T/G) was carried out for 79 of the CHC patients and 199 of the controls. Bi-directional amplicon sequencing of the two SNPs was carried out for the remaining 66 CHC patients. RESULTS: SNP rs12979860 genotyping was successful in 99.5% of the controls and 97.2% of the CHC patients, whereas the SNP rs8099917 genotyping was successful in 95.5% of the controls and 100% of the CHC patients. The genotype and allele distributions for both rs12979860 and rs8099917 were significantly different between the control and CHC patient groups, with significantly higher genotype frequencies of CC and TT in the controls (P = 0.037 and 0.046, respectively) and of TT and GG in the CHC patients (P = 0.0009 and 0.0001, respectively). Analysis of the CHC patients who achieved sustained virological response (SVR) to treatment (n = 55) indicated that the rs12979860 C allele and CC genotype were predictors of SVR (P = 0.02). No significant correlation was found between rs8099917 genotypes and treatment response, but carriers of the T allele showed significantly higher rates of SVR (P = 0.02). Linkage disequilibrium analysis of the group that achieved SVR showed a significant association between rs12979860 and rs8099917 (P = 0.07). CONCLUSION: The higher

  10. Arctic mustard flower color polymorphism controlled by petal-specific downregulation at the threshold of the anthocyanin biosynthetic pathway. (United States)

    Dick, Cynthia A; Buenrostro, Jason; Butler, Timothy; Carlson, Matthew L; Kliebenstein, Daniel J; Whittall, Justen B


    Intra- and interspecific variation in flower color is a hallmark of angiosperm diversity. The evolutionary forces underlying the variety of flower colors can be nearly as diverse as the colors themselves. In addition to pollinator preferences, non-pollinator agents of selection can have a major influence on the evolution of flower color polymorphisms, especially when the pigments in question are also expressed in vegetative tissues. In such cases, identifying the target(s) of selection starts with determining the biochemical and molecular basis for the flower color variation and examining any pleiotropic effects manifested in vegetative tissues. Herein, we describe a widespread purple-white flower color polymorphism in the mustard Parrya nudicaulis spanning Alaska. The frequency of white-flowered individuals increases with increasing growing-season temperature, consistent with the role of anthocyanin pigments in stress tolerance. White petals fail to produce the stress responsive flavonoid intermediates in the anthocyanin biosynthetic pathway (ABP), suggesting an early pathway blockage. Petal cDNA sequences did not reveal blockages in any of the eight enzyme-coding genes in white-flowered individuals, nor any color differentiating SNPs. A qRT-PCR analysis of white petals identified a 24-fold reduction in chalcone synthase (CHS) at the threshold of the ABP, but no change in CHS expression in leaves and sepals. This arctic species has avoided the deleterious effects associated with the loss of flavonoid intermediates in vegetative tissues by decoupling CHS expression in petals and leaves, yet the correlation of flower color and climate suggests that the loss of flavonoids in the petals alone may affect the tolerance of white-flowered individuals to colder environments.

  11. Arctic mustard flower color polymorphism controlled by petal-specific downregulation at the threshold of the anthocyanin biosynthetic pathway.

    Directory of Open Access Journals (Sweden)

    Cynthia A Dick

    Full Text Available Intra- and interspecific variation in flower color is a hallmark of angiosperm diversity. The evolutionary forces underlying the variety of flower colors can be nearly as diverse as the colors themselves. In addition to pollinator preferences, non-pollinator agents of selection can have a major influence on the evolution of flower color polymorphisms, especially when the pigments in question are also expressed in vegetative tissues. In such cases, identifying the target(s of selection starts with determining the biochemical and molecular basis for the flower color variation and examining any pleiotropic effects manifested in vegetative tissues. Herein, we describe a widespread purple-white flower color polymorphism in the mustard Parrya nudicaulis spanning Alaska. The frequency of white-flowered individuals increases with increasing growing-season temperature, consistent with the role of anthocyanin pigments in stress tolerance. White petals fail to produce the stress responsive flavonoid intermediates in the anthocyanin biosynthetic pathway (ABP, suggesting an early pathway blockage. Petal cDNA sequences did not reveal blockages in any of the eight enzyme-coding genes in white-flowered individuals, nor any color differentiating SNPs. A qRT-PCR analysis of white petals identified a 24-fold reduction in chalcone synthase (CHS at the threshold of the ABP, but no change in CHS expression in leaves and sepals. This arctic species has avoided the deleterious effects associated with the loss of flavonoid intermediates in vegetative tissues by decoupling CHS expression in petals and leaves, yet the correlation of flower color and climate suggests that the loss of flavonoids in the petals alone may affect the tolerance of white-flowered individuals to colder environments.

  12. Polymorphisms in the Toll-like receptor and the IL-23/IL-17 pathways were associated with susceptibility to inflammatory bowel disease in a Danish cohort

    DEFF Research Database (Denmark)

    Bank, Steffen; Andersen, Paal Skytt; Burisch, Johan;


    and the interferon gamma (IFNG) pathways are associated with risk of both CD and UC. METHODS: Using a candidate gene approach, 21 functional single nucleotide polymorphisms (SNPs) in 15 genes were assessed in a clinical homogeneous group of severely diseased ethnic Danish patients consisting of 624 patients with CD...

  13. Meta-analysis of the association between Trp64Arg polymorphism in β3-adrenergic receptor gene and overweight/obesity in children%儿童超重/肥胖与β3肾上腺素受体基因Trp64 Arg多态性的关联meta分析

    Institute of Scientific and Technical Information of China (English)

    吴静; 焦周阳; 张静; 罗强; 刘玉峰; 安金斗; 田培超; 张好好


    [Summary] In this study, PubMed, Embase, China National Knowledge Infrastructure, databases VIP Chinese Periodical Database, and Wanfang Chinese Periodical Database were systematically searched for the case-control study related β3-adrenergic receptor ( ADRB3 ) Trp64Arg gene polymorphism to overweight/obesity among children from 1962 to 2014.Twelve eligible studies with 2 222 overweight/obese children and 1 955 normal children were included according the uniform inclusion and exclusion criteria.Meta-analyses showed that Trp64Arg polymorphism was associated with significantly increased overweight/obesity risk in Arg carriers among children( OR=1.34,95%CI1.17-1.53).Afterstratificationforethnicity,highlysignificantcoorelationofTrp64Argpolymorphism to overweight/obesity in Asian children(OR=1.44, 95%CI 1.23-1.68) but not significant in Europe(OR=1.05, 95%CI 0.79-1.40).It suggested that Trp64Arg polymorphism is associated with overweight/obesity susceptibility in children.Our results support an strong association between Trp64Arg polymorphism and overweight/obesity among the Asian children investigated.%本研究通过计算机检索Pubmed、Embae、中国全文期刊数据库(包含博硕士论文数据库)、万方和维普中文科技期刊数据库,收集1962年至2014年β3肾上腺素受体(β3-adrenergic receptor, ADRB3)基因Trp64Arg多态性与儿童超重/肥胖的病例对照研究文献,共纳入12篇文献,其中儿童超重/肥胖者2222例,对照组1955人。 Meta分析结果显示,ADRΒ3基因Trp64Arg突变能够增加儿童超重/肥胖的发病风险(OR=1.34,95%CI 1.17~1.53),亚洲儿童中该基因突变型携带者超重/肥胖风险升高明显(OR=1.44,95%CI 1.23~1.68),欧洲儿童Arg携带者罹患超重/肥胖风险升高不明显(OR=1.05,95%CI 0.79~1.40)。提示β3肾上腺素受体基因Trp64Arg多态性与儿童超重/肥胖发病具有一定相关性

  14. Insulin-like Growth Factor Pathway Genetic Polymorphisms, Circulating IGF1 and IGFBP3, and Prostate Cancer Survival (United States)

    Lindström, Sara; Schumacher, Fredrick; Stevens, Victoria L.; Albanes, Demetrius; Berndt, Sonja I.; Boeing, Heiner; Bas Bueno-de-Mesquita, H.; Canzian, Federico; Chamosa, Saioa; Chanock, Stephen J.; Diver, W. Ryan; Gapstur, Susan M.; Gaziano, J. Michael; Giovannucci, Edward L.; Haiman, Christopher A.; Henderson, Brian; Johansson, Mattias; Marchand, Loïc Le; Palli, Domenico; Rosner, Bernard; Siddiq, Afshan; Stampfer, Meir; Stram, Daniel O.; Tamimi, Rulla; Travis, Ruth C.; Trichopoulos, Dimitrios; Willett, Walter C.; Yeager, Meredith; Kraft, Peter; Hsing, Ann W.; Pollak, Michael; Lin, Xihong


    Background The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown. Methods Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided. Results The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality. Conclusions The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.

  15. Association of morbid obesity,metabolic syndrome and polymorphism of β3-adrenergic receptor gene in the Hasake population in xinjiang%β3肾上腺素能受体基因多态与新疆哈萨克族人腹型肥胖和代谢综合征的相关研究

    Institute of Scientific and Technical Information of China (English)

    郭艳英; 潘慧娟; 王坤; 赵蕾; 何秉贤


    目的 检测新疆哈萨克族人群中β3肾上腺素能受体(β3-AR)Trp64Arg位点的等位基因频率和基因型频率,分析β3-AR基因在腹型肥胖、代谢综合征发生、发展中的作用.方法 应用聚合酶链反应和限制性片断长度多态性技术检测172例代谢综合征(MS)、92例单纯腹型肥胖和92例正常人的基因型,同时测定相关的生化指标,进行病例-对照研究.结果 β3-AR Trp64Arg位点的基因型频率在三组间差异无统计学意义.结论 β3-AR Trp64Arg多态与哈萨克族人腹型肥胖、MS的发生无明显关联.%Objective To investigate the genotype of Trp64Arg polymorphism of β3-adrenergic receptor gene and analyze the role ofβ3-adrenerglc receptor gene in the pathogenesis of morbid obesity and metabolic syndrome(MS).Methods PCR-restriction fragment length polymorphism Was used to detect the genotypes of 172 patients with MS,92 patient.with morbid obesity and 92 controls,and some biochemlcal indexes were detected.The association of the polymorohism with morbid obesity and MS Was assessed in case-control study.Resuits No statistically significant differences were found in the frequencies of Trp64Arg of β3-AR among the three groups.Conclusion Trp64Arg polymorphism of β3-AR was not significandy associated with morbid obesity and MS in the Hazak in xinjiang.

  16. The thiazide-sensitive Na(+)-Cl(-) cotransporter gene, C1784T, and adrenergic receptor-beta3 gene, T727C, may be gene polymorphisms susceptible to the antihypertensive effect of thiazide diuretics. (United States)

    Matayoshi, Tetsutaro; Kamide, Kei; Takiuchi, Shin; Yoshii, Masayoshi; Miwa, Yoshikazu; Takami, Yoichi; Tanaka, Chihiro; Banno, Mariko; Horio, Takeshi; Nakamura, Satoko; Nakahama, Hajime; Yoshihara, Fumiki; Inenaga, Takashi; Miyata, Toshiyuki; Kawano, Yuhei


    The response of blood pressure to thiazide diuretics (TZDs) differs among individuals. The prediction of the antihypertensive effect of TZDs is important for realizing individualized therapy in the management of hypertension. The aim of this study was to identify the single nucleotide polymorphisms (SNPs) susceptible to the antihypertensive effect of TZDs, particularly focusing on genes related to water-electrolyte absorption in the kidney. Seventy-six outpatients (mean age, 65.4+/-9.0 years) with essential hypertension (EHT) taking TZDs were retrospectively assessed. We defined as responders (R) those whose mean blood pressure was lowered by more than 5 mmHg after the use of TZDs. Forty-eight SNPs in 17 genes (ADD1, GNB3, TSC [SLC12A3], MLR [NR3C2], NCX1 [SLC8A1], WNK1, WNK4, AGT, ACE, AT1 [AGTR1], CYP11B2, ADRB1, ADRB2, ADRB3, ADRA1A, ADRA1B, ADRA2A) were genotyped in the 76 patients. The SNPs in TSC, MLR, NCX1, WNK1, and WNK4 were identified by direct sequencing and those with minor frequencies of greater than 5% were genotyped in this study. The comparison of polymorphism prevalence between R and non-responders (NR) showed significant differences in TSC C1784T (C allele vs. T allele, odds ratio (OR)=3.81, p =0.016, confidence interval (CI): 1.25-11.63) and ADRB3 T727C (Trp64Arg) (T allele vs. C allele, OR=4.59, p =0.005, CI: 1.54-13.68). The blood pressure (BP) in patients homozygous for the major alleles of both TSC C1784T and ADRB3 T727C were significantly reduced by TZD treatment; however, the BP in those homozygous for the minor allele and heterozygous (TSC C1784T: TT+CT; ADRB3 T727C: CC+CT) for both SNPs were not significantly changed after TZD treatment. Both newly detected TSC C1784T and ADRB3 T727C are gene polymorphisms susceptible to the antihypertensive effect of TZDs in patients with EHT. Thus, the prediction of BP reduction by TZDs may be possible by evaluating these two SNPs.

  17. The Gly16 Allele of the Gly16Arg Single-Nucleotide Polymorphism in the β2-Adrenergic Receptor Gene Augments Perioperative Use of Vasopressors

    DEFF Research Database (Denmark)

    Nielsen, Morten; Staalsø, Jonatan Myrup; Ullum, Henrik


    receptor (ADRB2) influences perioperative arterial blood pressure and consequently the use of vasopressors. METHODS: Five hundred seventy-one Danish Caucasians undergoing neurosurgery were genotyped for 5 marker single-nucleotide polymorphisms (SNPs) within ADRB2 (Gly16Arg, Gln27Glu, Thr164Ile, Arg175Arg......, and Gly351Gly). A pairwise tagging principle was used to identify ADRB2 haplotypes. Mean arterial blood pressure (MAP) was recorded in the supine awake state and, together with administration of vasopressors (ephedrine and/or phenylephrine), for 30 minutes after induction of general anesthesia...... (sevoflurane/remifentanil or propofol/remifentanil). RESULTS: Four hundred thirteen (72%) patients received ephedrine and/or phenylephrine. Only baseline MAP (P

  18. Maternal Folate Status and the BHMT c.716G>A Polymorphism Affect the Betaine Dimethylglycine Pathway during Pregnancy (United States)

    Colomina, Jose M.; Cavallé-Busquets, Pere; Fernàndez-Roig, Sílvia; Solé-Navais, Pol; Fernandez-Ballart, Joan D.; Ballesteros, Mónica; Ueland, Per M.; Meyer, Klaus; Murphy, Michelle M.


    The effect of the betaine: homocysteine methyltransferase BHMT c.716G>A (G: guanosine; A: adenosine) single nucleotide polymorphism (SNP) on the BHMT pathway is unknown during pregnancy. We hypothesised that it impairs betaine to dimethylglycine conversion and that folate status modifies its effect. We studied 612 women from the Reus Tarragona Birth Cohort from ≤12 gestational weeks (GW) throughout pregnancy. The frequency of the variant BHMT c.716A allele was 30.8% (95% confidence interval (CI): 28.3, 33.5). In participants with normal-high plasma folate status (>13.4 nmol/L), least square geometric mean [95% CI] plasma dimethylglycine (pDMG, µmol/L) was lower in the GA (2.35 [2.23, 2.47]) versus GG (2.58 [2.46, 2.70]) genotype at ≤12 GW (p < 0.05) and in the GA (2.08 [1.97, 2.19]) and AA (1.94 [1.75, 2.16]) versus GG (2.29 [2.18, 2.40]) genotypes at 15 GW (p < 0.05). No differences in pDMG between genotypes were observed in participants with possible folate deficiency (≤13.4 nmol/L) (p for interactions at ≤12 GW: 0.023 and 15 GW: 0.038). PDMG was lower in participants with the AA versus GG genotype at 34 GW (2.01 [1.79, 2.25] versus 2.44 [2.16, 2.76] and at labour, 2.51 [2.39, 2.64] versus 3.00 [2.84, 3.18], (p < 0.01)). Possible deficiency compared to normal-high folate status was associated with higher pDMG in multiple linear regression analysis (β coefficients [SEM] ranging from 0.07 [0.04], p < 0.05 to 0.20 [0.04], p < 0.001 in models from early and mid-late pregnancy) and the AA compared to GG genotype was associated with lower pDMG (β coefficients [SEM] ranging from −0.11 [0.06], p = 0.055 to −0.23 [0.06], p < 0.001). Conclusion: During pregnancy, the BHMT pathway is affected by folate status and by the variant BHMT c.716A allele. PMID:27735840

  19. Single Nucleotide Polymorphism Microarray Analysis in Cortisol-Secreting Adrenocortical Adenomas Identifies New Candidate Genes and Pathways

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    Cristina L. Ronchi


    Full Text Available The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0 to detect copy number alterations (CNAs and copy-neutral losses of heterozygosity (cnLOH in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (≥20% of cases, most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses, including genes involved in steroidogenesis (CYP11B1 or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT. Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors.

  20. Single nucleotide polymorphisms in the vitamin D pathway associating with circulating concentrations of vitamin D metabolites and non-skeletal health outcomes: Review of genetic association studies. (United States)

    Jolliffe, David A; Walton, Robert T; Griffiths, Christopher J; Martineau, Adrian R


    Polymorphisms in genes encoding proteins involved in vitamin D metabolism and transport are recognised to influence vitamin D status. Syntheses of genetic association studies linking these variants to non-skeletal health outcomes are lacking. We therefore conducted a literature review to identify reports of statistically significant associations between single nucleotide polymorphisms (SNP) in 11 vitamin D pathway genes (DHCR7, CYP2R1, CYP3A4, CYP27A1, DBP, LRP2, CUB, CYP27B1, CYP24A1, VDR and RXRA) and non-bone health outcomes and circulating levels of 25-hydroxyvitamin D (25[OH]D and 1,25-dihydroxyvitamin D (1,25[OH]2D). A total of 120 genetic association studies reported positive associations, of which 44 investigated determinants of circulating 25(OH)D and/or 1,25(OH)2D concentrations, and 76 investigated determinants of non-skeletal health outcomes. Statistically significant associations were reported for a total of 55 SNP in the 11 genes investigated. There was limited overlap between genetic determinants of vitamin D status and those associated with non-skeletal health outcomes: polymorphisms in DBP, CYP2R1 and DHCR7 were the most frequent to be reported to associate with circulating concentrations of 25(OH)D, while polymorphisms in VDR were most commonly reported to associate with non-skeletal health outcomes, among which infectious and autoimmune diseases were the most represented.

  1. Analysis of adrenergic regulation of melatonin synthesis in Siberian hamster pineal emphasizes the role of HIOMT. (United States)

    Ceinos, R M; Chansard, M; Revel, F; Calgari, C; Míguez, J M; Simonneaux, V


    Seasonal variations of environmental factors are translated into annual fluctuations in synthesis and release of melatonin, which in turn acts as a neuroendocrine messenger for the synchronization of annual functions. So far, most studies performed to understand the regulation of melatonin synthesis have used the non seasonal laboratory rat. It was demonstrated that nocturnal melatonin synthesis depends on alpha- and beta-adrenergic activation of the enzyme arylalkylamine N-acetyltransferase (AA-NAT). In this study, we investigated the mechanisms of melatonin synthesis in the Siberian hamster, a seasonal species with marked photoperiodic variation in melatonin peak duration and amplitude. A beta-adrenergic receptor agonist alone markedly stimulated AA-NAT activity and melatonin synthesis and release. An alpha-adrenergic receptor agonist, while having no effect per se, potentiated the beta-adrenergic stimulation of AA-NAT activity both in vitro and in vivo. Strikingly, the potentiation of AA-NAT activity did not result in a potentiation of melatonin synthesis, suggesting that the rate of melatonin production is limited downstream in the metabolic pathway, most probably at the level of hydroxyindole-O-methyltransferase (HIOMT). HIOMT presented a constitutively high activity that was not acutely (within hours) stimulated by beta-adrenergic agonist, but was rather up-regulated by chronic application of the agonist. This long-term beta-adrenergic regulation may explain the reported large photoperiodic variation of HIOMT activity that drives the photoperiodic variation in melatonin peak.

  2. Preliminary evidence for a role of the adrenergic nervous system in generalized anxiety disorder (United States)

    Zhang, Xiaobin; Norton, Joanna; Carrière, Isabelle; Ritchie, Karen; Chaudieu, Isabelle; Ryan, Joanne; Ancelin, Marie-Laure


    Generalized anxiety disorder (GAD) is a common chronic condition that is understudied compared to other psychiatric disorders. An altered adrenergic function has been reported in GAD, however direct evidence for genetic susceptibility is missing. This study evaluated the associations of gene variants in adrenergic receptors (ADRs) with GAD, with the involvement of stressful events. Data were obtained from 844 French community-dwelling elderly aged 65 or over. Anxiety disorders were assessed using the Mini-International Neuropsychiatry Interview, according to DSM-IV criteria. Eight single-nucleotide polymorphisms (SNPs) involved with adrenergic function were genotyped; adrenergic receptors alpha(1A) (ADRA1A), alpha(2A) (ADRA2A), and beta2 (ADRB2) and transcription factor TCF7L2. Questionnaires evaluated recent stressful life events as well as early environment during childhood and adolescence. Using multivariate logistic regression analyses four SNPs were significantly associated with GAD. A 4-fold modified risk was found with ADRA1A rs17426222 and rs573514, and ADRB2 rs1042713 which remained significant after Bonferroni correction. Certain variants may moderate the effect of adverse life events on the risk of GAD. Replication in larger samples is needed due to the small case number. This is the first study showing that ADR variants are susceptibility factors for GAD, further highlighting the critical role of the adrenergic nervous system in this disorder. PMID:28198454

  3. Preliminary evidence for a role of the adrenergic nervous system in generalized anxiety disorder. (United States)

    Zhang, Xiaobin; Norton, Joanna; Carrière, Isabelle; Ritchie, Karen; Chaudieu, Isabelle; Ryan, Joanne; Ancelin, Marie-Laure


    Generalized anxiety disorder (GAD) is a common chronic condition that is understudied compared to other psychiatric disorders. An altered adrenergic function has been reported in GAD, however direct evidence for genetic susceptibility is missing. This study evaluated the associations of gene variants in adrenergic receptors (ADRs) with GAD, with the involvement of stressful events. Data were obtained from 844 French community-dwelling elderly aged 65 or over. Anxiety disorders were assessed using the Mini-International Neuropsychiatry Interview, according to DSM-IV criteria. Eight single-nucleotide polymorphisms (SNPs) involved with adrenergic function were genotyped; adrenergic receptors alpha(1A) (ADRA1A), alpha(2A) (ADRA2A), and beta2 (ADRB2) and transcription factor TCF7L2. Questionnaires evaluated recent stressful life events as well as early environment during childhood and adolescence. Using multivariate logistic regression analyses four SNPs were significantly associated with GAD. A 4-fold modified risk was found with ADRA1A rs17426222 and rs573514, and ADRB2 rs1042713 which remained significant after Bonferroni correction. Certain variants may moderate the effect of adverse life events on the risk of GAD. Replication in larger samples is needed due to the small case number. This is the first study showing that ADR variants are susceptibility factors for GAD, further highlighting the critical role of the adrenergic nervous system in this disorder.

  4. Insight into Gene Polymorphisms Involved in Toll-Like Receptor/Interferon Signalling Pathways for Systemic Lupus Erythematosus in South East Asia

    Directory of Open Access Journals (Sweden)

    Hwa Chia Chai


    Full Text Available Polymorphisms in genes involved in toll-like receptor/interferon signalling pathways have been reported previously to be associated with SLE in many populations. This study aimed to investigate the role of seven single nucleotide polymorphisms within TNFAIP3, STAT4, and IRF5, which are involved in upstream and downstream pathways of type I interferon production, in SLE in the South East Asian populations. Genotyping of 360 Malaysian SLE patients and 430 normal healthy individuals revealed that minor alleles of STAT4 rs7574865 and rs10168266 were associated with elevated risk of SLE in the Chinese and Malay patients, respectively (P=0.028, odds ratio (OR=1.42; P=0.035, OR=1.80, respectively. Polymorphisms in TNFAIP3 and IRF5 did not show significant associations with SLE in any of the ethnicities. Combined analysis of the Malays, Chinese, and Indians for each SNP indicated that STAT4 rs10168266 was significantly associated with the Malaysian SLE as a whole (P=0.014; OR=1.435. The meta-analysis of STAT4 rs10168266, which combined the data of other studies and this study, further confirmed its importance as the risk factor for SLE by having pooled OR of 1.559 and P value of <0.001.

  5. Tailoring therapy for heart failure: the pharmacogenomics of adrenergic receptor signaling

    Directory of Open Access Journals (Sweden)

    Femminella GD


    Full Text Available Grazia Daniela Femminella,1 Vincenzo Barrese,2,3 Nicola Ferrara,1,4 Giuseppe Rengo4 1Department of Translational Medical Sciences, Federico II University, Naples, Italy; 2Department of Neuroscience, Reproductive Science and Odontostomatology, Federico II University, Naples, Italy; 3Division of Biomedical Sciences, St George’s University of London, London, UK; 4”Salvatore Maugeri” Foundation – IRCCS – Scientific Institute of Telese Terme, Telese Terme, Benevento, Italy Abstract: Heart failure is one of the leading causes of mortality in Western countries, and β-blockers are a cornerstone of its treatment. However, the response to these drugs is variable among individuals, which might be explained, at least in part, by genetic differences. Pharmacogenomics is the study of genetic contributions to drug response variability in order to provide evidence for a tailored therapy in an individual patient. Several studies have investigated the pharmacogenomics of the adrenergic receptor system and its role in the context of the use of β-blockers in treating heart failure. In this review, we will focus on the most significant polymorphisms described in the literature involving adrenergic receptors and adrenergic receptor-related proteins, as well as genetic variations influencing β-blocker metabolism. Keywords: adrenergic system, polymorphisms, β-blockers, functional recovery

  6. Association of polymorphism of β3-adrenergic receptor gene and the leptin gene with Kazak obese children in Xinjiang%β3肾上腺素能受体基因及瘦素基因多态性与新疆哈萨克族儿童肥胖的关系

    Institute of Scientific and Technical Information of China (English)

    朱翠翠; 张季红; 徐佩茹; 李敏; 马冬梅


    Objective To investigate the association between C2549A polymorphism of leptin gene and the Trp64Arg polymorphism of the β3-adrenergic receptor gene(β3-AR gene) and obesity in Kazak school-age children.Methods Totally 92 obese children and 71 healthy controls were selected from 6 to 12 years old in Kazak school-age children from the area around Urumqi.Genotype of the C2549A polymorphism of leptin gene and the Trp64Arg polymor phism of β3-AR gene were determined by polymerase chain reaction and restriction fragment length polymorphism methods.Results 1.The difference in distribution of the β3-AR gene Trp64Arg genotype of obesity and healthy controls of Kazak children was statistically significant (x2 =10.472,P < 0.05),but the difference in distribution of the alleles was not statistically significant (x2 =3.541,P > 0.05).2.The differences in distribution of the leptin C2549A genotype and alleles of the 2 groups were all statistically significant,and the odds ratio of the alleles(0.608) and 95% CI 0.380-0.972 suggested that the mutation occurrence of obesity might have certain protective effect.3.The difference in distribution of the genotype of β3-AR gene Trp64Arg polymorphism and leptin gene promoter area C2549A polymorphism in the same individual joint action of 2 groups was statistically significant (x2 =15.978,P < 0.05),but the difference in distribution of the alleles in the same individual joint action of 2 groups was not statistically significant (x2 =6.362,P > 0.05).Conclusions 1.There were distributions of the Trp64Arg polymorphism of β3-AR gene and the C2549A polymorphism of leptin gene in Kazak school-aged children in Xinjiang.2.These results suggested that C2549A mutation of leptin gene might have certain protective effect in Kazak children obesity,and the Trp64Arg polymorphism of β3-AR gene might be associated with Kazak children obesity.3.These results suggested that the Trp64Arg polymorphism of β3-AR gene and the C2549A polymorphism

  7. Inhaled adrenergics and anticholinergics in obstructive lung disease: do they enhance mucociliary clearance? (United States)

    Restrepo, Ruben D


    Pulmonary mucociliary clearance is an essential defense mechanism against bacteria and particulate matter. Mucociliary dysfunction is an important feature of obstructive lung diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, and bronchiectasis. This dysfunction in airway clearance is associated with accelerated loss of lung function in patients with obstructive lung disease. The involvement of the cholinergic and adrenergic neural pathways in the pathophysiology of mucus hypersecretion suggests the potential therapeutic role of bronchodilators as mucoactive agents. Although anticholinergics and adrenergic agonist bronchodilators have been routinely used, alone or in combination, to enhance mucociliary clearance in patients with obstructive lung disease, the existing evidence does not consistently show clinical effectiveness.

  8. Association of seven functional polymorphisms of one-carbon metabolic pathway with total plasma homocysteine levels and susceptibility to Parkinson's disease among South Indians. (United States)

    Kumudini, Nadella; Uma, Addepally; Naushad, Shaik Mohammad; Mridula, Rukmini; Borgohain, Rupam; Kutala, Vijay Kumar


    This study from South India was performed to ascertain the impact of seven functional polymorphisms of one-carbon metabolic pathway on total plasma homocysteine levels and susceptibility to PD. A total of 151 cases of Parkinson's disease and 416 healthy controls were analyzed for fasting plasma homocysteine levels by reverse phase HPLC. PCR-RFLP approaches were used to analyze glutamate carboxypeptidase II (GCPII) 1561 C>T, reduced folate carrier 1 (RFC1) 80 G>A, cytosolic serine hydroxymethyl transferase (cSHMT) 1420 C>T, methylene tetrahydrofolate reductase (MTHFR) 677 C>T, methionine synthase (MTR) 2756 A>G and methionine synthase reductase (MTRR) 66 A>G polymorphisms. PCR-AFLP was used for the analysis of thymidylate synthase (TYMS) 5'-UTR 28bp tandem repeat. PD cases exhibited elevated plasma homocysteine levels compared to controls (men: 28.8 ± 6.9 vs. 16.4 ± 8.8 μmol/L; women: 25.4 ± 5.3 vs. 11.2 ± 5.1μmol/L). Homocysteine levels showed positive correlation with male gender (r=0.39, pG (r=0.31, pT polymorphism. MTRR 66 A>G polymorphism showed independent risk for PD (OR: 3.42, 95% CI: 2.35-4.98) whereas cSHMT 1420 C>T conferred protection against PD (OR: 0.11, 95% CI: 0.07-0.17). Multifactor dimensionality reduction analysis showed synergistic interactions between MTHFR 677 C>T and MTRR 66 A>G, whereas cSHMT 1420 C>T exhibited counteracting interactions in altering susceptibility to PD. To conclude, PD cases exhibited hyperhomocysteinemia and MTRR 66 A>G and cSHMT 1420 C>T gene variants were shown to modulate PD risk by altering the homocysteine levels.

  9. Association of symptoms and severity of rift valley fever with genetic polymorphisms in human innate immune pathways.

    Directory of Open Access Journals (Sweden)

    Amy G Hise


    Full Text Available BACKGROUND: Multiple recent outbreaks of Rift Valley Fever (RVF in Africa, Madagascar, and the Arabian Peninsula have resulted in significant morbidity, mortality, and financial loss due to related livestock epizootics. Presentation of human RVF varies from mild febrile illness to meningoencephalitis, hemorrhagic diathesis, and/or ophthalmitis with residual retinal scarring, but the determinants for severe disease are not understood. The aim of the present study was to identify human genes associated with RVF clinical disease in a high-risk population in Northeastern Province, Kenya. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cross-sectional survey among residents (N = 1,080; 1-85 yrs in 6 villages in the Sangailu Division of Ijara District. Participants completed questionnaires on past symptoms and exposures, physical exam, vision testing, and blood collection. Single nucleotide polymorphism (SNP genotyping was performed on a subset of individuals who reported past clinical symptoms consistent with RVF and unrelated subjects. Four symptom clusters were defined: meningoencephalitis, hemorrhagic fever, eye disease, and RVF-not otherwise specified. SNPs in 46 viral sensing and response genes were investigated. Association was analyzed between SNP genotype, serology and RVF symptom clusters. The meningoencephalitis symptom phenotype cluster among seropositive patients was associated with polymorphisms in DDX58/RIG-I and TLR8. Having three or more RVF-related symptoms was significantly associated with polymorphisms in TICAM1/TRIF, MAVS, IFNAR1 and DDX58/RIG-I. SNPs significantly associated with eye disease included three different polymorphisms TLR8 and hemorrhagic fever symptoms associated with TLR3, TLR7, TLR8 and MyD88. CONCLUSIONS/SIGNIFICANCE: Of the 46 SNPs tested, TLR3, TLR7, TLR8, MyD88, TRIF, MAVS, and RIG-I were repeatedly associated with severe symptomatology, suggesting that these genes may have a robust association with RVFV

  10. Adrenergic blockade in diabetic and uninephrectomized rats

    DEFF Research Database (Denmark)

    Thulesen, J; Poulsen, Steen Seier; Jørgensen, P E


    was comparable. In adrenergic antagonist treated diabetic rats, it was reduced by at least 40% throughout the study period. Uninephrectomy caused a 50% reduction in the urinary excretion of EGF. This was not influenced by treatment with an adrenergic antagonist. After 3 weeks, saline-treated diabetic rats had......The present study reports on the effects of adrenergic blocking agents on the renal growth and on the renal content and urinary excretion of epidermal growth factor (EGF) in streptozotocin-induced diabetic or uninephrectomized rats. Diabetic and uninephrectomized rats were allocated to groups...... treated with either saline or adrenergic antagonists and compared to controls and sham-operated controls, respectively. 24-hour urine samples were obtained on days 7, 14, and 21 and renal tissue samples on day 21. The 24-hour urinary excretion of EGF from controls and saline-treated diabetic rats...

  11. A single bout of exercise induces beta-adrenergic desensitization in human adipose tissue. (United States)

    Marion-Latard, F; De Glisezinski, I; Crampes, F; Berlan, M; Galitzky, J; Suljkovicova, H; Riviere, D; Stich, V


    This study was designed to assess whether physiological activation of the sympathetic nervous system induced by exercise changes adipose tissue responsiveness to catecholamines in humans. Lipid mobilization in abdominal subcutaneous adipose tissue was studied with the use of a microdialysis method in 11 nontrained men (age: 22. 3 +/- 1.5 yr; body mass index: 23.0 +/- 1.6). Adipose tissue adrenergic sensitivity was explored with norepinephrine, dobutamine (beta(1)-agonist), or terbutaline (beta(2)-agonist) perfused during 30 min through probes before and after 60-min exercise (50% of the maximal aerobic power). The increase in extracellular glycerol concentration during infusion was significantly lower after the exercise when compared with the increase observed before the exercise (P < 0.05, P < 0.02, and P < 0.01, respectively, for norepinephrine, dobutamine, and terbutaline). In a control experiment realized without exercise, no difference in norepinephrine-induced glycerol increase between the two infusions was observed. To assess the involvement of catecholamines in the blunted beta-adrenergic-induced lipolytic response after exercise, adipose tissue adrenergic sensitivity was explored with two 60-min infusions of norepinephrine or epinephrine separated by a 60-min interval. With both catecholamines, the increase in glycerol was significantly lower during the second infusion (P < 0.05). The findings suggest that aerobic exercise, which increased adrenergic activity, induces a desensitization in beta(1)- and beta(2)-adrenergic lipolytic pathways in human subcutaneous adipose tissue.

  12. Multiple interactions between the alpha2C- and beta1-adrenergic receptors influence heart failure survival

    Directory of Open Access Journals (Sweden)

    Case Karen L


    Full Text Available Abstract Background Persistent stimulation of cardiac β1-adrenergic receptors by endogenous norepinephrine promotes heart failure progression. Polymorphisms of this gene are known to alter receptor function or expression, as are polymorphisms of the α2C-adrenergic receptor, which regulates norepinephrine release from cardiac presynaptic nerves. The purpose of this study was to investigate possible synergistic effects of polymorphisms of these two intronless genes (ADRB1 and ADRA2C, respectively on the risk of death/transplant in heart failure patients. Methods Sixteen sequence variations in ADRA2C and 17 sequence variations in ADRB1 were genotyped in a longitudinal study of 655 white heart failure patients. Eleven sequence variations in each gene were polymorphic in the heart failure cohort. Cox proportional hazards modeling was used to identify polymorphisms and potential intra- or intergenic interactions that influenced risk of death or cardiac transplant. A leave-one-out cross-validation method was utilized for internal validation. Results Three polymorphisms in ADRA2C and five polymorphisms in ADRB1 were involved in eight cross-validated epistatic interactions identifying several two-locus genotype classes with significant relative risks ranging from 3.02 to 9.23. There was no evidence of intragenic epistasis. Combining high risk genotype classes across epistatic pairs to take into account linkage disequilibrium, the relative risk of death or transplant was 3.35 (1.82, 6.18 relative to all other genotype classes. Conclusion Multiple polymorphisms act synergistically between the ADRA2C and ADRB1 genes to increase risk of death or cardiac transplant in heart failure patients.

  13. DNA Repair Gene Polymorphisms in the Nucleotide Excision Repair Pathway and Lung Cancer Risk: A Meta-analysis

    Institute of Scientific and Technical Information of China (English)

    Chao-rong Mei; Meng Luo; Hong-mei Li; Wen-jun Deng; Qing-hua Zhou


    Objective: A number of studies have reported the association of “XPA”, “XPC”, “XPD/ERCC2” gene polymorphisms with lung cancer risk. However, the results were conflict. To clarify the impact of polymorphisms of “XPA”, “XPC”; “XPD/ERCC2”, on lung cancer risk, a meta-analysis was performed in this study. Methods: The electronic databases PubMed and Embase were retrieved for studies included in this meta-analysis by “XPA”; “XPC”, “XPD/ERCC2”, “lung”, “cancer/neoplasm/tumor/carcinoma”, “polymorphism” (An upper date limit of October, 31, 2009). A meta-analysis was performed to evaluate the relationship among XPA, XPC and XPD polymorphism and lung cancer risks. Results: A total of 31 publications retrieved from Pubmed and Embase included in this study. XPC A939C CC genotype increased lung cancer risk in total population (recessive genetic model: OR=1.23, 95% Cl:1.05-1.44;homozygote comparison: OR=1.21,95%Cl:1.02-1.43and CC vs. CA contrast: OR=1.25,95%Cl:1.06-1.48), except in Asians. XPD A751C, 751C allele and CC genotype also increased lung cancer risk in total population and in Caucasians (recessive genetic model: Total population: OR=1.20, 95%Cl:1.07-1.35). No significant correlation was found between XPD A751C and lung cancer risk in Asians and African Americans. XPD G312A AA genotype increased lung cancer risk in total population, in Asians and Caucasians(recessive genetic model: Total population: OR=1.20, 95%Cl:1.06-1.36). No significant association was found between XPA G23A, XPC C499T, XPD C156A and lung cancer risk. Conclusion: Our results suggest that the polymorphisms in XPC and XPD involve in lung cancer risks. XPA polymorphisms is less related to lung cancer risk.

  14. β2肾上腺素能受体基因Gln27/Glu多态性与蒙古族原发性高血压的研究%Study of the β2-Adrenergic Receptor Gene Gln27/Glu Polymorphisms and Essential Hypertension in Mongolian Population

    Institute of Scientific and Technical Information of China (English)

    张晓云; 李云霞; 魏芳婧; 娜荣; 徐力; 阴淑莹


    目的 检测蒙古族原发性高血压(EH)人群中β2肾上腺素能受体基因Gln27/Glu多态性,探讨其与蒙古族人群EH和其他心血管病危险因素的关系.方法 选择蒙古族EH患者105例为观察组,另外选取蒙古族健康体检者102例为对照组,通过聚合酶链反应确定基因型,并测定所有患者的体质量指数(BMI)、空腹血三酰甘油、总胆固醇、低密度脂蛋白胆固醇、收缩压/舒张压、空腹血糖、尿酸等.结果 EH组和对照组Gln27/Glu多态性的基因型频率和等位基因频率比较差异无统计学意义(P>0.05),Gln27/Glu基因型个体的BMI显著高于Gln27/Gln基因型个体(P<0.05),三酰甘油、总胆固醇、低密度脂蛋白胆固醇、尿酸、空腹血糖等在三种基因型之间差异无统计学意义(P>0.05).结论 Gln27/Glu基因可能不是蒙古族EH的易患基因,该基因突变可能与肥胖有关.%Objective To study essential hypertension β-adrenergic rereptor( ADRB2 )gene Cln27/ Clu polymoiphism in Mongolian population, to test the hypothesis that polymorphism in the ADRB2 sene Cln27/Clu is associated with essential hypeitension( EH ) and other cardiovascular disease risk factors in Mongolian population. Methods 105 cases( observation group )of Mongolian patients with EH and 102 cases ( control group )of normal Mongolian were enrolled in this study. Targeted genotypes were determined by poly-merase chain reaction, and subjects were measured body mass index( BMI), lasting triglyceride( TC ), total cholesteioK TC ),low-density lipopiotein cholesteioK LDL-C ), and systolic/diastolic blood pressure,fasting glucose,and uric acid. Results Gln27/Glu polymoiphism senotypic and allele frequencies were not significantly different between the EH group and the control group(P >0. 05 ). BMI in individuals with Gln27/Glu genotype was significantly higher than the individuals with Gln27/Gln genotypes( P < 0. 05 ). And tiiglycei-ides,total cholesterol

  15. Alpha-adrenergic receptor blockade by phentolamine increases the efficacy of vasodilators in penile corpus cavernosum. (United States)

    Kim, N N; Goldstein, I; Moreland, R B; Traish, A M


    Penile trabecular smooth muscle tone, a major determinant of erectile function, is highly regulated by numerous inter- and intracellular pathways. The interaction between pathways mediating contraction and relaxation has not been studied in detail. To this end, we investigated the functional effects of alpha adrenergic receptor blockade with phentolamine and its interaction with vasodilators (sildenafil, vasoactive intestinal polypeptide (VIP) and PGE1) that elevate cyclic nucleotides on penile cavernosal smooth muscle contractility. In organ bath preparations of cavernosal tissue strips contracted with phenylephrine, phentolamine significantly enhanced relaxation induced by sildenafil, VIP and PGE1. Sildenafil, VIP or PGE1 also significantly enhanced relaxation induced by phentolamine in cavernosal tissue strips contracted with phenylephrine. To study the effects of alpha adrenergic receptor blockade and modification of cyclic nucleotide metabolism during active neurogenic input, cavernosal tissue strips in organ bath preparations were contracted with the non-adrenergic agonist endothelin-1 and subjected to electrical field stimulation (EFS) in the absence or presence of phentolamine and/or sildenafil. EFS (5-40Hz) typically caused biphasic relaxation and contraction responses. Phentolamine alone enhanced relaxation and reduced or prevented contraction to EFS. Sildenafil enhanced relaxation to EFS at lower frequencies (phentolamine and sildenafil enhanced EFS-induced relaxation at all frequencies tested. EFS, in the presence of 10 nM phentolamine and 30 nM sildenafil, produced enhanced relaxation responses which were quantitatively similar to those obtained in the presence of 50 nM sildenafil alone. Thus, blockade of alpha-adrenergic receptors with phentolamine increases the efficacy of cyclic nucleotide-dependent vasodilators. Furthermore, phentolamine potentiates relaxation and attenuates contraction in response to endogenous neurotransmitters which are released

  16. Multigenic control of measles vaccine immunity mediated by polymorphisms in measles receptor, innate pathway, and cytokine genes. (United States)

    Kennedy, Richard B; Ovsyannikova, Inna G; Haralambieva, Iana H; O'Byrne, Megan M; Jacobson, Robert M; Pankratz, V Shane; Poland, Gregory A


    Measles infection and vaccine response are complex biological processes that involve both viral and host genetic factors. We have previously investigated the influence of genetic polymorphisms on vaccine immune response, including measles vaccines, and have shown that polymorphisms in HLA, cytokine, cytokine receptor, and innate immune response genes are associated with variation in vaccine response but do not account for all of the inter-individual variance seen in vaccinated populations. In the current study we report the findings of a multigenic analysis of measles vaccine immunity, indicating a role for the measles virus receptor CD46, innate pattern-recognition receptors (DDX58, TLR2, 4, 5, 7 and 8) and intracellular signaling intermediates (MAP3K7, NFKBIA), and key antiviral molecules (VISA, OAS2, MX1, PKR) as well as cytokines (IFNA1, IL4, IL6, IL8, IL12B) and cytokine receptor genes (IL2RB, IL6R, IL8RA) in the genetic control of both humoral and cellular immune responses. This multivariate approach provided additional insights into the genetic control of measles vaccine responses over and above the information gained by our previous univariate SNP association analyses.

  17. The rush to adrenaline: drugs in sport acting on the beta-adrenergic system. (United States)

    Davis, E; Loiacono, R; Summers, R J


    Athletes attempt to improve performance with drugs that act on the beta-adrenergic system directly or indirectly. Of three beta-adrenoceptor (AR) subtypes, the beta(2)-AR is the main target in sport; they have bronchodilator and anabolic actions and enhance anti-inflammatory actions of corticosteroids. Although demonstrable in animal experiments and humans, there is little evidence that these properties can significantly improve performance in trained athletes. Their actions may also be compromised by receptor desensitization and by common, naturally occurring receptor mutations (polymorphisms) that can influence receptor signalling and desensitization properties in individuals. Indirectly acting agents affect release and reuptake of noradrenaline and adrenaline, thereby influencing all AR subtypes including the three beta-ARs. These agents can have potent psychostimulant effects that provide an illusion of better performance that does not usually translate into improvement in practice. Amphetamines and cocaine also have considerable potential for cardiac damage. beta-AR antagonists (beta-blockers) are used in sports that require steadiness and accuracy, such as archery and shooting, where their ability to reduce heart rate and muscle tremor may improve performance. They have a deleterious effect in endurance sports because they reduce physical performance and maximum exercise load. Recent studies have identified that many beta-AR antagonists not only block the actions of agonists but also activate other (mitogen-activated PK) signalling pathways influencing cell growth and fate. The concept that many compounds previously regarded as 'blockers' may express their own spectrum of pharmacological properties has potentially far-reaching consequences for the use of drugs both therapeutically and illicitly.

  18. Studies of the associations between functional beta2-adrenergic receptor variants and obesity, hypertension and type 2 diabetes in 7,808 white subjects

    DEFF Research Database (Denmark)

    Gjesing, A P; Andersen, G; Burgdorf, K S;


    Functional and common Arg16Gly and Gln27Glu polymorphisms have been identified in ADRB2, the gene encoding the beta2-adrenergic receptor. These variants have previously been examined for association with obesity, hypertension and diabetes with inconclusive results....

  19. Polymorphisms in the genes involved in the arachidonic acid-pathway, fish consumption and the risk of colorectal cancer.

    NARCIS (Netherlands)

    Siezen, Christine L E; Bueno-de-Mesquita, H Bas; Peeters, Petra H M; Kram, Nicolien R; Doeselaar, Marina van; Kranen, Henk J van


    The objective of this study on colorectal cancer was to investigate the associations between SNPs in the genes involved in the arachidonic acid (AA)-pathway, their haplotypes and colorectal cancer. Moreover, interactions between SNPs and fish consumption were considered. In this study, a total of 50

  20. Association of Polymorphisms in BDNF, MTHFR, and Genes Involved in the Dopaminergic Pathway with Memory in a Healthy Chinese Population (United States)

    Yeh, Ting-Kuang; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Pei-Jung; Wu, Chung-Hsin; Lee, Po-Lei; Chang, Chun-Yen


    The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single…

  1. Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett's Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium.

    Directory of Open Access Journals (Sweden)

    Katarina Lagergren

    Full Text Available The strong male predominance in oesophageal adenocarcinoma (OAC and Barrett's oesophagus (BO continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute.This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1, receptor beta (ESR2, and aromatase (CYP19A1, and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR, oxytocin protein (OXT, and cyclic ADP ribose hydrolase glycoprotein (CD38, were analysed using a gene-based approach, versatile gene-based test association study (VEGAS.Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058 and an increased risk of OAC and BO combined in males (p = 0.0023. Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035 and in males (p = 0.0012. We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only.Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.

  2. Roles of genetic polymorphisms in the folate pathway in childhood acute lymphoblastic leukemia evaluated by Bayesian relevance and effect size analysis.

    Directory of Open Access Journals (Sweden)

    Orsolya Lautner-Csorba

    Full Text Available In this study we investigated whether polymorphisms in the folate pathway influenced the risk of childhood acute lymphoblastic leukemia (ALL or the survival rate of the patients. For this we selected and genotyped 67 SNPs in 15 genes in the folate pathway in 543 children with ALL and 529 controls. The results were evaluated by gender adjusted logistic regression and by the Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA methods. Bayesian structure based odds ratios for the relevant variables and interactions were also calculated. Altogether 9 SNPs in 8 genes were associated with altered susceptibility to ALL. After correction for multiple testing, two associations remained significant. The genotype distribution of the MTHFD1 rs1076991 differed significantly between the ALL and control population. Analyzing the subtypes of the disease the GG genotype increased only the risk of B-cell ALL (p = 3.52×10(-4; OR = 2.00. The GG genotype of the rs3776455 SNP in the MTRR gene was associated with a significantly reduced risk to ALL (p = 1.21×10(-3; OR = 0.55, which resulted mainly from the reduced risk to B-cell and hyperdiploid-ALL. The TC genotype of the rs9909104 SNP in the SHMT1 gene was associated with a lower survival rate comparing it to the TT genotype (80.2% vs. 88.8%; p = 0.01. The BN-BMLA confirmed the main findings of the frequentist-based analysis and showed structural interactional maps and the probabilities of the different structural association types of the relevant SNPs especially in the hyperdiploid-ALL, involving additional SNPs in genes like TYMS, DHFR and GGH. We also investigated the statistical interactions and redundancies using structural model properties. These results gave further evidence that polymorphisms in the folate pathway could influence the ALL risk and the effectiveness of the therapy. It was also shown that in gene association studies the BN-BMLA could be a useful

  3. Associations between functional polymorphisms in the NFκB signaling pathway and response to anti-TNF treatment in Danish patients with inflammatory bowel disease. (United States)

    Bank, S; Andersen, P S; Burisch, J; Pedersen, N; Roug, S; Galsgaard, J; Turino, S Y; Brodersen, J B; Rashid, S; Rasmussen, B K; Avlund, S; Olesen, T B; Hoffmann, H J; Thomsen, M K; Thomsen, V Ø; Frydenberg, M; Nexø, B A; Sode, J; Vogel, U; Andersen, V


    Antitumor necrosis factor-α (TNF-α) is used for treatment of severe cases of inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). However, one-third of the patients do not respond to the treatment. Genetic markers may predict individual response to anti-TNF therapy. Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in 738 prior anti-TNF-naive Danish patients with IBD. The results were analyzed using logistic regression (crude and adjusted for age, gender and smoking status). Nineteen functional polymorphisms that alter the NFκB-mediated inflammatory response (TLR2 (rs3804099, rs11938228, rs1816702, rs4696480), TLR4 (rs5030728, rs1554973), TLR9 (rs187084, rs352139), LY96 (MD-2) (rs11465996), CD14 (rs2569190), MAP3K14 (NIK) (rs7222094)), TNF-α signaling (TNFA (TNF-α) (rs361525), TNFRSF1A (TNFR1) (rs4149570), TNFAIP3(A20) (rs6927172)) and other cytokines regulated by NFκB (IL1B (rs4848306), IL1RN (rs4251961), IL6 (rs10499563), IL17A (rs2275913), IFNG (rs2430561)) were associated with response to anti-TNF therapy among patients with CD, UC or both CD and UC (P ⩽ 0.05). In conclusion, the results suggest that polymorphisms in genes involved in activating NFκB through the Toll-like receptor (TLR) pathways, genes regulating TNF-α signaling and cytokines regulated by NFκB are important predictors for the response to anti-TNF therapy among patients with IBD. Genetically strong TNF-mediated inflammatory response was associated with beneficial response. In addition, the cytokines IL-1β, IL-6 and IFN-γ may be potential targets for treating patients with IBD who do not respond to anti-TNF therapy. These findings should be examined in independent cohorts before these results are applied in a clinical setting.

  4. Beta adrenergic receptors in human cavernous tissue

    Energy Technology Data Exchange (ETDEWEB)

    Dhabuwala, C.B.; Ramakrishna, C.V.; Anderson, G.F.


    Beta adrenergic receptor binding was performed with /sup 125/I iodocyanopindolol on human cavernous tissue membrane fractions from normal tissue and transsexual procedures obtained postoperatively, as well as from postmortem sources. Isotherm binding studies on normal fresh tissues indicated that the receptor density was 9.1 fmoles/mg. with a KD of 23 pM. Tissue stored at room temperature for 4 to 6 hours, then at 4C in saline solution for 19 to 20 hours before freezing showed no significant changes in receptor density or affinity, and provided evidence for the stability of postmortem tissue obtained within the same time period. Beta receptor density of 2 cavernous preparations from transsexual procedures was not significantly different from normal control tissues, and showed that high concentrations of estrogen received by these patients had no effect on beta adrenergic receptor density. Displacement of /sup 125/iodocyanopindolol by 5 beta adrenergic agents demonstrated that 1-propranolol had the greatest affinity followed by ICI 118,551, zinterol, metoprolol and practolol. When the results of these displacement studies were subjected to Scatfit, non- linear regression line analysis, a single binding site was described. Based on the relative potency of the selective beta adrenergic agents it appears that these receptors were of the beta 2 subtype.


    NARCIS (Netherlands)



    A neurochemical assessment of noradrenergic and adrenergic functioning was carried out with autistic patients and normal control individuals. Norepinephrine and related compounds were measured in autistic (n = 17 unmedicated, 23 medicated; age range 9-29 years old) and normal controls (n = 27; age r

  6. Mechanism of adrenergic stimulation of hepatic ketogenesis. (United States)

    Kosugi, K; Harano, Y; Nakano, T; Suzuki, M; Kashiwagi, A; Shigeta, Y


    The effects of alpha- and beta-adrenergic stimulation on ketogenesis were examined in freshly isolated rat hepatocytes in order to determine which alpha- or beta-adrenergic stimulation is involved in the enhancement of ketogenesis. In the presence of 0.3 mmol/L (U-14C)-palmitate, epinephrine, norepinephrine, and phenylephrine at 500 ng/mL increased ketogenesis by 25% (16.0 +/- 0.17 v 12.8 +/- 0.13 nmol/mg protein per hour), 20% (15.3 +/- 0.28) and 20% (15.4 +/- 0.36), respectively. However, isoproterenol even at 1 microgram/mL did not stimulate ketogenesis. Phentolamine (5 micrograms/mL) almost completely abolished the effect of epinephrine on ketogenesis (13.7 +/- 0.30 v 16.0 +/- 0.17) but propranolol did not inhibit the stimulation by epinephrine (15.6 +/- 0.38 v 16.0 +/- 0.17). Trifluoperazine (10 mumol/L), presumably an inhibitor of calcium-dependent protein kinase, abolished the effect of epinephrine (13.6 +/- 0.22 v 16.0 +/- 0.17). These results indicate that catecholamines increase ketogenesis predominantly through the alpha-adrenergic system independent of cyclic AMP, and calcium-dependent protein kinase is thought to be involved in the activation of ketogenesis. On the other hand, glucagon stimulated ketogenesis with an increase of cyclic AMP, which was not inhibited by alpha- and beta-adrenergic antagonists. Alpha-adrenergic stimulation increased hepatic glycogenolysis much more at much lower concentrations when compared with ketogenesis. Stimulation of ketogenesis by catecholamines seemed to be less sensitive and responsive compared with hepatic glycogenolysis.

  7. The signal transduction pathway of β2-adrenergic receptor regulating INcx in myocytes%β2肾上腺素受体对心肌细胞钠钙交换电流调控的信号转导途径

    Institute of Scientific and Technical Information of China (English)

    杨蕙; 伍卫; 邓春玉


    目的 研究β2肾上腺素受体(β2受体)对大鼠心肌细胞钠钙交换电流( INcx)调控作用的信号转导途径.方法 雄性健康Wistar大鼠12只,采用经典的酶分离心肌细胞方法,应用全细胞膜片钳技术记录给药前后INcX.药物组合方案包括:予以环磷酸腺苷(cAMP)激动剂forskolin灌流;灌流β2受体激动剂salbutamol后再以PKA(蛋白激酶A)抑制剂H89或抑制型G蛋白(Gi)抑制剂百日咳毒素(PTX)灌流.结果 forskolin可使INcX密度升高102.1%,H89可抑制salbutamol升高INcX密度的作用达34.7%,PTX能增大salbutamol的作用,Incx密度较单独予以salbutamol升高36.8%(P均<0.05).结论 β2受体激动可能通过刺激型G蛋白/Gi蛋白(Gi)-cAMP-PKA途径参与调节Incx.%Objective To investigate the signal transduction pathway of β2-adrenergic receptor( β2-AR) regulating INCX in myocytes. Methods Myocytes of twelve adult Wistar rats were enzymatically disassociated by Langedorff peifusion. Whole cell-patch clamp recording technique was used to record INCX in specific pipette solution and supeifusion according to specific holding potential and command potential program. The response to forskolin and the p2-AR agonist salbutamol was obtained solely or after treatment with H89 or pertussis toxin ( PTX). Results Treatment with forskolin increased inward INCX in ventricular myocytes by 102.1% ( P <0.05 ). H89 attenuated the rise of INCX induced by salbutamol (P <0.05 ). PTX enlarged the rise of INCX by 36.8% ( P < 0.05). Conclusion INCX might be regulated by β2 -AR through the pathway of Gs/Gi-Camp-PKA. [Chinese Journal of Cardiac Pacing and Electrophysiology ,2011,25(4):343 -345

  8. Acute exposure to long-chain fatty acids impairs {alpha}2-adrenergic receptor-mediated antilipolysis in human adipose tissue. (United States)

    Polak, Jan; Moro, Cédric; Bessière, David; Hejnova, Jindra; Marquès, Marie A; Bajzova, Magda; Lafontan, Max; Crampes, Francois; Berlan, Michel; Stich, Vladimir


    The acute in vitro and in vivo effects of long-chain fatty acids (LCFAs) on the regulation of adrenergic lipolysis were investigated in human adipose tissue. The effect of a 2 h incubation, without or with LCFA (200 mumol/l), on basal and hormonally induced lipolysis was tested in vitro on isolated fat cells. The lipolytic response to epinephrine was enhanced by suppression of the antilipolytic alpha(2)-adrenergic effect. Then, healthy lean and obese male subjects performed a 45 min exercise bout at 50% of their heart rate reserve either after an overnight fast or 3 h after a high-fat meal (HFM: 95% fat, 5% carbohydrates). Subcutaneous adipose tissue lipolysis was measured by microdialysis in the presence or absence of an alpha-antagonist (phentolamine). In vivo, a HFM increased plasma levels of nonesterified fatty acids in lean and obese subjects. In both groups, the HFM did not alter hormonal responses to exercise. Under fasting conditions, the alpha(2)-adrenergic antilipolytic effect was more pronounced in obese than in lean subjects. The HFM totally suppressed the alpha(2)-adrenergic antilipolytic effect in lean and obese subjects during exercise. LCFAs per se, in vitro as well as in vivo, suppress alpha(2)-adrenergic-mediated antilipolysis in adipose tissue. LCFA-mediated suppression of antilipolytic pathways represents another mechanism whereby a high fat content in the diet might increase adipose tissue lipolysis.

  9. Cytokine polymorphisms in Th1/Th2 pathway genes, body mass index, and risk of non-Hodgkin lymphoma. (United States)

    Chen, Yingtai; Zheng, Tongzhang; Lan, Qing; Foss, Francine; Kim, Christopher; Chen, Xuezhong; Dai, Min; Li, Yumin; Holford, Theodore; Leaderer, Brian; Boyle, Peter; Chanock, Stephen J; Rothman, Nathaniel; Zhang, Yawei


    We conducted a population-based, case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared with those with BMI less than 25 kg/m(2), women with BMI more than or equal to 25 kg/m(2) had 50% to 90% increased risk of NHL among women who carried IFNGR2 (rs9808753) AA, IL5 (rs2069812) CT/TT, IL7R (rs1494555) AA, and TNF (rs1799724) CC genotypes, but no increased risk among women with IFNGR2 AG/GG, IL5 CC, IL7R AG/GG, and TNF CT/TT genotypes. A significant interaction with BMI was only observed for IFNGR2 (rs9808753 P(forinteraction) = .034) and IL7R (rs1494555 P(forinteraction) = .016) for NHL overall; IL7R (rs1494555 P(forinteraction) = .016) and TNF (1799724 P(forinteraction) = .031) for B-cell lymphoma; and IL5 (rs2069812 P(forinteraction) = .034) for T-cell lymphoma. After stratification by common B-cell lymphoma subtypes, a significant interaction was observed for IFNGR2 (rs9808753 P(forinteraction) = .006), IL13 (rs20541 P(forinteraction) = .019), and IL7R (rs1494555 P(forinteraction) = .012) for marginal zone B-cell lymphoma; IL7R (rs1494555 P(forinteraction) = .017) for small lymphocytic lymphoma/chronic lymphocytic leukemia; and IL12A (rs568408 P(forinteraction) = .013) and TNF (1799724 P(forinteraction) = .04) for follicular lymphoma. The results suggest that common genetic variation in Th1/Th2 pathway genes may modify the association between BMI and NHL risk.

  10. β2 Adrenergic receptor on T lymphocytes and its clinical implications

    Institute of Scientific and Technical Information of China (English)

    Xuelai Fan; Yuedan Wang


    Sustained complex cross-talk between the immune system and the nervous system plays a vital role in retaining homeostasis in a healthy individual.One of the central regulatory mechanisms involved is the existence and functions of β2-adrenergic receptors (β2AR) on T lymphocytes.This article reviews research progress made recently,including the expression of adrenergic receptors on Tlymphocytes,the structure and intracellular pathways of β2AR,the activation of I32AR by either endogenous or exogenous agonists,and the effect of β2AR stimulation on T cells which alters T cell proliferation,differentiation,cytokine production and T-helper-mediated antibody production.Furthermore,we discuss the roles of β2AR played in the pathogenesis and treatment of autoimmune diseases.

  11. Adrenergic Receptors From Molecular Structure to in vivo function. (United States)

    Hein, L; Kobilka, B K


    Adrenergic receptors form the interface between the sympathetic nervous system and the cardiovascular system as well as many endocrine and parenchymal tissues. Although several hundred G-protein-coupled receptors have been identified, adrenergic receptors, along with the visual pigment rhodopsin, have been among the most extensively studied members of this family of receptors. This review focuses on recent advances in understanding the molecular structure, function, and regulation of adrenergic receptors using in vitro systems and integrates recent transgenic animal models that were generated to study the adrenergic system in vivo. (Trends Cardiovasc Med 1997;7:137-145). © 1997, Elsevier Science Inc.

  12. Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility. (United States)

    Lascorz, Jesús; Försti, Asta; Chen, Bowang; Buch, Stephan; Steinke, Verena; Rahner, Nils; Holinski-Feder, Elke; Morak, Monika; Schackert, Hans K; Görgens, Heike; Schulmann, Karsten; Goecke, Timm; Kloor, Matthias; Engel, Cristoph; Büttner, Reinhard; Kunkel, Nelli; Weires, Marianne; Hoffmeister, Michael; Pardini, Barbara; Naccarati, Alessio; Vodickova, Ludmila; Novotny, Jan; Schreiber, Stefan; Krawczak, Michael; Bröring, Clemens D; Völzke, Henry; Schafmayer, Clemens; Vodicka, Pavel; Chang-Claude, Jenny; Brenner, Hermann; Burwinkel, Barbara; Propping, Peter; Hampe, Jochen; Hemminki, Kari


    Genetic susceptibility accounts for approximately 35% of all colorectal cancer (CRC). Ten common low-risk variants contributing to CRC risk have been identified through genome-wide association studies (GWASs). In our GWAS, 610 664 genotyped single-nucleotide polymorphisms (SNPs) passed the quality control filtering in 371 German familial CRC patients and 1263 controls, and replication studies were conducted in four additional case-control sets (4915 cases and 5607 controls). Known risk loci at 8q24.21 and 11q23 were confirmed, and a previously unreported association, rs12701937, located between the genes GLI3 (GLI family zinc finger 3) and INHBA (inhibin, beta A) [P = 1.1 x 10(-3), odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05-1.23, dominant model in the combined cohort], was identified. The association was stronger in familial cases compared with unselected cases (P = 2.0 x 10(-4), OR 1.36, 95% CI 1.16-1.60, dominant model). Two other unreported SNPs, rs6038071, 40 kb upstream of CSNK2A1 (casein kinase 2, alpha 1 polypeptide) and an intronic marker in MYO3A (myosin IIIA), rs11014993, associated with CRC only in the familial CRC cases (P = 2.5 x 10(-3), recessive model, and P = 2.7 x 10(-4), dominant model). Three software tools successfully pointed to the overrepresentation of genes related to the mitogen-activated protein kinase (MAPK) signalling pathways among the 1340 most strongly associated markers from the GWAS (allelic P value genes involved in MAPK signalling events (P(trend) = 2.2 x 10(-16), OR(per allele) = 1.34, 95% CI 1.11-1.61).

  13. Polymorphisms in genes involved in the NF-κB signalling pathway are associated with bone mineral density, geometry and turnover in men.

    Directory of Open Access Journals (Sweden)

    Delnaz Roshandel

    Full Text Available INTRODUCTION: In this study, we aimed to investigate the association between single nucleotide polymorphisms (SNPs within two genes involved in the NF-κB cascade (GPR177 and MAP3K14 and bone mineral density (BMD assessed at different skeletal sites, radial geometric parameters and bone turnover. METHODS: Ten GPR177 SNPs previously associated with BMD with genome-wide significance and twelve tag SNPs (r(2≥0.8 within MAP3K14 (±10 kb were genotyped in 2359 men aged 40-79 years recruited from 8 centres for participation in the European Male Aging Study (EMAS. Measurement of bone turnover markers (PINP and CTX-I in the serum and quantitative ultrasound (QUS at the calcaneus were performed in all centres. Dual energy X-ray absorptiometry (DXA, at the lumbar spine and hip, and peripheral quantitative computed tomography (pQCT, at the distal and midshaft radius, were performed in a subsample (2 centres. Linear regression was used to test for association between the SNPs and bone measures under an additive genetic model adjusting for study centre. RESULTS: We validated the associations between SNPs in GPR177 and BMD(a previously reported and also observed evidence of pleiotrophic effects on density and geometry. Rs2772300 in GPR177 was associated with increased total hip and LS BMD(a, increased total and cortical vBMD at the radius and increased cortical area, thickness and stress strain index. We also found evidence of association with BMD(a, vBMD, geometric parameters and CTX-I for SNPs in MAP3K14. None of the GPR177 and MAP3K14 SNPs were associated with calcaneal estimated BMD measured by QUS. CONCLUSION: Our findings suggest that SNPs in GPR177 and MAP3K14 involved in the NF-κB signalling pathway influence bone mineral density, geometry and turnover in a population-based cohort of middle aged and elderly men. This adds to the understanding of the role of genetic variation in this pathway in determining bone health.

  14. Inter-individual variation in nucleotide excision repair pathway is modulated by non-synonymous polymorphisms in ERCC4 and MBD4 genes

    Energy Technology Data Exchange (ETDEWEB)

    Allione, Alessandra, E-mail: [Human Genetics Foundation (HuGeF), Via Nizza 52, 10126 Turin (Italy); Guarrera, Simonetta; Russo, Alessia [Human Genetics Foundation (HuGeF), Via Nizza 52, 10126 Turin (Italy); Ricceri, Fulvio [Human Genetics Foundation (HuGeF), Via Nizza 52, 10126 Turin (Italy); Department of Medical Sciences, University of Turin, Via Santena 19, 10126 Turin (Italy); Purohit, Rituraj [Human Genetics Foundation (HuGeF), Via Nizza 52, 10126 Turin (Italy); Bioinformatics Division, School of Bio Sciences and Technology, Vellore Institute of Technology University, Vellore 632014, Tamil Nadu (India); Pagnani, Andrea; Rosa, Fabio; Polidoro, Silvia; Voglino, Floriana [Human Genetics Foundation (HuGeF), Via Nizza 52, 10126 Turin (Italy); Matullo, Giuseppe [Human Genetics Foundation (HuGeF), Via Nizza 52, 10126 Turin (Italy); Department of Medical Sciences, University of Turin, Via Santena 19, 10126 Turin (Italy)


    Highlights: • We reported a large inter-individual variability of NER capacity. • ERCC4 rs1800124 and MBD4 rs10342 nsSNP variants were associated with DNA repair capacity. • DNA–protein interaction analyses showed alteration of binding for ERCC4 and MBD4 variants. • A new possible cross-talk between NER and BER pathways has been reported. - Abstract: Inter-individual differences in DNA repair capacity (DRC) may lead to genome instability and, consequently, modulate individual cancer risk. Among the different DNA repair pathways, nucleotide excision repair (NER) is one of the most versatile, as it can eliminate a wide range of helix-distorting DNA lesions caused by ultraviolet light irradiation and chemical mutagens. We performed a genotype–phenotype correlation study in 122 healthy subjects in order to assess if any associations exist between phenotypic profiles of NER and DNA repair gene single nucleotide polymorphisms (SNPs). Individuals were genotyped for 768 SNPs with a custom Illumina Golden Gate Assay, and peripheral blood mononuclear cells (PBMCs) of the same subjects were tested for a NER comet assay to measure DRC after challenging cells by benzo(a)pyrene diolepoxide (BPDE). We observed a large inter-individual variability of NER capacity, with women showing a statistically significant lower DRC (mean ± SD: 6.68 ± 4.76; p = 0.004) than men (mean ± SD: 8.89 ± 5.20). Moreover, DRC was significantly lower in individuals carrying a variant allele for the ERCC4 rs1800124 non-synonymous SNP (nsSNP) (p = 0.006) and significantly higher in subjects with the variant allele of MBD4 rs2005618 SNP (p = 0.008), in linkage disequilibrium (r{sup 2} = 0.908) with rs10342 nsSNP. Traditional in silico docking approaches on protein–DNA and protein–protein interaction showed that Gly875 variant in ERCC4 (rs1800124) decreases the DNA–protein interaction and that Ser273 and Thr273 variants in MBD4 (rs10342) indicate complete loss of protein

  15. Muscle Plasticity and β2-Adrenergic Receptors: Adaptive Responses of β2-Adrenergic Receptor Expression to Muscle Hypertrophy and Atrophy

    Directory of Open Access Journals (Sweden)

    Shogo Sato


    Full Text Available We discuss the functional roles of β2-adrenergic receptors in skeletal muscle hypertrophy and atrophy as well as the adaptive responses of β2-adrenergic receptor expression to anabolic and catabolic conditions. β2-Adrenergic receptor stimulation using anabolic drugs increases muscle mass by promoting muscle protein synthesis and/or attenuating protein degradation. These effects are prevented by the downregulation of the receptor. Endurance training improves oxidative performance partly by increasing β2-adrenergic receptor density in exercise-recruited slow-twitch muscles. However, excessive stimulation of β2-adrenergic receptors negates their beneficial effects. Although the preventive effects of β2-adrenergic receptor stimulation on atrophy induced by muscle disuse and catabolic hormones or drugs are observed, these catabolic conditions decrease β2-adrenergic receptor expression in slow-twitch muscles. These findings present evidence against the use of β2-adrenergic agonists in therapy for muscle wasting and weakness. Thus, β2-adrenergic receptors in the skeletal muscles play an important physiological role in the regulation of protein and energy balance.

  16. Influence of angiotensin converting enzyme gene insertion/deletion polymorphism and β3-adrenergic receptor gene Trp64Arg polymorphism on fetal growth and neonatal insulin sensitivity%血管紧张素转化酶基因插入/缺失多态性及β3肾上腺素能受体基因Trp64Arg多态性对胎儿宫内发育及新生儿胰岛素敏感性的影响

    Institute of Scientific and Technical Information of China (English)

    崔蕴璞; 韩彤妍; 王新利; 叶鸿瑁


    Objective To understand the influence of angiotensin converting enzyme(ACE)gene insertion/deletion(I/D)polymorphism and β3-adrenergic receptor(β3-AR)gene Trp64Arg polymorphism on fetal growth and neonatal insulin sensitivity.Methods Totally 296 newborn infants were selected into our study and divided into 2 groups according to gestational age and birth weight:adequate-for-gestationalage(AGA)group(222 cases)and small-for-gestational-age(SGA)group(74 case).Serum glucose and insulin were examined in the morning of the 3rd day before milk.Insulin sensitivity was evaluated by homeostasis model assessment(HOMA)equation.β3-AR gene Trp64Arg polymorphism and ACE gene I/D polymorphism(202 cases)were analysed using polymerase chain reaction-restricted fragment length polymorphism(PCR-RFLP)technique.Gestational age,birth weight,birth weight percentage,serum glucose,insulin and HOMA-IR were compared among different genotype groups.Statistical analysis was performed with the SPSS 10.0 software.Results No significant difference was found between the sernm glucose level of SGA group(4.03±1.05 mmol/L)and AGA group(4.05±1.14 mmol/L),P=0.008. The serum insulin level(converted into Ln)of SGA group(2.262±0.746)was significantly higher than that of AGA group(1.757±0.805),P<0.001.The HOMA-IR(also convened into Ln)level of SGA group(0.217±0.367)was also significantly higher than that of AGA group(0.001±0.378),P<0.001. In the SGA group β3-AR gene Arg64 allele carriers had higher serum insulin and HOMA-IR level(botll changed to Ln,2.654±0.701,0.371±0.338)compared with noncarriers(2.074±0.698,0.143± O.360),P<0.05.The ACE gene DD genotype carriers had higher serum insulin and HOMA-IR level(both were converted into Ln,2.19 4-0.91,0.5l 4-1.01)compared with II(1.77 ±0.85,0.02 ±0.93) and ID genotype group(1.77 ±0.83,0.05 ±0.91),P<0.05.The ACE gene DD carriers had lower birth weight percentage compared with II and ID genotype group.P<0.05.When both genes'polymorphisms were taken

  17. Signal Transduction Pathway of β2-Adrenergic Receptor Regulating INCX in Myocytes of Infarcted Rats%β2受体对心肌梗死大鼠心肌细胞钠钙交换电流调控的信号转导途径

    Institute of Scientific and Technical Information of China (English)

    杨蕙; 伍卫; 邓春玉


    [目的]研究β2肾上腺素受体(β2受体)对心肌梗死大鼠心肌细胞钠钙交换电流(INCX)调控作用的信号转导途径.[方法]雄性健康Wistar大鼠30只,随机分为正常对照和心肌梗死(MI)组,制作MI模型.采用经典的酶分离心肌细胞方法,应用全细胞膜片钳技术记录INCX,予以β2受体激动剂salbutamol、cAMP激动剂forskolin、抑制性cAMP类似物Rp-cAMPS、PKA抑制剂H89及Gi蛋白抑制剂后记录INCX的变化.[结果]在正常和梗死后4周心肌细胞,forskoin可使INCX电流密度升高108.9%和70.3%(P<0.05),抑制性cAMP类似物Rp-cAMPS可抑制salbutamol升高INCX电流密度的作用(P<O.05),PTX 能增大salbutamol的作用,INCX电流密度较单独予以salbutamol升高36.8%和50.6%(P<0.05),H89可抑制salbutamol升高INCX电流密度的作用(P<0.05).[结论]β2受体激动可能通过Gi-cAMP-PKA途径参与调节INCX.%[Objective] To investigate the signal transduction pathway of β2-adrenergic receptor (β2-AR) regulating INCX in myocytes from infarcted rats. [Methods] Thirty adult Wistar rats were divided into two groups at random: the control group (n = 15) and the post-myocardial infarction (post-MI) group (ra = 15). The chest of rats were opened and ligature were placed around the left anterior descending coronary artery. Rats in control group were sham-operated without coronary artery ligation. Myocytes were enzymatically disassociated by Langedorff perfusion. Whole cell-patch clamp recording technique was used to record INCX in specific pipette solution and superfusion according to specific holding potential and command potential program. [Results] In the control group and the post-MI group, treatment with forskolin increased inward INCX in ventricular myocytes by 108.9% and 70.3% (P < 0.05), respectively. An inhibitory cAMP analog (Rp-cAMPS) and H89 attenuated the rise of INCX induced by salbutamol (a selective beta2-AR agonist)(P< 0.05); pertussis toxin enlarged the rise

  18. [Mivazerol and other benzylimidazoles with alpha-2 adrenergic properties]. (United States)

    Cossement, E; Geerts, J P; Michel, P; Motte, G; Noyer, M


    4-Benzyl-imidazole compounds derived from Salbutanol are evaluated for potential adrenergic activities. The prevalent property of a series of new bioisosteres of catecholamines either of the saligenol-(ucb LO61) or benzamide-(Mivazerol) type is a selective alpha-adrenergic agonism, at the presynaptic level. The present study stresses the structural features responsible for the alpha-2-agonistic property.

  19. Effect of β3-adrenergic receptor gene Trp64Arg polymorphism on uric acid levels in a Chinese male type 2 diabetes mellitus population%β3肾上腺素受体基因Trp64Arg多态性与中国男性2型糖尿病患者合并高尿酸血症的相关性研究

    Institute of Scientific and Technical Information of China (English)

    黄琼; 张留福; 程雁; 司力; 魏伟


    目的:探讨中国人群男性2型糖尿病患者中β3肾上腺素受体基因Trp64Arg多态性与高尿酸血症的相关性.方法:196名高尿酸血症的2型糖尿病患者和196名正常尿酸水平的2型糖尿病患者进行基因分型.检测体重指数、腰臀比、收缩压、舒张压、血尿酸、肌酐、尿素氮、甘油三酯、低密度脂蛋白胆固醇脂、高密度脂蛋白胆固醇脂、空腹血糖和餐后血糖的水平.结果:高尿酸血症组中,携带不同β3肾上腺素受体Trp64Arg基因型的2型糖尿病患者其尿酸水平有统计学差异,且呈基因剂量效应[CC组(599.53±113.70) vs CT组(529.78±81.10) vs TT组(507.33±74.27),P<0.01].在该研究中,Trp64Arg TC+CC基因型患者的血尿酸水平亦显著高于TT基因型组p(557.95±99.91) vs (503.47±69.40) μmol/L,P<0.01].结论:β3肾上腺素受体基因Trp64Arg多态性与2型糖尿病合并高尿酸血症的具有相关性.%AIM:To investigate the association of β3-adrenergic receptor gene Trp64Arg polymorphism with hyperuricemia in a Chinese male type 2 diabetes mellitus patients population.METHODS:196 hyperuricemic and 196 normouricemic male subjects were genotyped in this study.Body mass index (BMI),waist to hip ratio (WHR),systolic blood pressure (SBP),diastolic blood pressure (DBP),serum uric acid,urea nitrogen,creatinine,triglyceride,total cholesterol,low-density lipoprotein-cholesterol (LDL-C),high-density lipoprotein-cholesterol (HDL-C),fasting plasma glucose (FPG),postprandial plasma glucose (PPG) were detected.RESULTS:We found patients with different Trp64Arg genotype showed significant differences in average uric acid concentrations (599.53±113.70 vs 529.78±81.10 vs 507.33±74.27,P<0.01) among CC,CT and TT genotype and there were significantly higher average uric acid concentrations in Trp64Arg TC + CC genotype individuals (557.95 ± 99.91 vs 503.47 ± 69.40 μ mol/L,P < 0.01) than those TT genotype subjects in the hyperuricemic group

  20. [Adrenergic innervation and norepinephrine content in postnatal rat uterus]. (United States)

    Itoh, M


    Using fluorescent histochemical method and high performance liquid chromatography with electrochemical detector, we investigated adrenergic innervation and norepinephrine content in the rat uterus in the process of the growth. The adrenergic nerve terminals in the rat uterus developed with age and reached to adult level at 7 weeks of age after birth, although the short adrenergic ganglionic cells and small intense fluorescent cells were present even at birth. Norepinephrine content per organ also increased with age and reached to adult level at 10 weeks of age after birth, while NE content per gram wet tissue weight had a peak in 3-day-old rat uterus. These morphological and biochemical data revealed that the sympathetic nervous system in rat uterus matures in 7 to 10 weeks after birth, while the short adrenergic nervous system is accomplished in earlier stage. The maturation of adrenergic innervation in the uterus was considerably later than in the other organs of rat and developed with the sexual maturation.

  1. Adrenergic urticaria: review of the literature and proposed mechanism. (United States)

    Hogan, Sara R; Mandrell, Joshua; Eilers, David


    Adrenergic urticaria is a rare type of stress-induced physical urticaria characterized by transient outbreaks of red papules surrounded by halos of hypopigmented, vasoconstricted skin. First described in 1985, there are 10 reported cases of adrenergic urticaria in the English-language medical literature. Episodes are caused by various triggers, including emotional upset, coffee, and chocolate, during which serum catecholamines and IgE are elevated, whereas histamine and serotonin levels remain within normal limits. The precise mechanisms leading to the pathogenesis of adrenergic urticaria have yet to be elucidated. Diagnosis can be made by intradermal injection of epinephrine or norepinephrine, which reproduces the characteristic rash, or by clinical observation. Trigger avoidance and oral propranolol are currently the best known treatments for adrenergic urticaria. Nonspecific therapies, including tranquilizers and antihistamines, may also ease symptoms. This article explores the pathophysiology of adrenergic urticaria and proposes a mechanism by which propranolol treats the condition.

  2. Phosphoinositide metabolism and adrenergic receptors in astrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Noble, E.P.; Ritchie, T.; de Vellis, J.


    Agonist-induced phosphoinositide (PI) breakdown functions as a signal generating system. Diacylglycerol, one breakdown product of phosphotidylinositol-4,5-diphosphate hydrolysis, can stimulate protein kinase C, whereas inositol triphosphate, the other product, has been proposed to be a second messenger for Ca/sup + +/ mobilization. Using purified astrocyte cultures from neonatal rat brain, the effects of adrenergic agonists and antagonists at 10/sup -5/ M were measured on PI breakdown. Astrocytes grown in culture were prelabeled with (/sup 3/H)inositol, and basal (/sup 3/H) inositol phosphate (IP/sub 1/) accumulation was measured in the presence of Li/sup +/. Epinephrine > norepinephrine (NE) were the most active stimulants of IP/sub 1/ production. The ..cap alpha../sub 1/ adrenoreceptor blockers, phentolamine and phenoxybenzamine, added alone had no effect on IP/sub 1/ production was reduced below basal levels. Propranolol partially blocked the effects of NE. Clonidine and isoproterenol, separately added, reduced IP/sub 1/ below basal levels and when added together diminished IP/sub 1/ accumulation even further. The role of adrenergic stimulation in the production of c-AMP.

  3. Alpha-Amylase Activity in Blood Increases after Pharmacological, But Not Psychological, Activation of the Adrenergic System (United States)

    Nater, Urs M.; La Marca, Roberto; Erni, Katja; Ehlert, Ulrike


    Background & Aim Alpha-amylase in both blood and saliva has been used as a diagnostic parameter. While studies examining alpha-amylase activity in saliva have shown that it is sensitive to physiological and psychological challenge of the adrenergic system, no challenge studies have attempted to elucidate the role of the adrenergic system in alpha-amylase activity in blood. We set out to examine the impact of psychological and pharmacological challenge on alpha-amylase in blood in two separate studies. Methods In study 1, healthy subjects were examined in a placebo-controlled, double-blind paradigm using yohimbine, an alpha2-adrenergic antagonist. In study 2, subjects were examined in a standardized rest-controlled psychosocial stress protocol. Alpha-amylase activity in blood was repeatedly measured in both studies. Results Results of study 1 showed that alpha-amylase in blood is subject to stronger increases after injection of yohimbine compared to placebo. In study 2, results showed that there was no significant effect of psychological stress compared to rest. Conclusions Alpha-amylase in blood increases after pharmacological activation of the adrenergic pathways suggesting that sympathetic receptors are responsible for these changes. Psychological stress, however, does not seem to have an impact on alpha-amylase in blood. Our findings provide insight into the mechanisms underlying activity changes in alpha-amylase in blood in healthy individuals. PMID:26110636

  4. Beta 2-adrenergic receptor gene association with overweight and asthma in children and adolescents and its relationship with physical fitness

    Directory of Open Access Journals (Sweden)

    Neiva Leite


    Full Text Available Objective: To investigate the association of Arg16Gly and Gln27Glu polymorphisms of β2-adrenergic receptor gene (ADRB2 with the occurrence of asthma and overweight and the gene's influence on anthropometric, clinic, biochemical and physical fitness variables in children and adolescents. Methods: Subjects were evaluated for allelic frequencies of the β2-adrenergic receptor gene, height, weight, body mass index (BMI, BMI Z-score, waist circumference (WC, pubertal stage, resting heart rate (HRres, blood pressure (BP, total cholesterol (TC, glucose, insulin, high density lipoprotein (HDL-C, low density lipoprotein (LDL-C, triglyceride (TG, Homeostasis Metabolic Assessment (HOMA2-IR, Quantitative Insulin Sensitivity Check Index (QUICKI and maximal oxygen uptake (VO2max. The participants were divided in four groups: overweight asthmatic (n=39, overweight non-asthmatic (n=115, normal weight asthmatic (n=12, and normal weight non-asthmatic (n=40. Results: Regarding the Gln27Glu polymorphism, higher total cholesterol was observed in usual genotype individuals than in genetic variant carriers (p=0.04. No evidence was found that the evaluated polymorphisms are influencing the physical fitness. The Arg16 allele was found more frequently among the normal weight asthmatic group when compared to the normal weight non-asthmatic group (p=0.02, and the Glu27 allele was more frequently found in the overweight asthmatics group when compared to the normal weight non-asthmatic group (p=0.03. Conclusions: The association of Arg16 allele with the occurrence of asthma and of the Glu27 allele with overweight asthmatic adolescents evidenced the contribution of the β2-adrenergic receptor gene to the development of obesity and asthma.

  5. Cholinergic and adrenergic influence on the teleost heart in vivo. (United States)

    Axelsson, M; Ehrenström, F; Nilsson, S


    The tonical cholinergic and adrenergic influence on the heart rate was investigated in vivo in seven species of marine teleosts (pollack, Pollachius pollachius; cuckoo wrasse, Labrus mixtus; ballan wrasse, Labrus berggylta; five-bearded rockling, Ciliata mustela; tadpole fish, Raniceps raninus; eel-pout, Zoarces viviparus and short-spined sea scorpion, Myoxocephalus scor pius) during rest and, in two of the species (P. pollachius and L. mixtus), also during moderate swimming exercise in a Blazka-type swim tunnel. Ventral aortic blood pressure and heart rate were recorded via a catheter implanted in an afferent branchial artery, and the influence of the cholinergic and adrenergic tonus on the heart rate was assessed by injection of atropine and sotalol respectively. During rest the adrenergic tonus was higher than the cholinergic tonus in all species except L. berggylta, where the reverse was true. In P. pollachius and L. mixtus, exercise appeared to produce a lowering of the cholinergic tonus on the heart and, possibly, a slight increase of the adrenergic tonus. The nature of the adrenergic tonus (humoral or neural) is not clear, but the low plasma concentrations of catecholamines both during rest and exercise could be interpreted in favour of a mainly neural adrenergic tonus on the teleost heart. These experiments are compatible with the view that both a cholinergic inhibitory tonus and an adrenergic excitatory tonus are general features in the control of the teleost heart in vivo, both at rest and during moderate swimming exercise.

  6. Recent progress in α1-adrenergic receptor research

    Institute of Scientific and Technical Information of China (English)

    Zhong-jian CHEN; Kenneth P MINNEMAN


    α1-Adrenergic receptors (AR) play an important role in the regulation of physiological responses mediated by norepinephrine and epinephrine, particularly in the cardiovascular system. The three cloned α1-AR subtypes (α1A, α1B, and α1D)are G protein-coupled receptors that signal through the Gq/11 signaling pathway,each showing distinct pharmacological properties and tissue distributions.However, due to the lack of highly subtype-selective drugs, the functional rolesof individual subtypes are still not clear. Development of new subtype-specific drugs will greatly facilitate the identification of the functions of each subtype.Conopeptide ρ-TIA has been found to be a new α1B-AR selective antagonist withdifferent modes of inhibition at α1-AR subtypes. In addition, recent studies using genetically engineered mice have shed some light on α1-AR functions in vivo,especially in the cardiovascular system and brain. Several proteins have been shown to interact directly with particular α1-AR, and may be important in regulating receptor function. Receptor heterodimerization has been shown to be important for cell surface expression, signaling and internalization. These new observations are likely to help elucidate the functional roles of individual α1-AR subtypes.

  7. The Effect of the Arg389Gly Beta-1 Adrenoceptor Polymorphism on Plasma Renin Activity and Heart Rate and the Genotype-Dependent Response to Metoprolol Treatment

    DEFF Research Database (Denmark)

    Petersen, Morten; Andersen, Jon T; Jimenez-Solem, Espen


    A gene-drug interaction has been indicated between beta-1 selective beta-blockers and the Arg389Gly polymorphism (rs1801253) in the adrenergic beta-1 receptor gene (ADRB1). We studied the effect of the ADRB1 Arg389Gly polymorphism on plasma renin activity (PRA) and heart rate (HR) and the genotype...

  8. Intake of Total and Subgroups of Fat Minimally Affect the Associations between Selected Single Nucleotide Polymorphisms in the PPARγ Pathway and Changes in Anthropometry among European Adults from Cohorts of the DiOGenes Study

    DEFF Research Database (Denmark)

    Larsen, Sofus C; Ängquist, Lars; Østergaard, Jane N


    nucleotide polymorphisms (SNPs) within 4 genes in the PPARγ pathway are associated with the OR of being a BW gainer or with annual changes in anthropometry and whether intake of total fat, monounsaturated fat, polyunsaturated fat, or saturated fat has a modifying effect on these associations. METHODS: A case......BACKGROUND: Although the peroxisome proliferator-activated receptor γ (PPARγ) pathway is central in adipogenesis, it remains unknown whether it influences change in body weight (BW) and whether dietary fat has a modifying effect on the association. OBJECTIVES: We examined whether 27 single......), phosphoenolpyruvate carboxykinase 2, PPARγ gene (PPARG), and sterol regulatory element binding transcription factor 1] according to evidence about biologic plausibility for interactions with dietary fat in weight regulation. Diet was assessed at baseline, and anthropometry was followed for 7 y. RESULTS: The ORs...

  9. Polymorphisms in the Toll-Like Receptor and the IL-23/IL-17 Pathways Were Associated with Susceptibility to Inflammatory Bowel Disease in a Danish Cohort

    DEFF Research Database (Denmark)

    Bank, Steffen; Andersen, Paal Skytt; Burisch, Johan


    BACKGROUND: The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Previous studies have shown that polymorphisms in the Toll-like receptor (TLR), the apoptosis, the IL-23/IL-17 a...

  10. Combinations of Polymorphisms in Genes Involved in the 5-Fluorouracil Metabolism Pathway Are Associated with Gastrointestinal Toxicity in Chemotherapy-Treated Colorectal Cancer Patients

    DEFF Research Database (Denmark)

    Afzal, Shoaib; Gusella, Milena; Vainer, Ben


    occurrence of severe toxicity during treatment. CONCLUSIONS: Our results indicate that MTHFR activity and a specific combination of the MTHFR 1298A>C and TYMS 3'-UTR ins/del polymorphisms are possible predictors of 5-FU treatment-related toxicity. Clin Cancer Res; 17(11); 1-8. ©2011 AACR....

  11. Beta(3)-adrenergic signaling acutely down regulates adipose triglyceride lipase in brown adipocytes. (United States)

    Deiuliis, Jeffrey A; Liu, Li-Fen; Belury, Martha A; Rim, Jong S; Shin, Sangsu; Lee, Kichoon


    Mice exposed to cold rely upon brown adipose tissue (BAT)-mediated nonshivering thermogenesis to generate body heat using dietary glucose and lipids from the liver and white adipose tissue. In this report, we investigate how cold exposure affects the PI3 K/Akt signaling cascade and the expression of genes involved in lipid metabolism and trafficking in BAT. Cold exposure at an early time point led to the activation of the PI3 K/Akt, insulin-like signaling cascade followed by a transient decrease in adipose triglyceride lipase (ATGL) gene and protein expression in BAT. To further investigate how cold exposure-induced signaling altered ATGL expression, cultured primary brown adipocytes were treated with the beta(3)-adrenergic receptor (beta(3)AR) agonist CL 316,243 (CL) resulting in activation of PI3 K/Akt, ERK 1/2, and p38 signaling pathways and significantly decreased ATGL protein levels. ATGL protein levels decreased significantly 30 min post CL treatment suggesting protein degradation. Inhibition of PKA signaling by H89 rescued ATGL levels. The effects of PKA signaling on ATGL were shown to be independent of relevant pathways downstream of PKA such as PI3 K/Akt, ERK 1/2, and p38. However, CL treatment in 3T3-L1 adipocytes did not decrease ATGL protein and mRNA expression, suggesting a distinct response in WAT to beta3-adrenergic agonism. Transitory effects, possibly attributed to acute Akt activation during the early recruitment phase, were noted as well as stable changes in gene expression which may be attributed to beta3-adrenergic signaling in BAT.

  12. Pharmacologic specificity of alpha-2 adrenergic receptor subtypes

    Energy Technology Data Exchange (ETDEWEB)

    Petrash, A.; Bylund, D.


    The authors have defined alpha-2 adrenergic receptor subtypes in human and rat tissues using prazosin as a subtype selective drug. Prazosin has a lower affinity (250 nM) at alpha-2A receptor and a higher affinity (5 nM) at alpha-2B receptors. In order to determine if other adrenergic drugs are selective for one or the other subtypes, the authors performed (/sup 3/H)yohimbine inhibition experiments with various adrenergic drugs in tissues containing alpha-2A, alpha-2B or both subtypes. Oxymetazoline, WB4101 and yohimbine were found to be 80-, 20- and 10-fold more potent at alpha-2A receptors than at alpha-2B receptors. Phentolamine, adazoxan, (+)- and (-)-mianserin, clonidine, (+)-butaclamol, (-)- and (+)-norepinephrine, epinephrine, dopamine and thioridazine were found to have equal affinities for the two subtypes. These results further validate the subdivision of alpha-2 adrenergic receptors into alpha-2A and alpha-2B subtypes.

  13. Relationship between the Mutation of IRS-1 Gene and β3-adrenergic Receptor Gene

    Institute of Scientific and Technical Information of China (English)

    丁国宪; 沈捷; 陈家伟


    Objective To explore the relationship between the mutation of Insulin receptor substrate-1 ( IRS-1) gene and β3-adrenergic receptor (β3-AR) gene associated with insulin resistance, to further elucidate the etiology and pathogenesis of type 2 DM, hypertension and coronary heart disease. Methods 281 Chinese subjects are divided into three groups according to the oral glucose tolerance test (OGTT), The subjects were genotyped for the codon 64 of β3-AR gene, the codon 972 of IRS-1 gene polymorphisms by applying polymerase chain reaction (PCR) restriction fragment-length polymorphisms (RFLP) screening. Results Our study found that there was significantly increased frequency of IRS-1 gene mutation in IGT subjects and type 2 DM patients (P<0.05, 0.01, respectively), increased frequency of β3-AR gene mutation in type 2 DM patients (P<0.01), compared with NGT subjects. After adjusted for age, sex and plasma glucose, the level of insulin was significantly correlated with polymorphism of IRS-1 gene and β3-AR gene (P<0.001 in all ) by multiple regression analysis. In the models of Logistic regression, type 2 DM is closely related to age and family history (OR=3.1966, 1.4670; P=0.0272, 0.009; respectively), and to the polymorphism of β3-AR gene (OR=1.7380, P=0.0356), but not related to the polymorphism of IRS-1 gene. Conclusions These results suggest that mutation of IRS-1 gene may be the risk factor for insulin resistance, whereas mutation of β3-AR gene may be a common risk factor for insulin resistance, obesity, type 2 DM and hypertension.

  14. Family Polymorphism

    DEFF Research Database (Denmark)

    Ernst, Erik


    safety and flexibility at the level of multi-object systems. We are granted the flexibility of using different families of kinds of objects, and we are guaranteed the safety of the combination. This paper highlights the inability of traditional polymorphism to handle multiple objects, and presents family...... polymorphism as a way to overcome this problem. Family polymorphism has been implemented in the programming language gbeta, a generalized version of Beta, and the source code of this implementation is available under GPL....

  15. Adrenergic receptor control mechanism for growth hormone secretion. (United States)

    Blackard, W G; Heidingsfelder, S A


    The influence of catecholamines on growth hormone secretion has been difficult to establish previously, possibly because of the suppressive effect of the induced hyperglycemia on growth hormone concentrations. In this study, an adrenergic receptor control mechanism for human growth hormone (HGH) secretion was uncovered by studying the effects of alpha and beta receptor blockade on insulin-induced growth hormone elevations in volunteer subjects. Alpha adrenergic blockade with phentolamine during insulin hypoglycemia, 0.1 U/kg, inhibited growth hormon elevations to 30-50% of values in the same subjects during insulin hypoglycemia without adrenergic blockade. More complete inhibition by phentolamine could not be demonstrated at a lower dose of insulin (0.05 U/kg). Beta adrenergic blockade with propranolol during insulin hypoglycemia significantly enhanced HGH concentrations in paired experiments. The inhibiting effect of alpha adrenergic receptor blockade on HGH concentrations could not be attributed to differences in blood glucose or free fatty acid values; however, more prolonged hypoglycemia and lower plasma free fatty acid values may have been a factor in the greater HGH concentrations observed during beta blockade. In the absence of insulin induced hypoglycemia, neither alpha nor beta adrenergic receptor blockade had a detectable effect on HGH concentrations. Theophylline, an inhibitor of cyclic 3'5'-AMP phosphodiesterase activity, also failed to alter plasma HGH concentrations. These studies demonstrate a stimulatory effect of alpha receptors and a possible inhibitory effect of beta receptors on growth hormone secretion.

  16. A single nucleotide polymorphism in the human bone morphogenetic protein-2 gene (109T>G) affects the Smad signaling pathway and the predisposition to ossification of the posterior longitudinal ligament of the spine

    Institute of Scientific and Technical Information of China (English)

    YAN Liang; CHANG Zhen; LIU Yang; LI Yi-bing; HE Bao-rong; HAO Ding-jun


    Background Although various systemic and local factors such as abnormal carbohydrate or calcium metabolism,aging,and hormonal disturbances have been suggested as causes of ossification of the posterior longitudinal ligament (OPLL),the etiology of OPLL is not fully understood.The purpose of this study was to investigate whether bone morphogenetic protein (BMP)-2 is a candidate gene to modify the susceptibility of OPLL and the mechanism of signal transduction in ossification.Methods A total of 420 OPLL patients and 506 age-and sex-matched controls were studied.The complete coding sequence of the human BMP-2 gene was analyzed using polymerase chain reaction (PCR) and direct sequencing.All single nucleotide polymorphisms (SNPs) were detected and genotyped.BMP-2 expression vectors containing positive polymorphisms were constructed and transfected into the C3H10T1/2 cells.The expression of BMP-2 and the Smad signal pathway in positive cell clones were detected by Western blotting.The alkaline phosphatase (ALP) activity was determined using quantitative detection kits.Results The frequencies for the 109T>G and 570A>T polymorphisms were different between the case and control groups.The "TG" genotype in 109T>G polymorphism is associated with the occurrence of OPLL,the frequency of the "G"allele is significantly higher in patients with OPLL than in control subjects (P <0.001).The "AT" genotype in 570A>T polymorphism is associated with the occurrence of OPLL,the frequency of the "T" allele is significantly higher in patients with OPLL than in control subjects (P=0.005).Western blotting analysis revealed that the expression of P-Smad1/5/8protein transfected by wild-type or mutant expression vectors were significantly higher than control groups (P <0.05),but there was no statistical difference in each experimental group (P >0.05).The expression of Smad4 protein transfected by wild-type or mutant expression vectors was significantly higher than control groups (P

  17. FAS-670A/G andFAS-1377G/A polymorphism in cell death pathway geneFAS and human male infertility

    Institute of Scientific and Technical Information of China (English)

    Deepika Jaiswal; Udai Shankar Dwivedi; Neeraj Kumar Agrawal; Sameer Trivedi; Kiran Singh


    Objective:To study the role and association of functional variations present inFAS gene with idiopathic male infertility.Methods:The case-control study comprised of two groups:160 idiopathic infertile nonobstructive azoospermia patients and200 fertile healthy control men. Genotyping for single-nucleotide polymorphism ofFAS-670A/G(rs1800682) andFAS-1377G/A (rs2234767) was done byPCR-RFLP method.DNA sequencing was used to ascertainPCR-RFLP results.ForFAS-670A/G andFAS-1377G/A functional polymorphism, allele and genotype distribution were evaluated usingChi-square test.Results:Allele and genotype distribution did not differ significantly between patients and controls forFAS-670A/G andFAS-1377 G/A.Conclusions:Human male infertility is a complex disorder and thus other genetic or environmental factors may be contributing to the complex etiology.

  18. The Q705K and F359L Single-Nucleotide Polymorphisms of NOD-Like Receptor Signaling Pathway: Association with Chronic Pancreatitis, Pancreatic Cancer, and Periodontitis. (United States)

    Miskiewicz, Andrzej; Szparecki, Grzegorz; Durlik, Marek; Rydzewska, Grażyna; Ziobrowski, Ireneusz; Górska, Renata


    The aim of this study was to establish the correlation between the occurrence of Q705K and F359L polymorphisms in patients diagnosed with pancreatic diseases and periodontal conditions of various degrees of severity. The above-mentioned genetic markers were assessed in patients with pancreatic cancer (n = 18) and chronic pancreatitis (n = 39) as well as in a healthy control group (n = 115). The established inclusion criteria were the following: Caucasian descent, non-smoking, and age range 20-80, with different levels of periodontitis activity according to S. Offenbacher's scale. The genotyping reactions were performed by means of an RT-PCR with the use of TaqMan(®) genotyping assay. Results of the study revealed that the state of periodontium was significantly worse in patients with chronic pancreatitis. The Q705K and F359L polymorphisms were associated with more advanced cases of periodontitis measured by clinical attachment level, whereas the Q705K was associated with intensified bleeding index. Furthermore, the F359L single-nucleotide polymorphism was significantly higher in the group with chronic pancreatitis (p periodontitis, pancreatic cancer, and chronic pancreatitis. These findings might constitute the basis for a new diagnostic and therapeutic approach.

  19. Regulatory volume increase in astrocytes exposed to hypertonic medium requires β1 -adrenergic Na(+) /K(+) -ATPase stimulation and glycogenolysis. (United States)

    Song, Dan; Xu, Junnan; Hertz, Leif; Peng, Liang


    The cotransporter of Na(+) , K(+) , 2Cl(-) , and water, NKKC1, is activated under two conditions in the brain, exposure to highly elevated extracellular K(+) concentrations, causing astrocytic swelling, and regulatory volume increase in cells shrunk in response to exposure to hypertonic medium. NKCC1-mediated transport occurs as secondary active transport driven by Na(+) /K(+) -ATPase activity, which establishes a favorable ratio for NKCC1 operation between extracellular and intracellular products of the concentrations of Na(+) , K(+) , and Cl(-) × Cl(-) . In the adult brain, astrocytes are the main target for NKCC1 stimulation, and their Na(+) /K(+) -ATPase activity is stimulated by elevated K(+) or the β-adrenergic agonist isoproterenol. Extracellular K(+) concentration is normal during regulatory volume increase, so this study investigated whether the volume increase occurred faster in the presence of isoproterenol. Measurement of cell volume via live cell microscopic imaging fluorescence to record fluorescence intensity of calcein showed that this was the case at isoproterenol concentrations of ≥1 µM in well-differentiated mouse astrocyte cultures incubated in isotonic medium with 100 mM sucrose added. This stimulation was abolished by the β1 -adrenergic antagonist betaxolol, but not by ICI118551, a β2 -adrenergic antagonist. A large part of the β1 -adrenergic signaling pathway in astrocytes is known. Inhibitors of this pathway as well as the glycogenolysis inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol hydrochloride and the NKCC1 inhibitors bumetanide and furosemide abolished stimulation by isoproterenol, and it was weakened by the Na(+) /K(+) -ATPase inhibitor ouabain. These observations are of physiological relevance because extracellular hypertonicity occurs during intense neuronal activity. This might trigger a regulatory volume increase, associated with the post-excitatory undershoot.

  20. Sexual dimorphism in adrenergic regulation of hepatic glycogenolysis

    Energy Technology Data Exchange (ETDEWEB)

    Studer, R.K.


    The total phosphorylase a plus b of hepatocytes isolated from females and incubated in the absence or presence of estradiol and progesterone at concentrations found in vivo does not vary during the estrous cycle. However, there is a slight but significant influence of the estrous cycle on basal and epinephrine-stimulated phosphorylase a activity, with a nadir being seen on diestrus. The relative contributions of the ..cap alpha..- and ..beta..-mediated pathways to phosphorylase a activation do not vary with the estrous cycle but are constant at 75 and 56%, respectively, of the response to 5 x 10/sup -8/ M epinephrine. When the epinephrine-stimulated glucose release from glycogen stores in cells from females and males is compared, the release from the female is greater than that from the male, while the ..cap alpha..-receptor-mediated stimulation in the female is comparable with that in the male. The epinephrine-stimulated increase in cytostolic free calcium (Ca/sub i/) is greater in the male than the female at 10/sup -6/ M but greater in the female than the male at 5 x 10/sup -9/ M. The changes in Ca/sub i/ are equivalent at intermediate epinephrine concentrations. When considered with the prior analysis of /sup 45/Ca efflux after adrenergic stimulation, this suggests there may be a sexual dimorphism in hepatocyte calcium transport systems. The glucose release for a given increase in Ca/sub i/ is greater in the female than the male probably due to the concomitant action of the ..beta..-mediated increase in cAMP and the ..cap alpha..-mediated increase in Ca/sub i/. This supports the conclusion that the ..beta..-mediated component does make a significant contribution to the catecholamine regulation of glycogenolysis in hepatocytes from adult female rats.

  1. An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice (United States)

    Montgomery, Megan D.; Chan, Trevor; Swigart, Philip M.; Myagmar, Bat-erdene; Dash, Rajesh; Simpson, Paul C.


    Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35–40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies. PMID:28081170

  2. Adrenergic Receptors and Metabolism: Role in development of cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Michele eCiccarelli


    Full Text Available Activation of the adrenergic system has a profound effects on metabolism. Increased circulating catecholamine and activation of the different adrenergic receptors deployed in the various organs produce important metabolic responses which include: 1 increased lipolysis and elevated levels of fatty acids in plasma, 2 increased gluconeogenesis by the liver to provide substrate for the brain and 3 moderate inhibition of insulin release by the pancreas to conserve glucose and to shift fuel metabolism of muscle in the direction of fatty acid oxidation. These physiological responses, typical of the stress conditions, are demonstrated to be detrimental for the functioning of different organs like the cardiac muscle when they become chronic. Indeed, a common feature of many pathological conditions involving over-activation of the adrenergic system is the development of metabolic alterations which can include insulin resistance, altered glucose and lipid metabolism and mitochondrial dysfunction. These patterns are involved with a variably extent among the different pathologies , however they are in general strictly correlated to the level of activation of the adrenergic system. Here we will review the effects of the different adrenergic receptors subtypes on the metabolic variation observed in important disease like Heart Failure.

  3. β-Adrenergic stimulation increases Cav3.1 activity in cardiac myocytes through protein kinase A.

    Directory of Open Access Journals (Sweden)

    Yingxin Li

    Full Text Available The T-type Ca(2+ channel (TTCC plays important roles in cellular excitability and Ca(2+ regulation. In the heart, TTCC is found in the sinoatrial nodal (SAN and conduction cells. Cav3.1 encodes one of the three types of TTCCs. To date, there is no report regarding the regulation of Cav3.1 by β-adrenergic agonists, which is the topic of this study. Ventricular myocytes (VMs from Cav3.1 double transgenic (TG mice and SAN cells from wild type, Cav3.1 knockout, or Cav3.2 knockout mice were used to study β-adrenergic regulation of overexpressed or native Cav3.1-mediated T-type Ca(2+ current (I(Ca-T(3.1. I(Ca-T(3.1 was not found in control VMs but was robust in all examined TG-VMs. A β-adrenergic agonist (isoproterenol, ISO and a cyclic AMP analog (dibutyryl-cAMP significantly increased I(Ca-T(3.1 as well as I(Ca-L in TG-VMs at both physiological and room temperatures. The ISO effect on I(Ca-L and I(Ca-T in TG myocytes was blocked by H89, a PKA inhibitor. I(Ca-T was detected in control wildtype SAN cells but not in Cav3.1 knockout SAN cells, indicating the identity of I(Ca-T in normal SAN cells is mediated by Cav3.1. Real-time PCR confirmed the presence of Cav3.1 mRNA but not mRNAs of Cav3.2 and Cav3.3 in the SAN. I(Ca-T in SAN cells from wild type or Cav3.2 knockout mice was significantly increased by ISO, suggesting native Cav3.1 channels can be upregulated by the β-adrenergic (β-AR system. In conclusion, β-adrenergic stimulation increases I(Ca-T(3.1 in cardiomyocytes(, which is mediated by the cAMP/PKA pathway. The upregulation of I(Ca-T(3.1 by the β-adrenergic system could play important roles in cellular functions involving Cav3.1.

  4. Lack of alpha(2)-adrenergic antilipolytic effect during exercise in subcutaneous adipose tissue of trained men. (United States)

    De Glisezinski, I; Marion-Latard, F; Crampes, F; Berlan, M; Hejnova, J; Cottet-Emard, J M; Stich, V; Rivière, D


    The aim of this study was to investigate the involvement of the antilipolytic alpha(2)-adrenergic receptor pathway in the regulation of lipolysis during exercise in subcutaneous abdominal adipose tissue (SCAAT). Seven trained men and 15 untrained men were studied. With the use of microdialysis, the extracellular glycerol concentration was measured in SCAAT at rest and during 60 min of exercise at 50% of maximal oxygen consumption. One microdialysis probe was perfused with Ringer solution; the other was supplemented with phentolamine (alpha(2)-adrenergic receptor antagonist). No differences in baseline extracellular or plasma glycerol concentrations were found between the two groups. The exercise-induced extracellular and plasma glycerol increase was higher in trained compared with untrained subjects (P < 0.05). Addition of phentolamine to the perfusate enhanced the exercise-induced response of extracellular glycerol in untrained subjects but not in trained subjects. The exercise-induced increase in plasma norepinephrine and epinephrine concentrations and the decrease in plasma insulin were not different in the two groups. These in vivo findings demonstrate higher exercise-induced lipolysis in trained compared with untrained subjects and show that, in trained subjects, the alpha(2)-mediated antilipolytic action is not involved in the regulation of lipolysis in SCAAT during exercise.

  5. Relaxing action of adrenergic β2-agonists on guinea-pig skinned tracheal muscle

    Directory of Open Access Journals (Sweden)

    Kayo Nemoto


    Full Text Available Although adrenergic β2-agonist-induced smooth muscle relaxation has been attributed to increased intracellular cyclic AMP (cAMP, a relaxation response has been observed at low β2-agonist concentrations that do not cause increased cAMP To elucidate the mechanism of tracheal muscle relaxation induced by low concentrations of β2-agonists, we used a guinea-pig skinned tracheal smooth muscle preparation to examine the effects on the contractile protein system. The isotonic contraction of β-escin-treated skinned tracheal muscle from guinea-pig was measured. When the intracellular Ca2+ concentration was maintained at 1 μmol/L in the presence of guanosine 5′-triphosphate (GTP; 100 μmol/L, neither isoproterenol (10nmol/L nor salbutamol (60 nmol/L affected Ca2+ sensitivity, but a significant decrease in Ca2+ sensitivity was observed in the presence of okadaic acid (1 μmol/L. The decrease in Ca2+ sensitivity was a slow response and was blocked by pretreatment with propranolol (1 μmol/L. Forskolin (1 μmol/L did not affect Ca2+ sensitivity. These results suggest that adrenergic b 2-agonists may activate protein phosphatase through an unknown pathway involving the β2-receptor, which enhances dephosphorylation of the myosin light chain and/or thin filament proteins, resulting in relaxation of the tracheal smooth muscle.

  6. Environmental novelty activates β2-adrenergic signaling to prevent the impairment of hippocampal LTP by Aβ oligomers. (United States)

    Li, Shaomin; Jin, Ming; Zhang, Dainan; Yang, Ting; Koeglsperger, Thomas; Fu, Hongjun; Selkoe, Dennis J


    A central question about human brain aging is whether cognitive enrichment slows the development of Alzheimer changes. Here, we show that prolonged exposure to an enriched environment (EE) facilitated signaling in the hippocampus of wild-type mice that promoted long-term potentiation. A key feature of the EE effect was activation of β2-adrenergic receptors and downstream cAMP/PKA signaling. This EE pathway prevented LTP inhibition by soluble oligomers of amyloid β-protein (Aβ) isolated from AD cortex. Protection by EE occurred in both young and middle-aged wild-type mice. Exposure to novelty afforded greater protection than did aerobic exercise. Mice chronically fed a β-adrenergic agonist without EE were protected from hippocampal impairment by Aβ oligomers. Thus, EE enhances hippocampal synaptic plasticity by activating β-adrenoceptor signaling and mitigating synaptotoxicity of human Aβ oligomers. These mechanistic insights support using prolonged exposure to cognitive novelty and/or oral β-adrenergic agonists to lessen the effects of Aβ accumulation during aging.

  7. 血管紧张素转化酶基因多态性与β受体阻滞剂治疗慢性心力衰竭患者预后的关系%Relationship between the polymorphism of angiotensin-converting enzyme and the prognosis of chronic heart failure patients treated with beta-adrenergic receptor blockers

    Institute of Scientific and Technical Information of China (English)

    郑茵; 方壮伟; 方团育; 吴智勇; 董吁钢; Dennis M. McNamara


    Objective: To evaluate the relationship between Angiotensin-Converting Enzyme ( ACE) polymor phisms and the prognosis of chronic heart failure( CHF) patients treatcd with β-blockers. Method: ACE I/D gene polymorphisms in 432 CHF- patients with systolic dysfunction (LVEF<0. 45) were detected by polymerase chain reaction (PCR) , and 26. 43±18. 19 months follow-up time were viewed to assess the end point of death in 432 CHD patients. At the same time, in diffcrent ACE I/D genotypes, relationships between the survival rate of CHF patients and β-blockers treatment were analyzed, too. Result: The survival of ACE D allele was significantly attenuated compared to Ⅰ allele (P=0. 027). In homozygous ACE DD patients, treatment withβ-blocker was associat ed with a significant improvement in survival rate(P=0. 003). However, In other patients treated with β-block ers , no obvious improvement of survival rate was viewcd in ACE Ⅱ、ID、DD genotype patients(P=0. 196). On the other hand, for patients without β-blockers treatment,there was a tendency of attenuation for survival rate in ACE DD not in ACE Ⅱ and ID patients, but with no statistical significance (P=0. 091). Conclusion : It shows that ACE DD genotype in CHF paticnts has significantly lower survival rate than in other genotype patients, which could be used as a predictive factor of prognosis for CHF patients, further,β-blocker therapy effects are related with ACE I/D gene polymorphisms, and β-blockers benefits ACE DD genotype patients most effcctively.%目的:探讨血管紧张素转化酶(ACE)基因多态性与β受体阻滞剂治疗心力衰竭患者预后的关系.方法:用聚合酶链式反应方法(PCR)检测432例收缩功能障碍性心力衰竭[左室射血分数(LVEF)<0.45]患者的ACE基因型,前瞻性随访所有患者(26.43±18.19)个月, 随访终点是死亡.分析不同ACE I/D基因分型中β受体阻滞剂治疗与慢性心力衰竭患者生存率的关系.结果:ACE D等位基因的

  8. Changes of lymphocyte beta-adrenergic receptors after surgical stress. (United States)

    Eandi, M; Buraglio, M; Arduino, C; Viano, I; Sansalvadore, G; Arbinolo, M A


    In this study the authors' purpose was to observe the effects of surgical stress on the number of lymphocyte beta-adrenergic receptors in hypertensive and normotensive subjects. It was noticed that after surgery a significant reduction occurred in the number of binding sites of lymphocytes of both hypertensive and normotensive subjects. The time course of recovery to the pre-operative values of binding sites varied between the two groups, being slower in normotensive than in hypertensive patients. This might suggest a different pattern of regulation of the beta-adrenergic receptor between hypertensive and normotensive subjects.

  9. [The sources of the adrenergic innervation of the rat uterus]. (United States)

    Proĭmina, F I; Rakitskaia, V V


    Complete disappearance of adrenergic fibers in the rat uterus is only possible after complete removal of ovaries along with ovarian plexus, transection of the uterus-vaginal connexion and removal of a portion of sympathetic nervous trunk. "Long" adrenergic neurons situated in spinal sympathetic ganglia, seem not to be the only source of sympathetic innervation of the myometrium's vessels. A part of nervous fibers of vascular plexuses and all muscle nerves are represented by "short" neurons starting from the ganglionic structures of the uterus-vaginal connexion.

  10. Gene Polymorphisms in Chronic Periodontitis

    Directory of Open Access Journals (Sweden)

    Marja L. Laine


    Full Text Available We aimed to conduct a review of the literature for gene polymorphisms associated with chronic periodontitis (CP susceptibility. A comprehensive search of the literature in English was performed using the keywords: periodontitis, periodontal disease, combined with the words genes, mutation, or polymorphism. Candidate gene polymorphism studies with a case-control design and reported genotype frequencies in CP patients were searched and reviewed. There is growing evidence that polymorphisms in the IL1, IL6, IL10, vitamin D receptor, and CD14 genes may be associated with CP in certain populations. However, carriage rates of the rare (-allele of any polymorphism varied considerably among studies and most of the studies appeared under-powered and did not correct for other risk factors. Larger cohorts, well-defined phenotypes, control for other risk factors, and analysis of multiple genes and polymorphisms within the same pathway are needed to get a more comprehensive insight into the contribution of gene polymorphisms in CP.

  11. Adrenergic receptor subtypes in the cerebral circulation of newborn piglets

    Energy Technology Data Exchange (ETDEWEB)

    Wagerle, L.C.; Delivoria-Papadopoulos, M.


    The purpose of this study was to identify the ..cap alpha..-adrenergic receptor subtype mediating cerebral vasoconstriction during sympathetic nerve stimulation in the newborn piglet. The effect of ..cap alpha../sub 1/- and ..cap alpha../sub 2/-antagonists prazosin and yohimbine on the cerebrovascular response to unilateral electrical stimulation (15 Hz, 15 V) of the superior cervical sympathetic trunk was studied in 25 newborn piglets. Regional cerebral blood flow was measured with tracer microspheres. Sympathetic stimulation decreased blood flow to the ipsilateral cerebrum hippocampus, choroid plexus, and masseter muscle. ..cap alpha../sub 1/-Adrenergic receptor blockade with prazosin inhibited the sympathetic vasoconstriction in the cerebrum, hippocampus, and masseter muscle and abolished it in the choroid plexus. ..cap alpha../sub s/-Adrenergic receptor blockade with yohimbine had no effect. Following the higher dose of yohimbine, however, blood flow to all brain regions was increased by approximately two-fold, possibly due to enhanced cerebral metabolism. These data demonstrate that vascular ..cap alpha../sub 1/-adrenergic receptors mediate vasoconstriction to neuroadrenergic stimulation in cerebral resistance vessels in the newborn piglet.

  12. Use of ß-adrenergic agonists in hybrid catfish (United States)

    Ractopamine hydrochloride (RH) is a potent ß-adrenergic agonist that has been used in some species of fish to improve growth performance and dress out characteristics. While this metabolic modifier has been shown to have positive effects on growth of fish, little research has focused on the mechani...

  13. The role of polymorphisms of genes repair pathway to the radiotoxicity in patients with cancer of the cervix; O papel dos polimorfismos de genes da via de reparo com a radiotoxidade em pacientes com cancer de colo uterino

    Energy Technology Data Exchange (ETDEWEB)

    Carvalho, Ana Terra Silva


    Background: In Brazil, cervical cancer is the second most common among women. Radiation therapy is part of its interdisciplinary management, playing an important role in their loco regional control. The major challenge of modern medicine in radiotherapy is to develop predictive methods that can determine the level of radiosensitivity of the patient and the healthy surrounding tissue in order to individualize the prescribed radiation dose, to prevent severe side effects and promoting better local tumor control. This study evaluated the acute and chronic adverse effects on the skin, lower gastrointestinal tract and urinary tract of radiotherapy in 47 cervical cancer patients. Methods and Materials: Biological material was collected and DNA from peripheral blood was extracted of ali patients studied. The fragments of TP53 and ATM were amplified to be sequenced, to verify if there are any polymorphisms witch could be responsible to the radiosensitivity of the patients. Results and Discussion: In a univariate analysis, the variable age was strongly associated with a risk of acute toxicity skin (p=O,023). Patients that received a high dose of external beam radiation and patients who have undergone brachytherapy, showed a significantly higher incidence of chronic urinary tract toxicity (p=O,031) and (p=O,019), respectively. The exchange G>A in the position 5557 of the A TM gene was significantly associated with the risk of acute lower gastrointestinal tract (p=O,008). There wasn't association between the other TP53 polymorphisms analyzed and the frequency of side effects (p>O,05). Our data revealed that patients who evolved significant association presented death (p=O,019) with the increase of chronic skin radiossensitivity. Conclusions: These observations corroborate the importance of investigating the genetic profile to predict adverse side effects in cervical cancer patients undergoing radiotherapy. These genes have an important role in DNA repair pathways and

  14. Treatment of asymptomatic catecholaminergic polymorphic ventricular tachycardia. (United States)

    Obeyesekere, Manoj N; Sy, Raymond W; Leong-Sit, Peter; Gula, Lorne J; Yee, Raymond; Skanes, Allan C; Klein, George J; Krahn, Andrew D


    Catecholaminergic polymorphic ventricular tachycardia is a rare genetic disorder caused by mutations in genes involved in the intracellular calcium homeostasis of cardiac cells. Affected patients typically present with life-threatening ventricular arrhythmias precipitated by emotional/physical stress. The diagnosis is based on the demonstration of polymorphic or bidirectional ventricular tachycardia associated with adrenergic stress. Genetic testing can be confirmatory in some patients. Treatment for catecholaminergic polymorphic ventricular tachycardia includes medical and surgical efforts to suppress the effects of epinephrine at the myocardial level and/or modulation of calcium homeostasis. Mortality is high when untreated and sudden cardiac death may be the first manifestation of the disease. First-degree relatives of a proband should be offered genetic testing if the causal mutation is known. If the family mutation is not known, relatives should be clinically evaluated with provocative testing. In the absence of rigorous trials, prophylactic treatment of the asymptomatic catecholaminergic polymorphic ventricular tachycardia patient appears to reduce morbidity and mortality.

  15. Changing face of β2-adrenergic and muscarinic receptor therapies in asthma. (United States)

    Wasilewski, Nastasia V; Lougheed, M Diane; Fisher, John T


    Despite current available treatment options, a significant proportion of patients with asthma remain uncontrolled and asthma pharmacotherapy continues to evolve. β2-Adrenergic receptor agonists play a major role as bronchodilators in asthma therapy, although new perspectives reflect the potential for bias G-protein coupled receptor signaling pathways. Due to the success of muscarinic antagonists in chronic obstructive pulmonary disease, and the elucidation that muscarinic receptors play a role in airway remodeling, muscarinic receptors represent an attractive therapeutic target in asthma. Although short-acting muscarinic antagonists are currently limited to their use in acute asthma and as alternative bronchodilators in individuals who experience side effects with β2-agonists, recent clinical trials indicate that the long-acting muscarinic antagonist, tiotropium, deserves consideration as a potential therapeutic agent for select populations. The continued evolution of anticholinergic therapy in asthma will require appropriately designed studies to assess mechanisms, efficacy and safety in asthma.

  16. Radiolabeled meta-iodobenzylguanidine and the adrenergic neurons of salivary glands

    Energy Technology Data Exchange (ETDEWEB)

    Sisson, J.C.; Wieland, D.M.; Jaques, S. Jr.; Sherman, P.; Fisher, S.; Mallette, S.; Meyers, L.; Mangner, T.J.


    The handling of radiolabeled meta-iodobenzylguanidine (MIBG) by salivary glands was evaluated. In the submaxillary glands of rats, the uptake of 125I-MIBG was decreased after 1) nerve injury induced by 6-hydroxydopamine, 2) inhibition of the uptake-1 pathway by desmethylimipramine, and 3) surgical denervation. However, the reduction in 125I-MIGB uptake was less than that of 3H-norepinephrine (3H-NE) and of the endogenous content of NE in the glands. Yet, the sympathomimetic phenylpropanolamine displaced about the same fraction of 125I-MIBG as 3H-NE. These results suggest that 40% or more of 125I-MIBG resides in extraneuronal sites but that at least 30% and possibly more lies in the adrenergic nerve terminals. Fasting and feeding rats produced changes in the rates of disappearance of 125I-MIBG and 3H-NE from the submaxillary gland that were different, and the rates of loss of 125I-MIBG cannot be used as an index of adrenergic nerve activity. In man, the concentrations of 123I-MIBG in the salivary glands, particularly the parotid gland, are readily visible and measureable. Imipramine reduced the uptake of 123I-MIBG into parotid glands little or not at all; some of the 123I-MIBG may enter neurons via an imipramine-insensitive pathway, but a substantial fraction probably arrives in intraneuronal locations. Thus, phenylpropanolamine displaced over 50% of the parotid pool of 123I-MIBG. However, in only the most severe case of generalized autonomic neuropathy was the uptake of 123I-MIBG reduced.

  17. Contribution of genetic polymorphisms on functional status at very old age: a gene-based analysis of 38 genes (311 SNPs) in the oxidative stress pathway. (United States)

    Dato, S; Soerensen, M; Lagani, V; Montesanto, A; Passarino, G; Christensen, K; Tan, Q; Christiansen, L


    Preservation of functional ability is a well-recognized marker of longevity. At a molecular level, a major determinant of the physiological decline occurring with aging is the imbalance between production and accumulation of oxidative damage to macromolecules, together with a decreased efficiency of stress response to avoid or repair such damage. In this paper we investigated the association of 38 genes (311 SNPs) belonging to the pro-antioxidant pathways with physical and cognitive performances, by analyzing single SNP and gene-based associations with Hand Grip strength (HG), Activities of Daily Living (ADL), Walking Speed (WS), Mini Mental State Examination (MMSE) and Composite Cognitive Score (CCS) in a Cohort of 1089 Danish nonagenarians. Moreover, for each gene analyzed in the pro-antioxidant pathway, we tested the influence on longitudinal survival. In the whole sample, nominal associations were found for TXNRD1 variability with ADL and WS, NDUFS1 and UCP3 with HG and WS, GCLC and UCP2 with WS (p<0.05). Stronger associations although not holding the multiple comparison correction, were observed between MMSE and NDUFV1, MT1A and GSTP1 variability (p<0.009). Moreover, we found that association between genetic variability in the pro-antioxidant pathway and functional status at old age is influenced by sex. In particular, most significant associations were observed in nonagenarian females, between HG scores and GLRX and UCP3 variability, between ADL levels and TXNRD1, MMSE and MT1A genetic variability. In males, a borderline statistically significant association with ADL level was found for UQCRFS1 gene. Nominally significant associations in relation to survival were found in the female sample only with SOD2, NDUFS1, UCP3 and TXNRD1 variability, the latter two confirming previous observations reported in the same cohort. Overall, our work supports the evidence that genes belonging to the pro-anti-oxidant pathway are able to modulate physical and cognitive

  18. Polymorphisms of Helicobacter pylori signaling pathway genes and gastric cancer risk in the European Prospective Investigation into Cancer-Eurgast cohort. (United States)

    Companioni, Osmel; Bonet, Catalina; Muñoz, Xavier; Weiderpass, Elisabete; Panico, Salvatore; Tumino, Rosario; Palli, Domenico; Agnoli, Claudia; Vineis, Paolo; Boutron-Ruault, Marie-Christine; Racine, Antoine; Clavel-Chapelon, Françoise; Travis, Ruth C; Khaw, Kay-Tee; Riboli, Elio; Murphy, Neil; Vergnaud, Anne-Claire; Trichopoulou, Antonia; Benetou, Vassiliki; Trichopoulos, Dimitrios; Lund, Eiliv; Johansen, Dorthe; Lindkvist, Björn; Johansson, Mattias; Sund, Malin; Ardanaz, Eva; Sánchez-Cantalejo, Emilio; Huerta, Jose M; Dorronsoro, Miren; Ramón Quirós, José; Tjonneland, Anne; Mortensen, Lotte Maxild; Overvad, Kim; Chang-Claude, Jenny; Rizzato, Cosmeri; Boeing, Heiner; Bueno-de-Mesquita, H Bas; Bueno de Mesquita, H Bas; Siersema, Peter; Peeters, Petra H M; Numans, Mattijs E; Carneiro, Fatima; Licaj, Idlir; Freisling, Heinz; Sala, Núria; González, Carlos A


    Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccharide and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while NFKB1 activates the transcription of pro-inflammatory cytokines to elicit an immune response. Single nucleotide polymorphisms (SNPs) in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1,284 matched controls from the European Prospective Investigation into Cancer cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log-additive model, we found a significant association between SNPs in CD14, NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant (p = 0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC (p = 0.0003) and CD14 with cardia GC (p = 0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results, we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC.

  19. Alpha 2-adrenergic receptor turnover in adipose tissue and kidney: irreversible blockade of alpha 2-adrenergic receptors by benextramine

    Energy Technology Data Exchange (ETDEWEB)

    Taouis, M.; Berlan, M.; Lafontan, M.


    The recovery of post- and extrasynaptic alpha 2-adrenergic receptor-binding sites was studied in vivo in male golden hamsters after treatment with an irreversible alpha-adrenoceptor antagonist benextramine, a tetramine disulfide that possesses a high affinity for alpha 2-binding sites. The kidney alpha 2-adrenergic receptor number was measured with (/sup 3/H)yohimbine, whereas (/sup 3/H)clonidine was used for fat cell and brain membrane alpha 2-binding site identification. Benextramine treatment of fat cell, kidney, and brain membranes reduced or completely suppressed, in an irreversible manner, (/sup 3/H) clonidine and (/sup 3/H)yohimbine binding without modifying adenosine (A1-receptor) and beta-adrenergic receptor sites. This irreversible binding was also found 1 and 2 hr after intraperitoneal administration of benextramine to the hamsters. Although it bound irreversibly to peripheral and central alpha 2-adrenergic receptors on isolated membranes, benextramine was unable to cross the blood-brain barrier of the hamster at the concentrations used (10-20 mg/kg). After the irreversible blockade, alpha 2-binding sites reappeared in kidney and adipose tissue following a monoexponential time course. Recovery of binding sites was more rapid in kidney than in adipose tissue; the half-lives of the receptor were 31 and 46 hr, respectively in the tissues. The rates of receptor production were 1.5 and 1.8 fmol/mg of protein/hr in kidney and adipose tissue. Reappearance of alpha 2-binding sites was associated with a rapid recovery of function (antilipolytic potencies of alpha 2-agonists) in fat cells inasmuch as occupancy of 15% of (/sup 3/H)clonidine-binding sites was sufficient to promote 40% inhibition of lipolysis. Benextramine is a useful tool to estimate turnover of alpha 2-adrenergic receptors under normal and pathological situations.

  20. Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption. (United States)

    Agné, Alisa M; Baldin, Jan-Peter; Benjamin, Audra R; Orogo-Wenn, Maria C; Wichmann, Lukas; Olson, Kenneth R; Walters, Dafydd V; Althaus, Mike


    In pulmonary epithelia, β-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H2S) on β-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 μM) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the β-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia (Xenopus laevis), Na2S inhibited the stimulation of amiloride-sensitive current by terbutaline. β-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na2S in a dose-dependent manner (5-50 μM). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H2S-generating enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H2S amounts within the employed concentration range. These data demonstrate that H2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of β-adrenergic agonists on lung liquid clearance.

  1. Adrenergic receptors and gastric secretion in dogs. Is a "tonic balance" relationship between vagal and beta 2-adrenergic activity a possibility?

    DEFF Research Database (Denmark)

    Gottrup, F; Hovendal, C; Bech, K


    The relative influence of adrenergic receptors on gastric acid secretion in the dog stomach with different vagal activity or "tone" is almost unknown. beta-adrenoceptors seem to be most important for the direct effect of adrenergic stimulation on acid secretion. In this study the effects of vagot...

  2. Polymorphic membrane protein (PMP) 20 and PMP 21 of Chlamydia pneumoniae induce proinflammatory mediators in human endothelial cells in vitro by activation of the nuclear factor-kappaB pathway. (United States)

    Niessner, Alexander; Kaun, Christoph; Zorn, Gerlinde; Speidl, Walter; Türel, Zeynep; Christiansen, Gunna; Pedersen, Anna-Sofie; Birkelund, Svend; Simon, Susan; Georgopoulos, Apostolos; Graninger, Wolfgang; de Martin, Rainer; Lipp, Joachim; Binder, Bernd R; Maurer, Gerald; Huber, Kurt; Wojta, Johann


    We tested whether polymorphic membrane proteins (PMPs) of Chlamydia pneumoniae might play a role in triggering an inflammatory response in human endothelial cells. Of 15 purified, recombinant chlamydial PMPs tested, 2 (PMP 20 and PMP 21) dose-dependently increased the production of the inflammatory mediators interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1), in cultured human endothelial cells; production of IL-8 was also increased. When endothelial cells were infected by live C. pneumoniae, an increase in the production of IL-6, IL-8, and MCP-1 was seen. We used adenovirus-induced overexpression of IkappaBalpha-an inhibitor of nuclear factor (NF)-kappaB-to demonstrate that PMP 20 and PMP 21 increase the production of IL-6 and MCP-1 in human endothelial cells by activation of the NF-kappaB pathway, because, in cells overexpressing IkappaBalpha, treatment with the respective PMP did not result in increased production of IL-6 and MCP-1. Thus, C. pneumoniae could, by interactions of its PMPs with the endothelium, contribute to the process of vascular injury during the development and progression of atherosclerotic lesions.

  3. Beta adrenergic blockade reduces utilitarian judgement. (United States)

    Terbeck, Sylvia; Sylvia, Terbeck; Kahane, Guy; Guy, Kahane; McTavish, Sarah; Sarah, McTavish; Savulescu, Julian; Julian, Savulescu; Levy, Neil; Neil, Levy; Hewstone, Miles; Miles, Hewstone; Cowen, Philip J


    Noradrenergic pathways are involved in mediating the central and peripheral effects of physiological arousal. The aim of the present study was to investigate the role of noradrenergic transmission in moral decision-making. We studied the effects in healthy volunteers of propranolol (a noradrenergic beta-adrenoceptor antagonist) on moral judgement in a set of moral dilemmas pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person) in a double-blind, placebo-controlled, parallel group design. Propranolol (40 mg orally) significantly reduced heart rate, but had no effect on self-reported mood. Importantly, propranolol made participants more likely to judge harmful actions as morally unacceptable, but only in dilemmas where harms were 'up close and personal'. In addition, longer response times for such personal dilemmas were only found for the placebo group. Finally, judgments in personal dilemmas by the propranolol group were more decisive. These findings indicate that noradrenergic pathways play a role in responses to moral dilemmas, in line with recent work implicating emotion in moral decision-making. However, contrary to current theorising, these findings also suggest that aversion to harming is not driven by emotional arousal. Our findings are also of significant practical interest given that propranolol is a widely used drug in different settings, and is currently being considered as a potential treatment for post-traumatic stress disorder in military and rescue service personnel.

  4. Beta-Adrenergic gene therapy for cardiovascular disease

    Directory of Open Access Journals (Sweden)

    Koch Walter J


    Full Text Available Abstract Gene therapy using in vivo recombinant adenovirus-mediated gene transfer is an effective technique that offers great potential to improve existing drug treatments for the complex cardiovascular diseases of heart failure and vascular smooth muscle intimal hyperplasia. Cardiac-specific adenovirus-mediated transfer of the carboxyl-terminus of the β-adrenergic receptor kinase (βARKct, acting as a Gβγ-β-adrenergic receptor kinase (βARK1 inhibitor, improves basal and agonist-induced cardiac performance in both normal and failing rabbit hearts. In addition, βARKct adenovirus infection of vascular smooth muscle is capable of significantly diminishing neointimal proliferation after angioplasty. Therefore, further investigation is warranted to determine whether inhibition of βARK1 activity and sequestration of Gβγ via an adenovirus that encodes the βARKct transgene might be a useful clinical tool for the treatment of cardiovascular pathologies.

  5. Neurohumoral activation in heart failure: the role of adrenergic receptors


    Patricia C. Brum; Rolim, Natale P. L.; BACURAU, Aline V. N.; Alessandra Medeiros


    Heart failure (HF) is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardia...

  6. Activation of antilipolytic alpha(2)-adrenergic receptors by epinephrine during exercise in human adipose tissue. (United States)

    Stich, V; de Glisezinski, I; Crampes, F; Suljkovicova, H; Galitzky, J; Riviere, D; Hejnova, J; Lafontan, M; Berlan, M


    The involvement of the antilipolytic alpha(2)-adrenergic pathway and the specific role of epinephrine in the control of lipolysis during exercise in adipose tissue (AT) were investigated in healthy male subjects (age: 24.1 +/- 2.2 yr; body mass index: 23.0 +/- 1.6). An in vitro study carried out on isolated adipocytes showed that the weak lipolytic effect of epinephrine was potentiated after blockade of alpha(2)-adrenergic receptor (AR) by an alpha(2)-AR antagonist and reached that of isoproterenol, a beta-AR agonist. The effect of the nonselective alpha(2)-AR antagonist phentolamine on the response of the extracellular glycerol concentration (EGC) in AT during two successive bouts of aerobic exercise (50% maximum O(2) uptake, 60 min duration) was evaluated using the microdialysis method. The metabolic responses measured in perfused probes with Ringer solution were compared with those obtained in perfused probes with Ringer plus 0.1 mmol/l phentolamine. Plasma norepinephrine level was not different during the two exercise bouts, whereas that of epinephrine was 2.5-fold higher during the second exercise. EGC in AT was twofold higher in the second compared with the first exercise, and the same response pattern was found for plasma glycerol. The exercise-induced increase in EGC was higher in the probe perfused with phentolamine compared with the control probe in both bouts of exercise. However, the potentiating effect of phentolamine on EGC was significant during the second exercise bout but did not reach a significant level during the first. These results suggest that epinephrine is involved in the control of lipid mobilization through activation of antilipolytic alpha(2)-AR in human subcutaneous AT during exercise.

  7. Zinc and water intake in rats: investigation of adrenergic and opiatergic central mechanisms

    Directory of Open Access Journals (Sweden)

    J.B. Fregoneze


    Full Text Available We have demonstrated that central administration of zinc in minute amounts induces a significant antidipsogenic action in dehydrated rats as well as in rats under central cholinergic and angiotensinergic stimulation. Here we show that acute third ventricle injections of zinc also block water intake induced by central ß-adrenergic stimulation in Wistar rats (190-250 g. Central inhibition of opioid pathways by naloxone reverses the zinc-induced antidipsogenic effect in dehydrated rats. After 120 min, rats receiving third ventricle injections of isoproterenol (160 nmol/rat exhibited a significant increase in water intake (5.78 ± 0.54 ml/100 g body weight compared to saline-treated controls (0.15 ± 0.07 ml/100 g body weight. Pretreatment with zinc (3.0, 30.0 and 300.0 pmol/rat, 45 min before isoproterenol injection blocked water intake in a dose-dependent way. At the highest dose employed a complete blockade was demonstrable (0.54 ± 0.2 ml/100 g body weight. After 120 min, control (NaAc-treated dehydrated rats, as expected, exhibited a high water intake (7.36 ± 0.39 ml/100 g body weight. Central administration of zinc blocked this response (2.5 ± 0.77 ml/100 g body weight. Naloxone pretreatment (82.5 nmol/rat, 30 min before zinc administration reverted the water intake to the high levels observed in zinc-free dehydrated animals (7.04 ± 0.56 ml/100 g body weight. These data indicate that zinc is able to block water intake induced by central ß-adrenergic stimulation and that zinc-induced blockade of water intake in dehydrated rats may be, at least in part, due to stimulation of central opioid peptides.

  8. Divergent Label-free Cell Phenotypic Pharmacology of Ligands at the Overexpressed β2-Adrenergic Receptors (United States)

    Ferrie, Ann M.; Sun, Haiyan; Zaytseva, Natalya; Fang, Ye


    We present subclone sensitive cell phenotypic pharmacology of ligands at the β2-adrenergic receptor (β2-AR) stably expressed in HEK-293 cells. The parental cell line was transfected with green fluorescent protein (GFP)-tagged β2-AR. Four stable subclones were established and used to profile a library of sixty-nine AR ligands. Dynamic mass redistribution (DMR) profiling resulted in a pharmacological activity map suggesting that HEK293 endogenously expresses functional Gi-coupled α2-AR and Gs-coupled β2-AR, and the label-free cell phenotypic activity of AR ligands are subclone dependent. Pathway deconvolution revealed that the DMR of epinephrine is originated mostly from the remodeling of actin microfilaments and adhesion complexes, to less extent from the microtubule networks and receptor trafficking, and certain agonists displayed different efficacy towards the cAMP-Epac pathway. We demonstrate that receptor signaling and ligand pharmacology is sensitive to the receptor expression level, and the organization of the receptor and its signaling circuitry.

  9. Adrenergic deficiency leads to impaired electrical conduction and increased arrhythmic potential in the embryonic mouse heart. (United States)

    Baker, Candice; Taylor, David G; Osuala, Kingsley; Natarajan, Anupama; Molnar, Peter J; Hickman, James; Alam, Sabikha; Moscato, Brittany; Weinshenker, David; Ebert, Steven N


    To determine if adrenergic hormones play a critical role in the functional development of the cardiac pacemaking and conduction system, we employed a mouse model where adrenergic hormone production was blocked due to targeted disruption of the dopamine β-hydroxylase (Dbh) gene. Immunofluorescent histochemical evaluation of the major gap junction protein, connexin 43, revealed that its expression was substantially decreased in adrenergic-deficient (Dbh-/-) relative to adrenergic-competent (Dbh+/+ and Dbh+/-) mouse hearts at embryonic day 10.5 (E10.5), whereas pacemaker and structural protein staining appeared similar. To evaluate cardiac electrical conduction in these hearts, we cultured them on microelectrode arrays (8×8, 200 μm apart). Our results show a significant slowing of atrioventricular conduction in adrenergic-deficient hearts compared to controls (31.4±6.4 vs. 15.4±1.7 ms, respectively, pheart rate and rhythm, mouse hearts from adrenergic-competent and deficient embryos were cultured ex vivo at E10.5, and heart rates were measured before and after challenge with the β-adrenergic receptor agonist, isoproterenol (0.5 μM). On average, all hearts showed increased heart rate responses following isoproterenol challenge, but a significant (phearts. These results show that adrenergic hormones may influence heart development by stimulating connexin 43 expression, facilitating atrioventricular conduction, and helping to maintain cardiac rhythm during a critical phase of embryonic development.

  10. Adrenergic effects on renal secretion of epidermal growth factor in the rat

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba


    , a beta-adrenergic blocking agent, decreased basal and beta-adrenergic stimulated total output of urinary EGF. Acetylcholine and the anticholinergic agent atropine had no effect on the output of EGF in urine. Also chemical sympathectomy induced by 6-hydroxydopamine reduced the urinary output of EGF. None...

  11. Autoantibodies against α1 adrenergic receptor related with cardiac remodeling in hypertensive patients by clinical observation

    Institute of Scientific and Technical Information of China (English)



    Objective To investigate the effects of autoantibodies against a adrenergic receptor on cardiac remodeling in patients with hypertension. Methods Five hundred and fifty three patients with hypertension in our hospital were selected. The autoantibodies againstα1 adrenergic receptor in sera of donor were detected by ELISA, and the Results of echocardiography were recorded. By

  12. Interaction between muscarinic and β-adrenergic receptors

    Institute of Scientific and Technical Information of China (English)

    Martin C. Michel


    In many tissues the parasympathetic and sympathetic nervous system regulate smooth musc tone via their transmitters aeetylcholine and noradrenaline, respectively. Direct smooth musc e e effects of acetylcholine via muscarinic receptors always promote contraction, but non-neuronal sources can importantly contribute to such stimulation. Direct smooth muscle effects of noradren- aline can promote contraction via al- and sometimes also α2-adrenoceptors but can promote re- laxation and inhibit contraction via β-adrenoceptors. I will focus on the interaction between sub- types of muscarinic and β-adrenergic receptors, largely using the urinary bladder as an exam- ple.

  13. Adrenergic regulation of HSL serine phosphorylation and activity in human skeletal muscle during the onset of exercise. (United States)

    Talanian, Jason L; Tunstall, Rebecca J; Watt, Matthew J; Duong, Mylinh; Perry, Christopher G R; Steinberg, Gregory R; Kemp, Bruce E; Heigenhauser, George J F; Spriet, Lawrence L


    Skeletal muscle hormone-sensitive lipase (HSL) activity is increased by contractions and increases in blood epinephrine (EPI) concentrations and cyclic AMP activation of the adrenergic pathway during prolonged exercise. To determine the importance of hormonal stimulation of HSL activity during the onset of moderate- and high-intensity exercise, nine men [age 24.3 +/- 1.2 yr, 80.8 +/- 5.0 kg, peak oxygen consumption (VO2 peak) 43.9 +/- 3.6 ml x kg(-1) x min(-1)] cycled for 1 min at approximately 65% VO2 peak, rested for 60 min, and cycled at approximately 90% VO2 peak for 1 min. Skeletal muscle biopsies were taken pre- and postexercise, and arterial blood was sampled throughout exercise. Arterial EPI increased (P HSL activity increased (P HSL Ser660 phosphorylation (approximately 55% increase) and ERK1/2 phosphorylation ( approximately 33% increase) were augmented following exercise at both intensities, whereas HSL Ser563 and Ser565 phosphorylation were not different from rest. The results indicate that increases in arterial EPI concentration during the onset of moderate- and high-intensity exercise increase cyclic AMP content, which results in the phosphorylation of HSL Ser660. This adrenergic stimulation contributes to the increase in HSL activity that occurs in human skeletal muscle in the first minute of exercise at 65% and 90% VO2 peak.

  14. Control of yeast mating signal transduction by a mammalian. beta. sub 2 -adrenergic receptor and G sub s. alpha. subunit

    Energy Technology Data Exchange (ETDEWEB)

    King, K.; Caron, M.G.; Lefkowitz, R.J. (Duke Univ. Medical Center, Durham, NC (USA)); Dohlman, H.G.; Thorner, J. (Univ. of California, Berkeley (USA))


    To facilitate functional and mechanistic studies of receptor-G protein interactions by expression of the human {beta}{sub 2}-adrenergic receptor (h{beta}-AR) has been expressed in Saccharomyces cerevisiae. This was achieved by placing a modified h{beta}-AR gene under control of the galactose-inducible GAL1 promoter. After induction by galactose, functional h{beta}-AR was expressed at a concentration several hundred times as great as that found in any human tissue. As determined from competitive ligand binding experiments, h{beta}-AR expressed in yeast displayed characteristic affinities, specificity, and stereoselectivity. Partial activation of the yeast pheromone response pathway by {beta}-adrenergic receptor agonists was achieved in cells coexpressing h{beta}-AR and a mammalian G protein (G{sub s}) {alpha} subunit - demonstrating that these components can couple to each other and to downstream effectors when expressed in yeast. This in vivo reconstitution system provides a new approach for examining ligand binding and G protein coupling to cell surface receptors.

  15. Antagonism of Nav channels and α1-adrenergic receptors contributes to vascular smooth muscle effects of ranolazine. (United States)

    Virsolvy, Anne; Farah, Charlotte; Pertuit, Nolwenn; Kong, Lingyan; Lacampagne, Alain; Reboul, Cyril; Aimond, Franck; Richard, Sylvain


    Ranolazine is a recently developed drug used for the treatment of patients with chronic stable angina. It is a selective inhibitor of the persistent cardiac Na(+) current (INa), and is known to reduce the Na(+)-dependent Ca(2+) overload that occurs in cardiomyocytes during ischemia. Vascular effects of ranolazine, such as vasorelaxation,have been reported and may involve multiple pathways. As voltage-gated Na(+) channels (Nav) present in arteries play a role in contraction, we hypothesized that ranolazine could target these channels. We studied the effects of ranolazine in vitro on cultured aortic smooth muscle cells (SMC) and ex vivo on rat aortas in conditions known to specifically activate or promote INa. We observed that in the presence of the Nav channel agonist veratridine, ranolazine inhibited INa and intracellular Ca(2+) calcium increase in SMC, and arterial vasoconstriction. In arterial SMC, ranolazine inhibited the activity of tetrodotoxin-sensitive voltage-gated Nav channels and thus antagonized contraction promoted by low KCl depolarization. Furthermore, the vasorelaxant effects of ranolazine, also observed in human arteries and independent of the endothelium, involved antagonization of the α1-adrenergic receptor. Combined α1-adrenergic antagonization and inhibition of SMCs Nav channels could be involved in the vascular effects of ranolazine.

  16. beta-Adrenergic agonist activity of a monoclonal anti-idiotypic antibody. (United States)

    Guillet, J G; Kaveri, S V; Durieu, O; Delavier, C; Hoebeke, J; Strosberg, A D


    Hybridoma cells bearing monoclonal antibody against the beta-adrenergic ligand alprenolol were used as an immunogen to raise monoclonal anti-idiotypic antibodies. Of six anti-idiotypic antibodies, which inhibit ligand binding, three were able to recognize beta-adrenergic receptors. One of them, mAb2B4, an IgM that could be amplified into ascites, binds to the beta-adrenergic catecholamine receptors of intact epidermoid A431 cells and precipitates receptors solubilized from plasma membranes by digitonin. This antibody identifies the beta 2-adrenergic receptor of A431 cells as a single 55-kDa protein and stimulates adenylate cyclase activity. This stimulation is inhibited by the beta-adrenergic antagonist propranolol.

  17. Alpha and beta adrenergic effects on metabolism in contracting, perfused muscle

    DEFF Research Database (Denmark)

    Richter, Erik; Ruderman, N B; Galbo, H


    The role of alpha- and beta-adrenergic receptor stimulation for the effect of epinephrine on muscle glycogenolysis, glucose- and oxygen uptake and muscle performance was studied in the perfused rat hindquarter at rest and during electrical stimulation (60 contractions/min). Adrenergic stimulation...... was obtained by epinephrine in a physiological concentration (2.4 X 10(-8) M) and alpha- and beta-adrenergic blockade by 10(-5) M phentolamine and propranolol, respectively. Epinephrine enhanced net glycogenolysis during contractions most markedly in slow-twitch red fibers. In these fibers the effect...... of alpha-adrenergic receptors and had a positive inotropic effect during contractions which was abolished by alpha- as well as by beta-adrenergic blockade. The results indicate that epinephrine has profound effects on contracting muscle, and that these effects are elicited through different combinations...

  18. The β3-adrenergic receptor is dispensable for browning of adipose tissues. (United States)

    de Jong, Jasper M A; Wouters, René T F; Boulet, Nathalie; Cannon, Barbara; Nedergaard, Jan; Petrovic, Natasa


    Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with β3-adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the β3-adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the β3-adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and β3-adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression (Ucp1, Pgc1a, Dio2 and Cidea) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the β3-adrenergic receptor. Experiments with the β3-adrenergic receptor agonist CL-316,243 verified the functional absence of β3-adrenergic signaling in these knockout mice. The β3-adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus, our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the β3-adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells. This should be taken into account in the increasing number of studies on the induction of browning and their extrapolation to human physiology.

  19. Alpha-adrenergic receptors in rat skeletal muscle

    DEFF Research Database (Denmark)

    Rattigan, S; Appleby, G J; Edwards, S J;


    Sarcolemma-enriched preparations from muscles rich in slow oxidative red fibres contained specific binding sites for the alpha 1 antagonist, prazosin (e.g. soleus Kd 0.13 nM, Bmax 29 fmol/mg protein). Binding sites for prazosin were almost absent from white muscle. Displacement of prazosin bindin...... adrenergic receptors are present on the sarcolemma of slow oxidative red fibres of rat skeletal muscle. The presence provides the mechanistic basis for apparent alpha-adrenergic effects to increase glucose and oxygen uptake in perfused rat hindquarter.......Sarcolemma-enriched preparations from muscles rich in slow oxidative red fibres contained specific binding sites for the alpha 1 antagonist, prazosin (e.g. soleus Kd 0.13 nM, Bmax 29 fmol/mg protein). Binding sites for prazosin were almost absent from white muscle. Displacement of prazosin binding...... from sarcolemma of soleus muscle (phentolamine greater than phenylephrine greater than idazoxan greater than yohimbine) suggested that the receptors were alpha 1. Binding sites for dihydroalprenolol (beta antagonist) were also more concentrated on red than white muscle and outnumbered prazosin sites...

  20. Bioisosteric phentolamine analogs as potent alpha-adrenergic antagonists. (United States)

    Hong, Seoung-Soo; Bavadekar, Supriya A; Lee, Sang-Il; Patil, Popat N; Lalchandani, S G; Feller, Dennis R; Miller, Duane D


    The synthesis and biological evaluation of a new series of bioisosteric phentolamine analogs are described. Replacement of the carbon next to the imidazoline ring of phentolamine with a nitrogen atom provides compounds (2, 3) that are about 1.6 times and 4.1 times more potent functionally than phentolamine on rat alpha1-adrenergic receptors, respectively. In receptor binding assays, the affinities of phentolamine and its bioisosteric analogs were determined on the human embryonic kidney (HEK) and Chinese Hamster ovary (CHO) cell lines expressing the human alpha1- and alpha2-AR subtypes, respectively. Analogs 2 and 3, both, displayed higher binding affinities at the alpha2- versus the alpha1-ARs, affinities being the least at the alpha1B-AR. Binding affinities of the methoxy ether analog 2 were greater than those of the phenolic analog 3 at all six alpha-AR subtypes. One of the nitrogen atoms in the imidazoline ring of phentolamine was replaced with an oxygen atom to give compounds 4 and 5, resulting in a 2-substituted oxazoline ring. The low functional antagonist activity on rat aorta, and binding potencies of these two compounds on human alpha1A- and alpha2A-AR subtypes indicate that a basic functional group is important for optimum binding to the alpha1- and alpha2A-adrenergic receptors.

  1. Blood flow distribution with adrenergic and histaminergic antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.


    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects.

  2. Vascular adrenergic receptor responses in skeletal muscle in myotonic dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Mechler, F.; Mastaglia, F.L.


    The pharmacological responses of vascular adrenergic receptors to intravenously administered epinephrine, phentolamine, and propranolol were assessed by measuring muscle blood flow (MBF) changes in the tibialis anterior muscle using the xenon 133 clearance technique and were compared in 8 normal subjects and 11 patients with myotonic dystrophy. In cases with advanced involvement of the muscle, the resting MBF was reduced and was not significantly altered by epinephrine before or after alpha- or beta-receptor blockade. In patients in whom the tibialis anterior muscle was normal or only minimally affected clinically, a paradoxical reduction in the epinephrine-induced increase in MBF was found after alpha blockade by phentolamine, and the epinephrine-induced MBF increase was not completely blocked by propranolol as in the normal subjects. These findings point to functional alteration in the properties of vascular adrenergic receptors in muscle in myotonic dystrophy. While this may be another manifestation of a widespread cell membrane defect in the disease, the possibility that the changes are secondary to the myotonic state cannot be excluded.

  3. Purification and reconstitution of the human platelet. cap alpha. /sub 2/-adrenergic receptor

    Energy Technology Data Exchange (ETDEWEB)

    Regan, J.W.; Cerione, R.A.; Nakata, H.; Benovic, J.L.; DeMarinis, R.M.; Caron, M.G.; Lefkowitz, R.J.


    Human platelet ..cap alpha../sub 2/-adrenergic receptors have been purified approx.80,000 fold to apparent homogeneity by a five step chromatographic procedure. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of radioiodinated protein from purified receptor preparations shows a single major band of M/sub r/ 64,000. The competitive binding of ligands to the purified receptor protein shows the proper ..cap alpha../sub 2/-adrenergic specificity. The ..cap alpha../sub 2/-adrenergic receptor contains an essential sulfhydryl residues. Thus, exposure of the purified receptor to the sulfhydryl specific reagent, phenylmercuric chloride (PMC), resulted in a 80% loss of binding activity. This loss of binding activity was prevented when exposure to PMC was done in the presence of ..cap alpha../sub 2/-adrenergic ligands and it was reversed by subsequent exposure to dithiothreitol. Partial proteolysis of purified ..cap alpha../sub 2/-adrenergic receptors was obtained with S. aureus V-8 protease, ..cap alpha..-chymotrypsin and papain. In a comparison with purified ..beta../sub 2/-adrenergic receptors no common partial proteolytic products were found. Partially purified preparations of the ..cap alpha../sub 2/-adrenergic receptor were successfully reconstituted into phospholipid vesicles with the inhibitory guanyl nucleotide-binding regulatory protein, N/sub i/. In these reconstituted preparations, epinephrine could stimulate, and phentolamine could block, the GTPase activity of N/sub i/.

  4. Effect of endurance training on adrenergic control of lipolysis in adipose tissue of obese women. (United States)

    Richterova, B; Stich, V; Moro, C; Polak, J; Klimcakova, E; Majercik, M; Harant, I; Viguerie, N; Crampes, F; Langin, D; Lafontan, M; Berlan, M


    The effect of a 12-wk training program on sc abdominal adipose tissue (SCAAT) was studied in 11 obese women. Before and after the training, biopsies of SCAAT were performed for mRNA levels determination. Using the microdialysis method, involvement of alpha(2)- and beta-adrenergic receptor (ARs) in the control of lipolysis in SCAAT was studied using local perfusion of epinephrine alone or supplemented with phentolamine, an alpha(2)-AR antagonist. In addition, the variation in dialysate glycerol concentrations during exercise (50% peak oxygen consumption at 40 min) in a probe perfused with Ringer's solution was compared with that obtained in a probe perfused with Ringer's solution plus phentolamine. Training did not promote changes in the expression of key genes of the lipolytic pathway. The epinephrine-induced rise in the dialysate glycerol concentration was identical before and after training and was similarly potentiated by phentolamine. During exercise, the potentiating effect of phentolamine on the glycerol response was apparent before, but not after, training. The exercise-induced increase in plasma norepinephrine was lower after training (P = 0.04). In conclusion, training did not modify either the expression of genes involved in the control of lipolysis or alpha(2)- and beta-ARs in situ sensitivity to epinephrine in SCAAT. Training reduced the antilipolytic action of catecholamines mediated by alpha(2)-ARs during exercise, probably due to a reduction of exercise-induced catecholamine increase.

  5. β-adrenergic-blocking drugs and melanoma: current state of the art. (United States)

    De Giorgi, Vincenzo; Grazzini, Marta; Gandini, Sara; Benemei, Silvia; Asbury, Curtis D; Marchionni, Niccolò; Geppetti, Pierangelo


    The purpose of this review is to present the preclinical, epidemiological and clinical data relevant to the association between β-blockers and melanoma progression. Preclinical studies have shown that β-adrenergic receptor (β-AR) signaling can inhibit multiple cellular processes involved in melanoma progression and metastasis. These observations have suggested the possibility that drugs originally intended for the treatment of cardiovascular disease, the β-AR blockers, may provide new therapeutic opportunities for the control of tumor progression. A large number of observational studies demonstrated the protective effect of β-blockers in breast cancer but, more recently, similar findings were also reported in other cancers such as prostate cancer and melanoma. With regard to melanoma, two recently published studies demonstrated a great reduction in the risk of disease progression for each year of treatment with β-blockers. The results from these studies have suggested a potential role for targeting the β-AR pathway in melanoma patients. Questions regarding the type of β-blocker or tumor characteristics, appropriate treatment paradigms and, most importantly, efficacy must be answered in randomized clinical studies before β-blockers can be considered a therapeutic option for patients with melanoma.

  6. Site-specific O-glycosylation by Polypeptide GalNAc-transferase T2 Co-regulates Beta1-adrenergic Receptor N-terminal Cleavage. (United States)

    Goth, Christoffer K; Tuhkanen, Hanna E; Khan, Hamayun; Lackman, Jarkko J; Wang, Shengjun; Narimatsu, Yoshiki; Holst Hansen, Lasse; Overall, Christopher; Clausen, Henrik; Schjoldager, Katrine T; Petäjä-Repo, Ulla E


    The β1-adrenergic receptor (β1AR) is a G protein-coupled receptor (GPCR) and the predominant adrenergic receptor subtype in the heart, where it mediates cardiac contractility and the force of contraction. Although it is the most important target for β-adrenergic antagonists, such as beta-blockers, relatively little is still known about its regulation. We have previously shown that β1AR undergoes constitutive and regulated N-terminal cleavage participating in receptor down-regulation, and moreover that the receptor is modified by O-glycosylation. Here we demonstrate that the polypeptide GalNAc-transferase 2 (GalNAc-T2) specifically O-glycosylates β1AR at five residues in the extracellular N-terminus, including the Ser49 residue at a location of the common Ser49Gly single-nucleotide polymorphism. Using in vitro O-glycosylation and proteolytic cleavage assays, a cell line deficient in O-glycosylation, GalNAc-T edited cell line model systems, and a GalNAc-T2 knockout rat model, we show that GalNAc-T2 co-regulates the metalloproteinase-mediated limited proteolysis of β1AR. Furthermore, we demonstrate that impaired O-glycosylation and enhanced proteolysis leads to attenuated receptor signaling, as the maximal response elicited by the βAR agonist isoproterenol and it potency in a cAMP accumulation assay was decreased in HEK293 cells lacking GalNAc-T2. Our findings reveal, for the first time, a GPCR as a target for co-regulatory functions of site-specific O-glycosylation mediated by a unique GalNAc-T isoform. The results provide a new level of β1AR regulation that may open up possibilities for new therapeutic strategies for cardiovascular diseases.

  7. Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. (United States)

    Lorton, Dianne; Bellinger, Denise L


    Cross-talk between the sympathetic nervous system (SNS) and immune system is vital for health and well-being. Infection, tissue injury and inflammation raise firing rates of sympathetic nerves, increasing their release of norepinephrine (NE) in lymphoid organs and tissues. NE stimulation of β2-adrenergic receptors (ARs) in immune cells activates the cAMP-protein kinase A (PKA) intracellular signaling pathway, a pathway that interfaces with other signaling pathways that regulate proliferation, differentiation, maturation and effector functions in immune cells. Immune-SNS cross-talk is required to maintain homeostasis under normal conditions, to develop an immune response of appropriate magnitude after injury or immune challenge, and subsequently restore homeostasis. Typically, β2-AR-induced cAMP is immunosuppressive. However, many studies report actions of β2-AR stimulation in immune cells that are inconsistent with typical cAMP-PKA signal transduction. Research during the last decade in non-immune organs, has unveiled novel alternative signaling mechanisms induced by β2-AR activation, such as a signaling switch from cAMP-PKA to mitogen-activated protein kinase (MAPK) pathways. If alternative signaling occurs in immune cells, it may explain inconsistent findings of sympathetic regulation of immune function. Here, we review β2-AR signaling, assess the available evidence for alternative signaling in immune cells, and provide insight into the circumstances necessary for "signal switching" in immune cells.

  8. Phospholemman and beta-adrenergic stimulation in the heart. (United States)

    Wang, JuFang; Gao, Erhe; Song, Jianliang; Zhang, Xue-Qian; Li, Jifen; Koch, Walter J; Tucker, Amy L; Philipson, Kenneth D; Chan, Tung O; Feldman, Arthur M; Cheung, Joseph Y


    Phosphorylation at serine 68 of phospholemman (PLM) in response to beta-adrenergic stimulation results in simultaneous inhibition of cardiac Na(+)/Ca(2+) exchanger NCX1 and relief of inhibition of Na(+)-K(+)-ATPase. The role of PLM in mediating beta-adrenergic effects on in vivo cardiac function was investigated with congenic PLM-knockout (KO) mice. Echocardiography showed similar ejection fraction between wild-type (WT) and PLM-KO hearts. Cardiac catheterization demonstrated higher baseline contractility (+dP/dt) but similar relaxation (-dP/dt) in PLM-KO mice. In response to isoproterenol (Iso), maximal +dP/dt was similar but maximal -dP/dt was reduced in PLM-KO mice. Dose-response curves to Iso (0.5-25 ng) for WT and PLM-KO hearts were superimposable. Maximal +dP/dt was reached 1-2 min after Iso addition and declined with time in WT but not PLM-KO hearts. In isolated myocytes paced at 2 Hz. contraction and intracellular Ca(2+) concentration ([Ca(2+)](i)) transient amplitudes and [Na(+)](i) reached maximum 2-4 min after Iso addition, followed by decline in WT but not PLM-KO myocytes. Reducing pacing frequency to 0.5 Hz resulted in much smaller increases in [Na(+)](i) and no decline in contraction and [Ca(2+)](i) transient amplitudes with time in Iso-stimulated WT and PLM-KO myocytes. Although baseline Na(+)-K(+)-ATPase current was 41% higher in PLM-KO myocytes because of increased alpha(1)- but not alpha(2)-subunit activity, resting [Na(+)](i) was similar between quiescent WT and PLM-KO myocytes. Iso increased alpha(1)-subunit current (I(alpha1)) by 73% in WT but had no effect in PLM-KO myocytes. Iso did not affect alpha(2)-subunit current (I(alpha2)) in WT and PLM-KO myocytes. In both WT and NCX1-KO hearts, PLM coimmunoprecipitated with Na(+)-K(+)-ATPase alpha(1)- and alpha(2)-subunits, indicating that association of PLM with Na(+)-K(+)-ATPase did not require NCX1. We conclude that under stressful conditions in which [Na(+)](i) was high, beta-adrenergic agonist

  9. The pineal gland: A model for adrenergic modulation of ubiquitin ligases (United States)

    Liu, Wenjun; Reiter, Russel J.


    Introduction A recent study of the pineal gland of the rat found that the expression of more than 3000 genes showed significant day/night variations (The Hartley dataset). The investigators of this report made available a supplemental table in which they tabulated the expression of many genes that they did not discuss, including those coding for components of the ubiquitin proteasome system. Herein we identify the genes of the ubiquitin proteasome system whose expression were significantly influenced by environmental lighting in the Hartley dataset, those that were stimulated by DBcAMP in pineal glands in culture, and those that were stimulated by norepinephrine. Purpose Using the Ubiquitin and Ubiquitin-like Conjugation Database (UUCA) we identified ubiquitin ligases and conjugases, and deubiquitinases in the Hartley dataset for the purpose of determining whether expression of genes of the ubiquitin proteasome pathway were significantly influenced by day/night variations and if these variations were regulated by autonomic innervation of the pineal gland from the superior cervical ganglia. Methods In the Hartley experiments pineal glands groups of rats sacrificed during the day and groups sacrificed during the night were examined for gene expression. Additional groups of rats had their superior cervical ganglia removed surgically or surgically decentralized and the pineal glands likewise examined for gene expression. Results The genes with at least a 2-fold day/night significant difference in expression included genes for 5 ubiquitin conjugating enzymes, genes for 58 ubiquitin E3 ligases and genes for 6 deubiquitinases. A 35-fold day/night difference was noted in the expression of the gene Sik1, which codes for a protein containing both an ubiquitin binding domain (UBD) and an ubiquitin-associated (UBA) domain. Most of the significant differences in these genes were prevented by surgical removal, or disconnection, of the superior cervical ganglia, and most were

  10. [Involvement of adrenergic mechanisms in developing the nervous syndrome of high pressure and nitrogen narcosis]. (United States)

    Sledkov, A I; Bernarskii, K V; Shilina, M N


    Involvement of the adrenergic mediator system in central mechanisms of hyperbaric nitrogen narcosis or the high pressure nervous syndrome (NSHP) produced by nitrogen or heliox gas mixtures under increased pressure was studied in mice and rabbit experiments with the use of pharmacological substances-analyzers. Accumulated data are indicative of lack of a significant role of the adrenergic system in the NSHP genesis and a protective effect of activation of the central but not peripheric adrenergic mediation in development of the behavioural and electrophysiological symptomatics of nitrogen narcosis. Mechanisms of NSHP and nitrogen narcosis and possible principles of pharmacological correction are under discussion.

  11. G-Protein Inwardly Rectifying Potassium Channel 1 (GIRK1 Knockdown Decreases Beta-Adrenergic, MAP Kinase and Akt Signaling in the MDA-MB-453 Breast Cancer Cell Line

    Directory of Open Access Journals (Sweden)

    Michael W. Hance


    Full Text Available Previous data from our laboratory have indicated that there is a functional link between the beta-adrenergic receptor signaling pathway and the G-protein inwardly rectifying potassium channel (GIRK1 in breast cancer cell lines and that these pathways are involved in growth regulation of these cells. To determine functionality, MDA-MB-453 breast cancer cells were stimulated with ethanol, known to open GIRK channels. Decreased GIRK1 protein levels were seen after treatment with 0.12% ethanol. In addition, serum-free media completely inhibited GIRK1 protein expression. This data indicates that there are functional GIRK channels in breast cancer cells and that these channels are involved in cellular signaling. In the present research, to further define the signaling pathways involved, we performed RNA interference (siRNA studies. Three stealth siRNA constructs were made starting at bases 1104, 1315, and 1490 of the GIRK1 sequence. These constructs were transfected into MDA-MB-453 cells, and both RNA and protein were isolated. GIRK1, β2-adrenergic and 18S control levels were determined using real-time PCR 24 hours after transfection. All three constructs decreased GIRK1 mRNA levels. However, β2 mRNA levels were unchanged by the GIRK1 knockdown. GIRK1 protein levels were also reduced by the knockdown, and this knockdown led to decreases in beta-adrenergic, MAP kinase and Akt signaling.

  12. EEG differences between the opioid and adrenergic psyhoneuroendocrine rat types

    DEFF Research Database (Denmark)

    Cristea, A; Moldovan, M; Munteanu, A M


    Our work is based on the hypothesis of the existence of an opioid psychoneuroendocrine type named "O" type (Cristea, 1993), opposed to the well known adrenergic "A" type described by Roseman and Friedman in 1980. In the present study we tested the differences between the background EEG activity...... adult (140 g) male Wistar population using the distribution of the tail retraction time (TRT) during a tail-flick test. The epidural EEG activity, was quantified within the 1-30 Hz band by six numerical parameters: root mean square (RMS), mean spectral frequency (MSF), spectral edge frequency at 95...... theta RSP asymmetry both during consciousness and ether anesthesia while no such theta gradient could be shown for the "O" type. The differences between the "A" and "O" types are enhanced under light Ether anesthesia to which the "A" type is more resistant. The EEG complementarity between the "A" and "O...

  13. Dopaminergic and beta-adrenergic effects on gastric antral motility

    DEFF Research Database (Denmark)

    Bech, K; Hovendal, C P; Gottrup, F


    of bethanechol or pentagastrin inducing motor activity patterns as in the phase III of the MMC and the digestive state respectively. The stimulated antral motility was dose-dependently inhibited by dopamine. The effect was significantly blocked by specifically acting dopaminergic blockers, while alpha- and beta......-adrenergic blockers were without any significant effects. Dose-response experiments with bethanechol and dopamine showed inhibition of a non-competitive type. Isoprenaline was used alone and in conjunction with selective blockade of beta 1- and beta 2-receptors during infusion of bethanechol which induces a pattern...... similar to phase III in the migrating myoelectric complex. The stimulated antral motility was dose-dependently inhibited by isoprenaline. The effect could be significantly blocked by propranolol (beta 1 + beta 2-adrenoceptor blocker) and by using in conjunction the beta 1-adrenoceptor blocker practolol...


    Directory of Open Access Journals (Sweden)

    Dario eLeosco


    Full Text Available In heart failure (HF, exercise has been shown to modulate cardiac sympathetic hyperactivation which is one of the earliest features of neurohormonal derangement in this syndrome and correlates with adverse outcome. An important molecular alteration related to chronic sympathetic overstimulation in HF is represented by cardiac β-adrenergic receptor (β-AR dysfunction . It has been demonstrated that exercise reverses β-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation. In particular, several evidence indicate that exercise reduces levels of cardiac G-protein coupled receptor kinase-2 (GRK2 which is known to be involved in both β1-AR and β2-AR dysregulation in HF. Similar alterations of β-AR system have been described also in the senescent heart. It has also been demonstrated that exercise training restores adrenal GRK2/α-2AR/cathecolamine (CA production axis. At vascular level, exercise shows a therapeutic effect on age-related impairment of vascular reactivity to adrenergic stimulation and restores β-AR-dependent vasodilatation by increasing vascular β-AR responsiveness and reducing endothelial GRK2 activity. Sympathetic nervous system overdrive is thought to account for >50 % of all cases of hypertension and a lack of balance between parasympathetic and sympathetic modulation has been observed in hypertensive subjects. Non-pharmacological, lifestyle interventions have been associated with reductions in SNS overactivity and blood pressure in hypertension. Several evidence have highlighted the blood pressure lowering effects of aerobic endurance exercise in patients with hypertension and the significant reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining the favourable effects of exercise on blood pressure control.

  15. Alpha 2 adrenergic receptors in hyperplastic human prostate: identification and characterization using (/sup 3/H) rauwolscine

    Energy Technology Data Exchange (ETDEWEB)

    Shapiro, E.; Lepor, H.


    (/sup 3/H)Rauwolscine ((/sup 3/H)Ra), a selective ligand for the alpha 2 adrenergic receptor, was used to identify and characterize alpha 2 adrenergic receptors in prostate glands of men with benign prostatic hyperplasia. Specific binding of (/sup 3/H)Ra to prostatic tissue homogenates was rapid and readily reversible by addition of excess unlabelled phentolamine. Scatchard analysis of saturation experiments demonstrates a single, saturable class of high affinity binding sites (Bmax = 0.31 +/- 0.04 fmol./microgram. DNA, Kd = 0.9 +/- 0.11 nM.). The relative potency of alpha adrenergic drugs (clonidine, alpha-methylnorepinephrine and prazosin) in competing for (/sup 3/H)Ra binding sites was consistent with the order predicted for an alpha 2 subtype. The role of alpha 2 adrenergic receptors in normal prostatic function and in men with bladder outlet obstruction secondary to BPH requires further investigation.

  16. Adrenergic effects on secretion of amylase from the rat salivary glands

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier; Nexø, Ebba


    The present study was undertaken to investigate the effect of adrenergic agents on secretion of amylase from the salivary glands in vivo. Saliva was collected from the distal oesophagus in conscious rats. Adrenaline increased the concentration of amylase in saliva and serum significantly....... The result of infusion of alpha- and beta-adrenergic antagonists as well as noradrenaline and isoproterenol showed that secretion of salivary amylase is predominantly mediated by stimulation of beta-adrenergic receptors, especially of the beta 1-subtype. Investigation of the isoenzyme pattern in saliva......, pancreatic juice and serum demonstrated that the major component in serum is salivary amylase. This study has shown that beta-adrenergic agents stimulate secretion of amylase from the salivary glands in rats. Though the secretion is mainly exocrine small amounts of amylase is found in serum, which seems...

  17. Differential Regulation of Two Palmitoylation Sites in the Cytoplasmic Tail of the β1-Adrenergic Receptor*



    S-Palmitoylation of G protein-coupled receptors (GPCRs) is a prevalent modification, contributing to the regulation of receptor function. Despite its importance, the palmitoylation status of the β1-adrenergic receptor, a GPCR critical for heart function, has never been determined. We report here that the β1-adrenergic receptor is palmitoylated on three cysteine residues at two sites in the C-terminal tail. One site (proximal) is adjacent to the seventh transmembrane domain and is a consensus ...

  18. [Modifying effect of incorporated 137Cs on the mechanism of adrenergic control of myocardial contraction]. (United States)

    Lobanok, L M; Bulanova, K Ia; Gerasimovich, N V; Sineleva, M V; Miliutin, A A


    Incorporated 137Cs (absorbed dose of 0.26 Gy) causes decrease of myocardial's contractile function and inotropic response to beta-adrenagonists effect, isoproterenol-stimulated adenylate cyclase activity and beta-adrenoreceptors affinity. Adrenergic effects, mediated by alpha-adrenergic structures on heart contractile function, on the contrary, become stronger, that is due to the increase of the receptors' density on sarcolemma surface.

  19. Antagonism of apomorphine-enhanced startle by alpha 1-adrenergic antagonists. (United States)

    Davis, M; Kehne, J H; Commissaris, R L


    The present study investigated the possible involvement of central noradrenergic neurons in mediating the excitatory effect of the dopamine agonist apomorphine on the acoustic startle response in rats. Experiment 1 assessed the effects of intraperitoneal (i.p.) administration of adrenergic antagonists on apomorphine-enhanced startle. The excitation of startle produced by apomorphine (1.0-3.0 mg/kg i.p.) was blocked by the alpha 1-adrenergic antagonists prazosin (0.03-1.0 mg/kg) and WB-4101 (1.0 mg/kg). Prazosin was very potent in this regard, having an ED50 of 0.03 mg/kg. Blockade of beta-adrenergic receptors with propranolol (20 mg/kg) or blockade of peripheral alpha-adrenergic receptors with phentolamine (10 mg/kg) failed to alter the effect of apomorphine. Prazosin did not block the enhancement of startle produced by other drugs (5-methoxy-N,N-dimethyltryptamine, strychnine), nor did it alter the entry of apomorphine into the brain. The alpha 1-adrenergic antagonists piperoxane (0.03 mg/kg), yohimbine (0.03 mg/kg) or RX781094 (0.07 mg/kg) markedly potentiated apomorphine excitation. These data indicated that specific blockade of central alpha 1-adrenergic receptors prevents apomorphine-enhanced startle. In contrast to the effects of alpha 1-adrenergic antagonists, Experiment 2 found that other drugs that produce an acute (clonidine, 0.040 mg/kg) or chronic (intraventricular 6-hydroxydopamine, 2 X 200 micrograms; DSP4, 50 mg/kg i.p.) disruption of noradrenergic transmission failed to affect apomorphine excitation. Thus, the ability of alpha 1-adrenergic antagonists to block apomorphine's excitation of startle cannot be explained by a simple dopamine-norepinephrine interaction. Alternative hypothesis are discussed.

  20. Impact of the Tamsulosin in Alpha Adrenergic Receptor of Airways at Patients with Increased Bronchial Reactibility


    Mustafa, Lirim; Ilazi, Ali; Dauti, Arta; Islami, Pellumb; Kastrati, Bashkim; Islami, Hilmi


    Objective: In this work, effect of tamsulosin as antagonist of alpha1A and alpha1B adrenergic receptor and effect of agonists of beta2 adrenergic receptor–salbutamol in patients with increased bronchial reactibility was studied. Methods: Parameters of the lung function are determined with Body plethysmography six (6) hours after administration of tamsulosin. Raw and ITGV were registered and specific resistance (SRaw) was calculated as well. Tamsulosin was administered in per os manner as a pr...

  1. Immunoanalogue of vertebrate beta-adrenergic receptor in the unicellular eukaryote Paramecium. (United States)

    Wiejak, Jolanta; Surmacz, Liliana; Wyroba, Elzbieta


    Cell fractionation, SDS-PAGE, quantitative Western blot, confocal immunolocalization and immunogold labelling were performed to find an interpretation of the physiological response of the unicellular eukaryote Paramecium to beta-adrenergic ligands. The 69 kDa polypeptide separated by SDS-PAGE in S2 and P2 Paramecium subcellular fractions cross-reacted with antibody directed against human beta2-adrenergic receptor. This was detected by Western blotting followed by chemiluminescent detection. Quantitative image analysis showed that beta-selective adrenergic agonist (-)-isoproterenol--previously shown to enhance phagocytic activity--evoked redistribution of the adrenergic receptor analogue from membraneous (P2) to cytosolic (S2) fraction. The relative increase in immunoreactive band intensity in S2 reached 80% and was paralleled by a 59% decrease in P2 fraction. Confocal immunofluorescence revealed beta2-adrenergic receptor sites on the cell surface and at the ridge of the cytopharynx--where nascent phagosomes are formed. This localization was confirmed by immunoelectron microscopy. These results indicate that the 69 kDa Paramecium polypeptide immunorelated to vertebrate beta2-adrenergic receptor appeared in this evolutionary ancient cell as a nutrient receptor.

  2. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by β-Adrenergic Stimulation (United States)

    Shawl, Asif Iqbal; Im, Soo-Yeul; Nam, Tae-Sik; Lee, Sun-Hwa; Ko, Jae-Ki; Jang, Kyu Yoon; Kim, Donghee; Kim, Uh-Hyun


    Ca2+ signaling plays a fundamental role in cardiac hypertrophic remodeling, but the underlying mechanisms remain poorly understood. We investigated the role of Ca2+-mobilizing second messengers, NAADP and cADPR, in the cardiac hypertrophy induced by β-adrenergic stimulation by isoproterenol. Isoproterenol induced an initial Ca2+ transients followed by sustained Ca2+ rises. Inhibition of the cADPR pathway with 8-Br-cADPR abolished only the sustained Ca2+ increase, whereas inhibition of the NAADP pathway with bafilomycin-A1 abolished both rapid and sustained phases of the isoproterenol-mediated signal, indicating that the Ca2+ signal is mediated by a sequential action of NAADP and cADPR. The sequential production of NAADP and cADPR was confirmed biochemically. The isoproterenol-mediated Ca2+ increase and cADPR production, but not NAADP production, were markedly reduced in cardiomyocytes obtained from CD38 knockout mice. CD38 knockout mice were rescued from chronic isoproterenol infusion-induced myocardial hypertrophy, interstitial fibrosis, and decrease in fractional shortening and ejection fraction. Thus, our findings indicate that β-adrenergic stimulation contributes to the development of maladaptive cardiac hypertrophy via Ca2+ signaling mediated by NAADP-synthesizing enzyme and CD38 that produce NAADP and cADPR, respectively. PMID:26959359

  3. The adrenergic retulation of the cardiovascular system in the South American rattlesnake, Crotalus durissus

    DEFF Research Database (Denmark)

    Galli, G.L.J.; Jensen, Nini Skovgaard; Abe, A.S.


    The present study investigates adrenergic regulation of the systemic and pulmonary circulations of the anaesthetised South American rattlesnake, Crotalus durissus. Haemodynamic measurements were made following bolus injections of adrenaline and adrenergic antagonists administered through a systemic...... arterial catheter. Adrenaline caused a marked systemic vasoconstriction that was abolished by phentolamine, indicating this response was mediated through α-adrenergic receptors. Injection of phentolamine gave rise to a pronounced vasodilatation (systemic conductance (Gsys) more than doubled), while...... injection of propranolol caused a systemic vasoconstriction, pointing to a potent α-adrenergic, and a weaker β-adrenergic tone in the systemic vasculature of Crotalus. Overall, the pulmonary vasculature was far less responsive to adrenergic stimulation than the systemic circulation. Adrenaline caused...

  4. Psychological stress promotes neutrophil infiltration in colon tissue through adrenergic signaling in DSS-induced colitis model. (United States)

    Deng, Que; Chen, Hongyu; Liu, Yanjun; Xiao, Fengjun; Guo, Liang; Liu, Dan; Cheng, Xiang; Zhao, Min; Wang, Xiaomeng; Xie, Shuai; Qi, Siyong; Yin, Zhaoyang; Gao, Jiangping; Chen, Xintian; Wang, Jiangong; Guo, Ning; Ma, Yuanfang; Shi, Ming


    Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition. Psychological stress has been postulated to affect the clinical symptoms and recurrence of IBD. The exact molecular mechanisms are not fully understood. In the present study, we demonstrate that psychological stress promotes neutrophil infiltration into colon tissues in dextran sulfate sodium (DSS)-induced colitis model. The psychological stress resulted in abnormal expression of the proinflammatory cytokines (IL-1β, IL-6, IL-17A, and IL-22) and neutrophil chemokines (CXCL1 and CXCL2) and overactivation of the STAT3 inflammatory signaling pathway. Under chronic unpredictable stress, the adrenergic nervous system was markedly activated, as the expression of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, in bone marrow and colonic epithelium was enhanced, especially in the myenteric ganglia. The β-AR agonist isoproterenol mimicked the effects of psychological stress on neutrophilia, neutrophil infiltration, and colonic damage in DSS-induced colitis. The β1-AR/β2-AR inhibitor propranolol reduced the numbers of the neutrophils in the circulation, suppressed neutrophil infiltration into colonic tissues, and attenuated the colonic tissue damage promoted by chronic stress. Propranolol also abolished stress-induced upregulation of proinflammatory cytokines and neutrophil chemokines. Our data reveal a close linkage between the β1-AR/β2-AR activation and neutrophil trafficking and also suggest the critical roles of adrenergic nervous system in exacerbation of inflammation and damage of colonic tissues in experimental colitis. The current study provides a new insight into the mechanisms underlying the association of psychological stress with excessive inflammatory response and pathophysiological consequences in IBD. The findings also suggest a potential application of neuroprotective agents to prevent relapsing immune activation in the treatment of IBD.

  5. Non-amyloidogenic effects of α2 adrenergic agonists: implications for brimonidine-mediated neuroprotection (United States)

    Nizari, Shereen; Guo, Li; Davis, Benjamin M; Normando, Eduardo M; Galvao, Joana; Turner, Lisa A; Bizrah, Mukhtar; Dehabadi, Mohammad; Tian, Kailin; Francesca Cordeiro, M


    The amyloid beta (Aβ) pathway is strongly implicated in neurodegenerative conditions such as Alzheimer's disease and more recently, glaucoma. Here, we identify the α2 adrenergic receptor agonists (α2ARA) used to lower intraocular pressure can prevent retinal ganglion cell (RGC) death via the non-amyloidogenic Aβ-pathway. Neuroprotective effects were confirmed in vivo and in vitro in different glaucoma-related models using α2ARAs brimonidine (BMD), clonidine (Clo) and dexmedetomidine. α2ARA treatment significantly reduced RGC apoptosis in experimental-glaucoma models by 97.7% and 92.8% (BMD, P<0.01) and 98% and 92.3% (Clo, P<0.01)) at 3 and 8 weeks, respectively. A reduction was seen in an experimental Aβ-induced neurotoxicity model (67% BMD and 88.6% Clo, both P<0.01, respectively), and in vitro, where α2ARAs significantly (P<0.05) prevented cell death, under both hypoxic (CoCl2) and stress (UV) conditions. In experimental-glaucoma, BMD induced ninefold and 25-fold and 36-fold and fourfold reductions in Aβ and amyloid precursor protein (APP) levels at 3 and 8 weeks, respectively, in the RGC layer, with similar results with Clo, and in vitro with all three α2ARAs. BMD significantly increased soluble APPα (sAPPα) levels at 3 and 8 weeks (2.1 and 1.6-fold) in vivo and in vitro with the CoCl2 and UV-light insults. Furthermore, treatment of UV-insulted cells with an sAPPα antibody significantly reduced cell viability compared with BMD-treated control (52%), co-treatment (33%) and untreated control (27%). Finally, we show that α2ARAs modulate levels of laminin and MMP-9 in RGCs, potentially linked to changes in Aβ through APP processing. Together, these results provide new evidence that α2ARAs are neuroprotective through their effects on the Aβ pathway and sAPPα, which to our knowledge, is the first description. Studies have identified the need for α-secretase activators and sAPPα-mimetics in neurodegeneration; α2ARAs, already clinically available

  6. Postnatal development of adrenergic responsiveness in the rabbit heart. (United States)

    Feng, Z P; Dryden, W F; Gordon, T


    It is uncertain how changes in the beta-adrenoceptor population influence the contractility of developing heart. To resolve this we have examined postnatal developmental changes in the adrenergic responsiveness of the rabbit heart. The inotropic effect of isoproterenol on isolated left ventricular papillary muscles from rabbits aged 3, 21, and 90 days was compared with the relative number of beta-adrenoceptors at each age measured using [3H]dihydroalprenolol ([3H]DHA) as the specific ligand. The maximum tension developed in response to isoproterenol increases from 37 +/- 7 to 175 +/- 33% above control twitch tension between 3 and 21 days of age; this is followed by a decrease to 68 +/- 12% in the young adult. During this period of development, there is a decline in EC50 towards increased sensitivity. These differences are partially accounted for by an increase in the numbers of specific [3H]DHA binding sites from 17.3 +/- 2.3 to 56.6 +/- 9.9 fmol/mg wet tissue weight from 3 to 21 days, and a subsequent decrease to 32 +/- 4.5 fmol/mg tissue in the young adult. The proportionally larger increase in contractility compared with the number of beta-adrenoceptor binding sites during the first 3 weeks of life is discussed in terms of the developmental changes in the efficacy of coupling between receptor occupancy and contraction.

  7. Altered adrenergic response and specificity of the receptors in rat ascites hepatoma AH130. (United States)

    Sanae, F; Miyamoto, K; Koshiura, R


    Adenylate cyclase activation through adrenergic receptors in rat ascites hepatoma (AH) 130 cells in response to adrenergic drugs was studied, and receptor binding and displacement were compared with those of normal rat hepatocytes. Epinephrine (Epi) and norepinephrine (NE) activated AH130 adenylate cyclase about half as much as isoproterenol (IPN) but equaled IPN after treatment with the alpha-antagonist phentolamine or islet-activating protein (IAP). The three catecholamines in hepatocytes were similar regardless of phentolamine or IAP. These catecholamines activated adenylate cyclase in order of IPN greater than NE greater than Epi in AH130 cells but IPN greater than Epi greater than NE in hepatocytes. We then used the alpha 1-selective ligand [3H]prazosin, the alpha 2-selective ligand [3H]clonidine, and the beta-ligand [125I]iodocyanopindolol [( 125I]ICYP), and found that AH130 cells had few prazosin-binding sites, about eight times as many clonidine-binding sites with high affinity, and many more ICYP-binding sites than in hepatocytes. The dissociation constant (Ki) of the beta 1-selective drug metoprolol by Hofstee plots for AH130 cells was lower than that for hepatocytes. The inhibition of specific ICYP binding by the beta 2-selective agonist salbutamol for AH130 cells gave only one Ki value which was much higher than both high and low Ki values of the drug for hepatocytes. These findings indicate that the alpha- and beta-adrenergic receptors in hepatocytes are predominantly alpha 1-type and beta 2-type, but that those in AH130 cells are predominantly alpha 2-type and beta 1-type, and the low adrenergic response of AH130 cells is due to the dominant appearance of alpha 2-adrenergic receptors, linked with the inhibitory guanine-nucleotide binding regulatory protein, instead of alpha 1-adrenergic receptors, and beta 1-adrenergic receptors with low affinity for the hormone.

  8. Species differences in the localization and number of CNS beta adrenergic receptors: Rat versus guinea pig

    Energy Technology Data Exchange (ETDEWEB)

    Booze, R.M.; Crisostomo, E.A.; Davis, J.N.


    The localization and number of beta adrenergic receptors were directly compared in the brains of rats and guinea pigs. The time course of association and saturability of (125I)cyanopindolol (CYP) binding to slide-mounted tissue sections was similar in rats (Kd = 17 pM) and guinea pigs (Kd = 20 pM). The beta-1 and beta-2 receptor subtypes were examined through the use of highly selective unlabeled receptor antagonists, ICI 118,551 (50 nM) and ICI 89,406 (70 nM). Dramatic species differences between rats and guinea pigs were observed in the neuroanatomical regional localization of the beta adrenergic receptor subtypes. For example, in the thalamus prominent beta-1 and beta-2 receptor populations were identified in the rat; however, the entire thalamus of the guinea pig had few, if any, beta adrenergic receptors of either subtype. Hippocampal area CA1 had high levels of beta-2 adrenergic receptors in both rats and guinea pigs but was accompanied by a widespread distribution of beta-2 adrenergic receptors only in rats. Quantitative autoradiographic analyses of 25 selected neuroanatomical regions (1) confirmed the qualitative differences in CNS beta adrenergic receptor localization, (2) determined that guinea pigs had significantly lower levels of beta adrenergic receptors than rats and (3) indicated a differential pattern of receptor subtypes between the two species. Knowledge of species differences in receptor patterns may be useful in designing effective experiments as well as in exploring the relationships between receptor and innervation patterns. Collectively, these data suggest caution be used in extrapolation of the relationships of neurotransmitters and receptors from studies of a single species.

  9. Inhibition of Brain Swelling after Ischemia-Reperfusion by β-Adrenergic Antagonists: Correlation with Increased K+ and Decreased Ca2+ Concentrations in Extracellular Fluid

    Directory of Open Access Journals (Sweden)

    Dan Song


    Full Text Available Infarct size and brain edema following ischemia/reperfusion are reduced by inhibitors of the Na+, K+, 2Cl−, and water cotransporter NKCC1 and by β1-adrenoceptor antagonists. NKCC1 is a secondary active transporter, mainly localized in astrocytes, driven by transmembrane Na+/K+ gradients generated by the Na+,K+-ATPase. The astrocytic Na+,K+-ATPase is stimulated by small increases in extracellular K+ concentration and by the β-adrenergic agonist isoproterenol. Larger K+ increases, as occurring during ischemia, also stimulate NKCC1, creating cell swelling. This study showed no edema after 3 hr medial cerebral artery occlusion but pronounced edema after 8 hr reperfusion. The edema was abolished by inhibitors of specifically β1-adrenergic pathways, indicating failure of K+-mediated, but not β1-adrenoceptor-mediated, stimulation of Na+,K+-ATPase/NKCC1 transport during reoxygenation. Ninety percent reduction of extracellular Ca2+ concentration occurs in ischemia. Ca2+ omission abolished K+ uptake in normoxic cultures of astrocytes after addition of 5 mM KCl. A large decrease in ouabain potency on K+ uptake in cultured astrocytes was also demonstrated in Ca2+-depleted media, and endogenous ouabains are needed for astrocytic K+ uptake. Thus, among the ionic changes induced by ischemia, the decrease in extracellular Ca2+ causes failure of the high-K+-stimulated Na+,K+-ATPase/NKCC1 ion/water uptake, making β1-adrenergic activation the only stimulus and its inhibition effective against edema.

  10. Activation of alpha2-adrenergic receptors blunts epinephrine-induced lipolysis in subcutaneous adipose tissue during a hyperinsulinemic euglycemic clamp in men. (United States)

    Stich, Vladimir; Pelikanova, Tereza; Wohl, Petr; Sengenès, Coralie; Zakaroff-Girard, Alexia; Lafontan, Max; Berlan, Michel


    The aim of this study was to investigate whether hyperinsulinemia modifies adrenergic control of lipolysis, with particular attention paid to the involvement of antilipolytic alpha2-adrenergic receptors (AR). Eight healthy male subjects (age: 23.9 +/- 0.9 yr; body mass index: 23.8 +/- 1.9) were investigated during a 6-h euglycemichyperinsulinemic clamp and in control conditions. Before and during the clamp, the effect of graded perfusions of isoproterenol (0.1 and 1 microM) or epinephrine (1 and 10 microM) on the extracellular glycerol concentration in subcutaneous abdominal adipose tissue was evaluated by using the microdialysis method. Both isoproterenol and epinephrine induced a dose-dependent increase in extracellular glycerol concentration when infused for 60 min through the microdialysis probes before and during hours 3 and 6 of the clamp. The catecholamine-induced increase was significantly lower during the clamp than before it, with the inhibition being more pronounced in hour 6 of the clamp. Isoproterenol (1 microM)-induced lipolysis was reduced by 28 and 44% during hours 3 and 6 of the clamp, respectively, whereas the reduction of epinephrine (100 microM)-induced lipolysis was significantly greater (by 63 and 70%, P < 0.01 and P < 0.04, respectively) during the same time intervals. When epinephrine was infused in combination with 100 microM phentolamine (a nonselective alpha-AR antagonist), the inhibition of epinephrine (10 microM)-induced lipolysis was only of 19 and 40% during hours 3 and 6 of the clamp, respectively. The results demonstrate that, in situ, insulin counteracts the epinephrine-induced lipolysis in adipose tissue. The effect involves 1) reduction of lipolysis stimulation mediated by the beta-adrenergic pathway and 2) the antilipolytic component of epinephrine action mediated by alpha2-ARs.

  11. Polymorphous computing fabric (United States)

    Wolinski, Christophe Czeslaw; Gokhale, Maya B.; McCabe, Kevin Peter


    Fabric-based computing systems and methods are disclosed. A fabric-based computing system can include a polymorphous computing fabric that can be customized on a per application basis and a host processor in communication with said polymorphous computing fabric. The polymorphous computing fabric includes a cellular architecture that can be highly parameterized to enable a customized synthesis of fabric instances for a variety of enhanced application performances thereof. A global memory concept can also be included that provides the host processor random access to all variables and instructions associated with the polymorphous computing fabric.

  12. Reconciling thermal and structural data from the polymorphic transitions of malonamide

    Energy Technology Data Exchange (ETDEWEB)

    Cheung, Eugene Y. [TransForm Pharmaceuticals, 29 Hartwell Avenue, Lexington, MA 02421 (United States)], E-mail:; Peterson, Matthew L. [TransForm Pharmaceuticals, 29 Hartwell Avenue, Lexington, MA 02421 (United States)


    Although screening for organic polymorphs has become a hot topic in recent years, polymorph screens continue to be largely based on solution crystallization. Other routes to different crystal forms, such as grinding, annealing, and melt crystallization can also be used to look for polymorphs when chemical stability allows. Thermal analysis is often the first method for identifying polymorphic transitions in solids. However, reconciling the thermal data with the structural data is rarely straightforward without a single crystal X-ray structure. By using differential scanning calorimetry, infrared spectroscopy, and powder X-ray diffraction, the polymorphic transitions of malonamide have now been studied, and two solid state pathways, solid state grinding and annealing, are verified to independently yield the tetragonal polymorph of malonamide from the monoclinic form. In addition, melt recrystallization yields a third polymorph, which has now been confirmed to be the orthorhombic polymorph.

  13. β-Adrenergic Regulation of Cardiac Progenitor Cell Death Versus Survival and Proliferation (United States)

    Khan, Mohsin; Mohsin, Sadia; Avitabile, Daniele; Siddiqi, Sailay; Nguyen, Jonathan; Wallach, Kathleen; Quijada, Pearl; McGregor, Michael; Gude, Natalie; Alvarez, Roberto; Tilley, Douglas G.; Koch, Walter J.; Sussman, Mark A.


    Rationale Short-term β-adrenergic stimulation promotes contractility in response to stress but is ultimately detrimental in the failing heart because of accrual of cardiomyocyte death. Endogenous cardiac progenitor cell (CPC) activation may partially offset cardiomyocyte losses, but consequences of long-term β-adrenergic drive on CPC survival and proliferation are unknown. Objective We sought to determine the relationship between β-adrenergic activity and regulation of CPC function. Methods and Results Mouse and human CPCs express only β2 adrenergic receptor (β2-AR) in conjunction with stem cell marker c-kit. Activation of β2-AR signaling promotes proliferation associated with increased AKT, extracellular signal-regulated kinase 1/2, and endothelial NO synthase phosphorylation, upregulation of cyclin D1, and decreased levels of G protein–coupled receptor kinase 2. Conversely, silencing of β2-AR expression or treatment with β2-antagonist ICI 118, 551 impairs CPC proliferation and survival. β1-AR expression in CPC is induced by differentiation stimuli, sensitizing CPC to isoproterenol-induced cell death that is abrogated by metoprolol. Efficacy of β1-AR blockade by metoprolol to increase CPC survival and proliferation was confirmed in vivo by adoptive transfer of CPC into failing mouse myocardium. Conclusions β-adrenergic stimulation promotes expansion and survival of CPCs through β2-AR, but acquisition of β1-AR on commitment to the myocyte lineage results in loss of CPCs and early myocyte precursors. PMID:23243208

  14. Social crowding stress diminishes the pituitary-adrenocortical and hypothalamic histamine response to adrenergic stimulation. (United States)

    Bugajski, J; Gadek-Michalska, A; Borycz, J


    Social stress of crowding almost totally reduced the rise in serum corticosterone elicited by intracerebroventricular administration of isoprenaline, a beta-adrenergic receptor agonist, after 3 and 7 day of crowding and substantially diminished that response after 14 and 21 days. Crowding stress totally abolished the increase in hypothalamic histamine induced by isoprenaline in control rats. Crowding also significantly diminished the increase in serum corticosterone evoked by clonidine, an alpha 2-adrenergic agonist, and abolished the clonidine-induced elevation in hypothalamic histamine levels. The stimulatory effect of phenylephrine, an alpha 1-adrenergic agonist, on corticosterone secretion was only moderately diminished in crowded rats. Neither phenylephrine nor crowding stress changed significantly the hypothalamic histamine levels. These results indicate that social stress of crowding considerably impairs the hypothalamic-pituitary-adrenocortical responsiveness to central beta- and alpha 2-adrenergic receptor stimulation. Crowding also abolishes the rise in hypothalamic histamine induced by beta- and alpha 2-adrenergic agonist, suggesting a role of hypothalamic histamine in the HPA adaptation to the social stress of crowding.

  15. Beta-Adrenergic Receptors and Mechanisms in Asthma: The New Long-Acting Beta-Agonists

    Directory of Open Access Journals (Sweden)

    Robert G Townley


    Full Text Available The objective is to review β-adrenergic receptors and mechanisms in the immediate and late bronchial reaction in asthma and the new long-acting β-agonist. This will be discussed in light of the controversy of the potential adverse effect of regular use of long-acting β-agonists. We studied the effect of formoterol on the late asthmatic response (LAR and airway inflammation in guinea-pigs. Formoterol suppressed the LAR, antigen-induced airway inflammation and hyperresponsiveness, although isoproterenol failed to inhibit these parameters. β-Adrenergic hyporesponsiveness, and cholinergic and a- adrenergic hyperresponsiveness have been implicated in the pathogenesis of asthma. A decrease in β-adrenoreceptor function can result either from exogenously administered β-agonist or from exposure to allergens resulting in a late bronchial reaction. There is increasing evidence that eosinophils, macrophages, and lymphocytes which are of primary importance in the late bronchial reaction are also modulated by β2- adrenoreceptors. In functional studies of guinea-pig or human isolated trachea and lung parenchyma, PAF and certain cytokines significantly reduced the potency of isoproterenol to reverse methacholine- or histamine-induced contraction. The effect of glucocorticoids on pulmonary β-adrenergic receptors and responses suggests an important role for glucocorticoids to increase β-adrenergic receptors and responsiveness.

  16. Adrenergic blockade does not abolish elevated glucose turnover during bacterial infection

    Energy Technology Data Exchange (ETDEWEB)

    Hargrove, D.M.; Bagby, G.J.; Lang, C.H.; Spitzer, J.J. (Louisiana State Univ., New Orleans (USA))


    Infusions of adrenergic antagonists were used to investigate the role of catecholamines in infection-induced elevations of glucose kinetics. Infection was produced in conscious catheterized rats by repeated subcutaneous injections of live Escherichia coli over 24 h. Glucose kinetics were measured by the constant intravenous infusion of (6-{sup 3}H)- and (U-{sup 14}C)glucose. Compared with noninfected rats, infected animals were hyperthermic and showed increased rates of glucose appearance, clearance, and recycling as well as mild hyperlacticacidemia. Plasma catecholamine concentrations were increased by 50-70% in the infected rats, but there were no differences in plasma glucagon, corticosterone, and insulin levels. Adrenergic blockade was produced by primed constant infusion of both propranolol ({beta}-blocker) and phentolamine ({alpha}-blocker). A 2-h administration of adrenergic antagonists did not attenuate the elevated glucose kinetics or plasma lactate concentration in the infected rats, although it abolished the hyperthermia. In a second experiment, animals were infused with propranolol and phentolamine beginning 1 h before the first injection of E. coli and throughout the course of infection. Continuous adrenergic blockade failed to attenuate infection-induced elevations in glucose kinetics and plasma lactate. These results indicate that the adrenergic system does not mediate the elevated glucose metabolism observed in this mild model of infection.

  17. Ganglionic adrenergic action modulates ovarian steroids and nitric oxide in prepubertal rat. (United States)

    Delgado, Silvia Marcela; Casais, Marilina; Sosa, Zulema; Rastrilla, Ana María


    Both peripheral innervation and nitric oxide (NO) participate in ovarian steroidogenesis. The purpose of this work was to analyse the ganglionic adrenergic influence on the ovarian release of steroids and NO and the possible steroids/NO relationship. The experiments were carried out in the ex vivo coeliac ganglion-superior ovarian nerve (SON)-ovary system of prepubertal rats. The coeliac ganglion-SON-ovary system was incubated in Krebs Ringer-bicarbonate buffer in presence of adrenergic agents in the ganglionic compartment. The accumulation of progesterone, androstenedione, oestradiol and NO in the ovarian incubation liquid was measured. Norepinephrine in coeliac ganglion inhibited the liberation of progesterone and increased androstenedione, oestradiol and NO in ovary. The addition of alpha and beta adrenergic antagonists also showed different responses in the liberation of the substances mentioned before, which, from a physiological point of view, reveals the presence of adrenergic receptors in coeliac ganglion. In relation to propranolol, it does not revert the effect of noradrenaline on the liberation of progesterone, which leads us to think that it might also have a "per se" effect on the ganglion, responsible for the ovarian response observed for progesterone. Finally, we can conclude that the ganglionic adrenergic action via SON participates on the regulation of the prepubertal ovary in one of two ways: either increasing the NO, a gaseous neurotransmitter with cytostatic characteristics, to favour the immature follicles to remain dormant or increasing the liberation of androstenedione and oestradiol, the steroids necessary for the beginning of the near first estral cycle.

  18. Impact of the Tamsulosin in Alpha Adrenergic Receptor of Airways at Patients with Increased Bronchial Reactibility (United States)

    Mustafa, Lirim; Ilazi, Ali; Dauti, Arta; Islami, Pellumb; Kastrati, Bashkim; Islami, Hilmi


    Objective: In this work, effect of tamsulosin as antagonist of alpha1A and alpha1B adrenergic receptor and effect of agonists of beta2 adrenergic receptor–salbutamol in patients with increased bronchial reactibility was studied. Methods: Parameters of the lung function are determined with Body plethysmography six (6) hours after administration of tamsulosin. Raw and ITGV were registered and specific resistance (SRaw) was calculated as well. Tamsulosin was administered in per os manner as a preparation in the shape of the capsules with a brand name of “Prolosin”, produced by Niche Generics Limited, Hitchin, Herts. Results: After six (6) hours of administration of tamsulosin, results gained indicate that blockage of alpha1A and alpha1B-adrenergic receptor (0.8 mg per os) has not changed significantly (p > 0.1) the bronchomotor tonus of tracheobronchial tree in comparison to the check-up that has inhaled salbutamol agonist of adrenergic beta2 receptor (2 inh. x 0.2 mg), (p < 0.05). Blood pressure suffered no significant decrease following administration of the 0.8 mg dose of tamsulosin. Conclusion: This suggests that even after six hours of administration of tamsulosin, and determining of lung function parameters, the activity of alpha1A and alpha1B-adrenergic receptor in the smooth bronchial musculature has not changed in patients with increased bronchial reactibility. PMID:26543414

  19. Role of hippocampal β-adrenergic and glucocorticoid receptors in the novelty-induced enhancement of fear extinction. (United States)

    Liu, Jian-Feng; Yang, Chang; Deng, Jia-Hui; Yan, Wei; Wang, Hui-Min; Luo, Yi-Xiao; Shi, Hai-Shui; Meng, Shi-Qiu; Chai, Bai-Sheng; Fang, Qin; Chai, Ning; Xue, Yan-Xue; Sun, Jia; Chen, Chen; Wang, Xue-Yi; Wang, Ji-Shi; Lu, Lin


    Fear extinction forms a new memory but does not erase the original fear memory. Exposure to novelty facilitates transfer of short-term extinction memory to long-lasting memory. However, the underlying cellular and molecular mechanisms are still unclear. Using a classical contextual fear-conditioning model, we investigated the effect of novelty on long-lasting extinction memory in rats. We found that exposure to a novel environment but not familiar environment 1 h before or after extinction enhanced extinction long-term memory (LTM) and reduced fear reinstatement. However, exploring novelty 6 h before or after extinction had no such effect. Infusion of the β-adrenergic receptor (βAR) inhibitor propranolol and glucocorticoid receptor (GR) inhibitor RU486 into the CA1 area of the dorsal hippocampus before novelty exposure blocked the effect of novelty on extinction memory. Propranolol prevented activation of the hippocampal PKA-CREB pathway, and RU486 prevented activation of the hippocampal extracellular signal-regulated kinase 1/2 (Erk1/2)-CREB pathway induced by novelty exposure. These results indicate that the hippocampal βAR-PKA-CREB and GR-Erk1/2-CREB pathways mediate the extinction-enhancing effect of novelty exposure. Infusion of RU486 or the Erk1/2 inhibitor U0126, but not propranolol or the PKA inhibitor Rp-cAMPS, into the CA1 before extinction disrupted the formation of extinction LTM, suggesting that hippocampal GR and Erk1/2 but not βAR or PKA play critical roles in this process. These results indicate that novelty promotes extinction memory via hippocampal βAR- and GR-dependent pathways, and Erk1/2 may serve as a behavioral tag of extinction.

  20. Cerebral aterial spasm. I. Adrenergic mechanism in experimental cerebral vasospasm.

    Directory of Open Access Journals (Sweden)



    Full Text Available This study demonstrates that an adrenergic mechanism plays an important role in producing the delayed cerebral vasospasm which follows subarachnoid hemorrhage. Results were as follows: 1. Experimental subarachnoid hemorrhage (SAH was produced by injection of fresh arterial blood into the cisterna magna in cats. The cerebral vasospasm was shown angiographically to be biphasic in nature: immediate constriction lasting 1 h and marked prolonged spasm occurring between the 3rd and 5th day after SAH. The amount of noradrenaline (NA and dopamine-beta-hydroxylase (DBH activity decreased over a period of 24 h both within the wall of the basilar artery and in the locus ceruleus and then gradually increased, reaching a maximum on the 3rd day after SAH. 2. Topical application of spasmogenic substances (NA and blood produced a marked constriction of the hypersensitive basilar artery on the 3rd day after SAH. 3. 6-Hydroxydopamine (6-OHDA injection into the cisterna magna produced prolonged vasocilatation. The dilated vessel responded with mild transient constriction after the topical application of NA or fresh blood. DBH activity and NA concentration in the vessels, locus ceruleus and medial hypothalamus decreased markedly on the 3rd day after the cisternal injection of 6-OHDA. 4. Various spasmogenic substances (i.e. serotonin, NA, prostaglandins and methemoglobin were measured in a mixture of equal volume of CSF and blood in cats. ONly the serotonin in the mixed fluid produced vasoconstriction. Spasmogenic substances decreased markedly in the mixed fluid incubated for 3 days at 37 degrees C, and none of these substances apart from methemoglobin was present in a concentration sufficient to produce constriction of vessels. 5. These results suggest that early spasm is induced by serotonin around the arteries of the cranial base, and delayed spasm might be caused by hyperreaction of cerebral vessels to spasmogenic substances such as methemoglobin, during the

  1. DNA synthesis in mouse brown adipose tissue is under. beta. -adrenergic control

    Energy Technology Data Exchange (ETDEWEB)

    Rehnmark, S.; Nedergaard, J. (Univ. of Stockholm (Sweden))


    The rate of DNA synthesis in mouse brown adipose tissue was followed with injections of ({sup 3}H)thymidine. Cold exposure led to a large increase in the rate of ({sup 3}H)thymidine incorporation, reaching a maximum after 8 days, after which the activity abruptly ceased. A series of norepinephrine injections was in itself able to increase ({sup 3}H)thymidine incorporation. When norepinephrine was injected in combination with the {alpha}-adrenergic antagonist phentolamine or with the {beta}-adrenergic antagonist propranolol, the stimulation was fully blocked by propranolol. It is suggested that stimulation of DNA synthesis in brown adipose tissue is a {beta}-adrenergically mediated process and that the tissue is an interesting model for studies of physiological control of DNA synthesis.

  2. Prenatal exposure to methylmercury alters development of adrenergic receptor binding sites in peripheral sympathetic target tissues

    Energy Technology Data Exchange (ETDEWEB)

    Slotkin, T.A.; Orband, L.; Cowdery, T.; Kavlock, R.J.; Bartolome, J.


    In order to assess the impact of prenatal exposure to methylmercury on sympathetic neurotransmission, effects on development of adrenergic receptor binding sites in peripheral tissues was evaluated. In the liver, methylmercury produced a dose-dependent increase in alpha/sub 1/, alpha/sub 2/, and beta-receptor binding of radioliganda throughout the first 5 weeks of postnatal life. Similarly, renal alpha-receptor subtypes showed increased binding capabilities, but binding to alpha-receptor sites was reduced. At least some of the changes in receptors appear to be of functional significance, as physiological reactivity to adrenergic stimulation is altered in the same directions in these two tissues. The actions of methylmercury displayed tissue specificity in that the same receptor populations were largely unaffected in other tissues (lung, heart). These results suggest that methylmercury exposure in utero alters adrenergic responses through targeted effects on postsynaptic receptor populations in specific tissues.

  3. The role of adrenergic receptors in the motility of duodenum and choledochoduodenal junction in the pig. (United States)

    Blichowski, A; Andrzejewski, W; Gaszyński, W; Kozulski, W


    The role of adenergic receptors in the motility of duodenum and choledochoduodenal junction in the pig. Acta Physiol. Pol., 1977, 28 (6): 521-528. The choldeochoduodenal junction in the Vietnamese pig is functionally and anatomically a part of duodenal wall. In view of this, investigations were carried out for establishing the role of adrenergic receptors in the development of motor function of this part of the intestinal tract. The experiments were performed on domestic Vietnamese pigs (Sus scrofa domestica) and they showed that after stimulation of alpha and beta adrenergic receptors the motor activity of the duodenal muscular coat and the choledochoduodenal junction is inhibited. The obtained results suggest similar reactions of the adrenergic receptors in both examined parts of the intestinal tract in the pig.

  4. Adrenergic effects on secretion of epidermal growth factor from Brunner's glands

    DEFF Research Database (Denmark)

    Poulsen, Steen Seier


    The influence of the sympathetic nervous system and adrenergic agonists on flow rate and secretion of epidermal growth factor (EGF) from Brunner's glands has been investigated in the rat. Chemical sympathectomy by administration of 6-hydroxydopamine increased volume secretion and output of EGF from...... Brunner's glands but depleted the glands of EGF. Infusion of noradrenaline, an alpha-adrenergic agonist, inhibited basal and vasoactive intestinal polypeptide (VIP) stimulated flow rate and output of EGF from Brunner's glands and increased the amount of EGF in the tissue. Vasoactive intestinal polypeptide...... also increased the amount of EGF in Brunner's gland tissue and this was unchanged after simultaneous infusion of VIP and noradrenaline as well as VIP and isoproterenol, a beta-adrenergic agonist. Isoproterenol had no effect on basal and VIP stimulated secretion of EGF from Brunner's glands...

  5. Nitric oxide-dependent activation of CaMKII increases diastolic sarcoplasmic reticulum calcium release in cardiac myocytes in response to adrenergic stimulation.

    Directory of Open Access Journals (Sweden)

    Jerry Curran

    Full Text Available Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca(2+ leak through ryanodine receptors. Beta-adrenergic (β-AR tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII and the subsequent phosphorylation of the ryanodine receptor. When β-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent evidence has indicated that CaMKII activation can be regulated by cellular oxidizing agents, such as reactive oxygen species. Here, we investigate how the cellular second messenger, nitric oxide, mediates CaMKII activity downstream of the adrenergic signaling cascade and promotes the generation of arrhythmogenic spontaneous Ca(2+ waves in intact cardiomyocytes. Both SCaWs and SR Ca(2+ leak were measured in intact rabbit and mouse ventricular myocytes loaded with the Ca-dependent fluorescent dye, fluo-4. CaMKII activity in vitro and immunoblotting for phosphorylated residues on CaMKII, nitric oxide synthase, and Akt were measured to confirm activity of these enzymes as part of the adrenergic cascade. We demonstrate that stimulation of the β-AR pathway by isoproterenol increased the CaMKII-dependent SR Ca(2+ leak. This increased leak was prevented by inhibition of nitric oxide synthase 1 but not nitric oxide synthase 3. In ventricular myocytes isolated from wild-type mice, isoproterenol stimulation also increased the CaMKII-dependent leak. Critically, in myocytes isolated from nitric oxide synthase 1 knock-out mice this effect is ablated. We show that isoproterenol stimulation leads to an increase in nitric oxide production, and nitric oxide alone is sufficient to activate CaMKII and increase SR Ca(2+ leak. Mechanistically, our data links Akt to nitric oxide synthase 1 activation downstream of β-AR stimulation. Collectively, this evidence supports the hypothesis

  6. Quantitation of alpha 1-adrenergic receptors in porcine uterine and mesenteric arteries

    Energy Technology Data Exchange (ETDEWEB)

    Farley, D.B.; Ford, S.P.; Reynolds, L.P.; Bhatnagar, R.K.; Van Orden, D.E.


    The activation of vascular alpha-adrenergic receptors may be involved in the control of uterine blood flow. A radioligand binding assay with the use of the alpha 1-adrenergic antagonist /sup 3/H-WB-4101 was established to characterize the alpha-adrenergic receptors in uterine and mesenteric arterial membranes obtained from nonpregnant pigs. Specific binding of /sup 3/H-WB-4101 was rapid, saturable, and exhibited the alpha-adrenergic agonist potency order of (-)-epinephrine inhibition constant (Ki) . 0.6 mumol/L greater than (-)-norepinephrine (Ki . 1.5 mumol/L) much greater than (-)-isoproterenol (Ki . 120 mumol/L). The alpha-adrenergic antagonist phentolamine (Ki . 6.0 nmol/L) was 200 times more potent than the beta-adrenergic antagonist (+/-)-propranolol (Ki . 1,200 nmol/L); the alpha 1-selective antagonist prazosin (Ki . 1.2 nmol/L) was 130 times more potent than the alpha 2-selective antagonist yohimbine (Ki . 160 nmol/L). Scatchard analysis, as well as iterative curve-fitting analysis, demonstrated that /sup 3/H-WB-4101 binding by arterial membranes was to a single class of binding sites. Uterine arteries exhibited greater maximal binding capacity (BMax) than that of mesenteric arteries (47.5 +/- 3.2 versus 30.9 +/- 3.6 fmol per milligram of protein, p less than 0.01), but the uterine artery dissociation constant (Kd) was higher, thus indicating a lower affinity, when compared with mesenteric artery (0.43 +/- 0.04 versus 0.33 +/- 0.04 nmol/L, p less than 0.05).

  7. Biochemical and pharmacological studies of the hepatic alpha sub 1 -adrenergic receptor

    Energy Technology Data Exchange (ETDEWEB)

    Tchakarov, L.E.


    The structure and the regulation of the hepatic {alpha}{sub 1}-adrenergic receptors have been studied in the rat. The in vitro incubation of isolated liver cells in a serum-free buffer for 4 hr leads to the conversion of the adrenergic activation of glycogen phosphorylase from an {alpha}{sub 1}- to a {beta}-adrenoceptor-mediated event. This change is associated with no change in the glycogenolytic response to vasopressin and a reduction of the glycogenolytic response to glucagon. The time-dependent shift in the adrenergic control of glycogenolysis does not influence the density or the affinity of ({sup 3}H)prazosin-labeled {alpha}{sub 1}-receptors and ({sup 3}H)CGP-12177-labeled {beta}-receptors. The change in the adrenergic control of glycogenolysis is reversed by a 30-min incubation with 50 nM lipomodulin, whereas in freshly isolated cells lipomodulin doesn't affect the predominant {alpha}-receptor response. Conversely, exposure of freshly isolated cells to a monoclonal antibody to lipomodulin in the presence of 10 {mu}M phenylephrine, or to 2 {mu}g/ml mellitin, results in a shift in the adrenergic control of glycogenolysis from {alpha}{sub 1}- to {beta}-type within 30 min. The mechanism of activation of the Ca{sup 2+}-linked receptors for vasopressin and adrenaline was studied in isolated liver cells. A novel irreversible antagonist for the {alpha}{sub 1}-adrenergic receptors, I-phenyoxybenzamine (I-POB) has been synthesized and pharmacologically characterized.

  8. Characterization of beta-adrenergic receptors in dispersed rat testicular interstitial cells

    Energy Technology Data Exchange (ETDEWEB)

    Poyet, P.; Labrie, F.


    Recent studies have shown that beta-adrenergic agents stimulate steroidogenesis and cyclic AMP formation in mouse Leydig cells in culture. To obtain information about the possible presence and the characteristics of a beta-adrenergic receptor in rat testicular interstitial cells, the potent beta-adrenergic antagonist (/sup 125/I)cyanopindolol (CYP) was used as ligand. Interstitial cells prepared by collagenase dispersion from rat testis were incubated with the ligand for 2 h at room temperature. (/sup 125/I)cyanopindolol binds to a single class of high affinity sites at an apparent KD value of 15 pM. A number of sites of 6,600 sites/cell is measured when 0.1 microM (-) propranolol is used to determine non-specific binding. The order of potency of a series of agonists competing for (/sup 125/I)cyanopindolol binding is consistent with the interaction of a beta 2-subtype receptor: zinterol greater than (-) isoproterenol greater than (-) epinephrine = salbutamol much greater than (-) norepinephrine. In addition, it was observed that the potency of a large series of specific beta 1 and beta 2 synthetic compounds for displacing (/sup 125/I)cyanopindolol in rat interstitial cells is similar to the potency observed for these compounds in a typical beta 2-adrenergic tissue, the rat lung. For example, the potency of zinterol, a specific beta 2-adrenergic agonist, is 10 times higher in interstitial cells and lung than in rat heart, a typical beta 1-adrenergic tissue. Inversely, practolol, a typical beta 1-antagonist, is about 50 times more potent in rat heart than in interstitial cells and lung.

  9. Distribution of adrenergic receptors in the enteric nervous system of the guinea pig, mouse, and rat. (United States)

    Nasser, Yasmin; Ho, Winnie; Sharkey, Keith A


    Adrenergic receptors in the enteric nervous system (ENS) are important in control of the gastrointestinal tract. Here we describe the distribution of adrenergic receptors in the ENS of the ileum and colon of the guinea pig, rat, and mouse by using single- and double-labelling immunohistochemistry. In the myenteric plexus (MP) of the rat and mouse, alpha2a-adrenergic receptors (alpha2a-AR) were widely distributed on neurons and enteric glial cells. alpha2a-AR mainly colocalized with calretinin in the MP, whereas submucosal alpha2a-AR neurons colocalized with vasoactive intestinal polypeptide (VIP), neuropeptide Y, and calretinin in both species. In the guinea pig ileum, we observed widespread alpha2a-AR immunoreactivity on nerve fibers in the MP and on VIP neurons in the submucosal plexus (SMP). We observed extensive beta1-adrenergic receptor (beta1-AR) expression on neurons and nerve fibers in both the MP and the SMP of all species. Similarly, the beta2-adrenergic receptor (beta2-AR) was expressed on neurons and nerve fibers in the SMP of all species, as well as in the MP of the mouse. In the MP, beta1- and beta2-AR immunoreactivity was localized to several neuronal populations, including calretinin and nitrergic neurons. In the SMP of the guinea pig, beta1- and beta2-AR mainly colocalized with VIP, whereas, in the rat and mouse, beta1- and beta2-AR were distributed among the VIP and calretinin populations. Adrenergic receptors were widely localized on specific neuronal populations in all species studied. The role of glial alpha2a-AR is unknown. These results suggest that sympathetic innervation of the ENS is directed toward both enteric neurons and enteric glia.

  10. Synthesis and characterization of arylamine derivatives of rauwolscine as molecular probes for alpha 2-adrenergic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Lanier, S.M.; Graham, R.M.; Hess, H.J.; Grodski, A.; Repaske, M.G.; Nunnari, J.M.; Limbird, L.E.; Homcy, C.J.


    The selective alpha 2-adrenergic receptor antagonist rauwolscine was structurally modified to yield a series of arylamine carboxamide derivatives, which were investigated as potential molecular probes for the localization and structural characterization of alpha 2-adrenergic receptors. The arylamine carboxamides differ in the number of carbon atoms separating the reactive phenyl moiety from the fused ring structure of the parent compound, rauwolscine carboxylate. Competitive inhibition studies with (/sup 3/H)rauwolscine in rat kidney membranes indicate that the affinity for the carboxamide derivatives is inversely related to the length of the carbon spacer arm with rauwolscine 4-aminophenyl carboxamide exhibiting the highest affinity (Kd = 2.3 +/- 0.2 nM). Radioiodination of rau-AMPC yields a ligand, /sup 125/I-rau-AMPC, which binds to rat kidney alpha 2-adrenergic receptors with high affinity, as determined by both kinetic analysis (Kd = k2/k1 = 0.016 min-1/2.1 X 10(7) M-1 min-1 = 0.76 nM) and equilibrium binding studies (Kd = 0.78 +/- 0.16 nM). /sup 125/I-rau-AMPC was quantitatively converted to the photolabile arylazide derivative 17 alpha-hydroxy-20 alpha-yohimban-16 beta-(N-4-azido-3-(/sup 125/I)iodophenyl) carboxamide (/sup 125/I-rau-AZPC). In a partially purified receptor preparation from porcine brain, this compound photolabels a major (Mr = 62,000) peptide. The labeling of this peptide is inhibited by adrenergic agonists and antagonists with a rank order of potency consistent with an alpha 2-adrenergic receptor binding site. Both /sup 125/I-rau-AMPC and the photolabile arylazide derivative, /sup 125/I-rau-AZPC, should prove useful as molecular probes for the structural and biochemical characterization of alpha 2-adrenergic receptors.

  11. Distinctive left-sided distribution of adrenergic-derived cells in the adult mouse heart.

    Directory of Open Access Journals (Sweden)

    Kingsley Osuala

    Full Text Available Adrenaline and noradrenaline are produced within the heart from neuronal and non-neuronal sources. These adrenergic hormones have profound effects on cardiovascular development and function, yet relatively little information is available about the specific tissue distribution of adrenergic cells within the adult heart. The purpose of the present study was to define the anatomical localization of cells derived from an adrenergic lineage within the adult heart. To accomplish this, we performed genetic fate-mapping experiments where mice with the cre-recombinase (Cre gene inserted into the phenylethanolamine-n-methyltransferase (Pnmt locus were cross-mated with homozygous Rosa26 reporter (R26R mice. Because Pnmt serves as a marker gene for adrenergic cells, offspring from these matings express the β-galactosidase (βGAL reporter gene in cells of an adrenergic lineage. βGAL expression was found throughout the adult mouse heart, but was predominantly (89% located in the left atrium (LA and ventricle (LV (p<0.001 compared to RA and RV, where many of these cells appeared to have cardiomyocyte-like morphological and structural characteristics. The staining pattern in the LA was diffuse, but the LV free wall displayed intermittent non-random staining that extended from the apex to the base of the heart, including heavy staining of the anterior papillary muscle along its perimeter. Three-dimensional computer-aided reconstruction of XGAL+ staining revealed distribution throughout the LA and LV, with specific finger-like projections apparent near the mid and apical regions of the LV free wall. These data indicate that adrenergic-derived cells display distinctive left-sided distribution patterns in the adult mouse heart.

  12. The QseC adrenergic signaling cascade in Enterohemorrhagic E. coli (EHEC.

    Directory of Open Access Journals (Sweden)

    David T Hughes


    Full Text Available The ability to respond to stress is at the core of an organism's survival. The hormones epinephrine and norepinephrine play a central role in stress responses in mammals, which require the synchronized interaction of the whole neuroendocrine system. Mammalian adrenergic receptors are G-coupled protein receptors (GPCRs; bacteria, however, sense these hormones through histidine sensor kinases (HKs. HKs autophosphorylate in response to signals and transfer this phosphate to response regulators (RRs. Two bacterial adrenergic receptors have been identified in EHEC, QseC and QseE, with QseE being downstream of QseC in this signaling cascade. Here we mapped the QseC signaling cascade in the deadly pathogen enterohemorrhagic E. coli (EHEC, which exploits this signaling system to promote disease. Through QseC, EHEC activates expression of metabolic, virulence and stress response genes, synchronizing the cell response to these stress hormones. Coordination of these responses is achieved by QseC phosphorylating three of the thirty-two EHEC RRs. The QseB RR, which is QseC's cognate RR, activates the flagella regulon which controls bacteria motility and chemotaxis. The QseF RR, which is also phosphorylated by the QseE adrenergic sensor, coordinates expression of virulence genes involved in formation of lesions in the intestinal epithelia by EHEC, and the bacterial SOS stress response. The third RR, KdpE, controls potassium uptake, osmolarity, and also the formation of lesions in the intestine. Adrenergic regulation of bacterial gene expression shares several parallels with mammalian adrenergic signaling having profound effects in the whole organism. Understanding adrenergic regulation of a bacterial cell is a powerful approach for studying the underlying mechanisms of stress and cellular survival.

  13. Glycyrrhetic acid synergistically enhances β₂-adrenergic receptor-Gs signaling by changing the location of Gαs in lipid rafts.

    Directory of Open Access Journals (Sweden)

    Qian Shi

    Full Text Available Glycyrrhetic acid (GA exerts synergistic anti-asthmatic effects via a β₂-adrenergic receptor (β₂AR-mediated pathway. Cholesterol is an important component of the structure and function of lipid rafts, which play critical roles in the β₂AR-Gs-adenylate cyclase (AC-mediated signaling pathway. Owing to the structural similarities between GA and cholesterol, we investigated the possibility that GA enhances β₂AR signaling by altering cholesterol distribution. Azide-terminal GA (ATGA was synthesized and applied to human embryonic kidney 293 (HEK293 cells expressing fusion β₂AR, and the electron spin resonance (ESR technique was utilized. GA was determined to be localized predominantly on membrane and decreased their cholesterol contents. Thus, the fluidity of the hydrophobic region increased but not the polar surface of the cell membrane. The conformations of membrane proteins were also changed. GA further changed the localization of Gαs from lipid rafts to non-raft regions, resulting the binding of β₂AR and Gαs, as well as in reduced β₂AR internalization. Co-localization of β₂AR, Gαs, and AC increased isoproterenol-induced cAMP production and cholesterol reloading attenuated this effect. A speculation wherein GA enhances beta-adrenergic activity by increasing the functional linkage between the subcomponents of the membrane β₂AR-protein kinase A (PKA signaling pathway was proposed. The enhanced efficacy of β₂AR agonists by this novel mechanism could prevent tachyphylaxis.

  14. Adrenergic regulation of cellular plasticity in brown, beige/brite and white adipose tissues. (United States)

    Ramseyer, Vanesa D; Granneman, James G


    The discovery of brown adipose tissue in adult humans along with the recognition of adipocyte heterogeneity and plasticity of white fat depots has renewed the interest in targeting adipose tissue for therapeutic benefit. Adrenergic activation is a well-established means of recruiting catabolic adipocyte phenotypes in brown and white adipose tissues. In this article, we review mechanisms of brown adipocyte recruitment by the sympathetic nervous system and by direct β-adrenergic receptor activation. We highlight the distinct modes of brown adipocyte recruitment in brown, beige/brite, and white adipose tissues, UCP1-independent thermogenesis, and potential non-thermogenic, metabolically beneficial effects of brown adipocytes.

  15. Beta-adrenergic stimulation of phagocytosis in the unicellular eukaryote Paramecium aurelia. (United States)

    Wyroba, E


    Bete-adrenergic agonists isoproterenol and norepinephrine enhanced phagocytosis in Paramecium. Stimulation was stereospecific, dose-dependent and inhibited by the beta-agonists propranolol and alprenolol. Phorbol ester and forskolin potentiated the stimulatory effect of catecholamines on Paramecium phagocytosis. The dansyl analogue of propranolol (DAPN) was used for fluorescent visualization of the beta-adrenergic receptor sites in Paramecium which have been found to be localized at the cell membrane and within the membrane of the nascent digestive vacuoles. The appearance of the characteristic fluorescent pattern has been blocked by 1-propranolol.

  16. AHSG tag single nucleotide polymorphisms associate with type 2 diabetes and dyslipidemia: studies of metabolic traits in 7,683 white Danish subjects

    DEFF Research Database (Denmark)

    Andersen, Gitte; Burgdorf, Kristoffer Sølvsten; Sparsø, Thomas;


    been largely successful. We related seven frequent AHSG tag single nucleotide polymorphisms to a range of metabolic traits, including type 2 diabetes, obesity, and dyslipidemia. RESEARCH DESIGN AND METHODS: The polymorphisms were genotyped in 7,683 white Danish subjects using Taqman allelic......OBJECTIVE: The gene encoding the alpha2 Heremans-Schmid glycoprotein (AHSG) is a credible biological and positional candidate gene for type 2 diabetes and the metabolic syndrome, and previous attempts to relate AHSG variation with type 2 diabetes and obesity in Swedish and French Caucasians have......, epistatic effects between AHSG variants and insulin receptor substrate-1 (IRS1) and beta-2-adrenergic receptor polymorphisms were investigated. RESULTS: The -469T>G (rs2077119) and IVS6+98C>T (rs2518136) polymorphisms were associated with type 2 diabetes (P = 0.007 and P = 0.006, respectively, or P...

  17. Impact of CYP2D6 polymorphisms on clinical efficacy and tolerability of metoprolol tartrate. (United States)

    Hamadeh, I S; Langaee, T Y; Dwivedi, R; Garcia, S; Burkley, B M; Skaar, T C; Chapman, A B; Gums, J G; Turner, S T; Gong, Y; Cooper-DeHoff, R M; Johnson, J A


    Metoprolol is a selective β-1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Our objective was to investigate the influence of CYP2D6 polymorphisms on the efficacy and tolerability of metoprolol tartrate. Two hundred and eighty-one participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response-guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (P metoprolol response or tolerability.

  18. Changes in postnatal norepinephrine alter alpha-2 adrenergic receptor development. (United States)

    Sanders, J D; Happe, H K; Bylund, D B; Murrin, L C


    Alpha-2 adrenergic receptors (A2AR) regulate multiple brain functions and are enriched in developing brain. Studies demonstrate norepinephrine (NE) plays a role in regulating brain maturation, suggesting it is important in A2AR development. To investigate this we employed models of NE absence and excess during brain development. For decreases in NE we used N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4), a specific noradrenergic neurotoxin. Increased noradrenergic terminal density was produced by methylazoxymethanol acetate (MAM) treatment. A2AR density was assayed with [(3)H]RX821002 autoradiography. DSP4 lesions on postnatal day (PND) 3 produce A2AR decreases in many regions by PND 5. A2AR recover to control levels by PND 15 and 25 and there is no further change in total receptor density. We also assayed A2AR in brains lesioned with DSP4 on PND 13, 23, 33 and 43 and harvested 22 days post-lesion. A2AR levels remain similar to control at each of these time points. We examined A2AR functionality and high affinity state with epinephrine-stimulated [(35)S]GTPγS and [(125)I]p-iodoclonidine autoradiography, respectively. On PND 25, control animals and animals lesioned with DSP4 on PND 3 have similar levels of [(35)S]GTPγS incorporation and no change in high affinity state. This is in contrast to increases in A2AR high affinity state produced by DSP4 lesions of mature brain. We next investigated A2AR response to increases in norepinephrine levels produced by MAM. In contrast to DSP4 lesions, increasing NE results in a large increase in A2AR. Animals treated with MAM on gestational day 14 had cortical [(3)H]RX821002 binding 100-200% greater than controls on PND 25, 35, 45, 55 and 65. These data indicate that NE regulation of A2AR differs in developing and mature brain and support the idea that NE regulates A2AR development and this has long term effects on A2AR function.

  19. Genetic polymorphisms in Kawasaki disease

    Institute of Scientific and Technical Information of China (English)

    Ho-chang KUO; Wei-chiao CHANG


    Kawasaki disease (KD) is an acute febrile systemic vasculitis,and the cause of KD is not well understood.It is likely due to multiple interactions between genes and environmental factors.The development of genetic association and genome-wide association studies (GWAS) has opened an avenue to better understanding the molecular mechanisms underlying KD.A novel ITPKC signaling pathway was recently found to be responsible for the susceptibility to KD.Furthermore,the GWAS demonstrated the functionally related susceptibility loci for KD in the Caucasian population.In the last decade,the identification of several genomic regions linked to the pathogenesis of KD has made a major breakthrough in understanding the genetics of KD.This review will focus on genetic polymorphisms associated with KD and describe some of the possible clinical implications and molecular mechanisms that can be used to explain how genetic variants regulate the pathogenesis in KD.

  20. Ghrelin secretion stimulated by β1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice (United States)

    Zhao, Tong-Jin; Sakata, Ichiro; Liang, Guosheng; Richardson, James A.; Brown, Michael S.; Goldstein, Joseph L.; Zigman, Jeffrey M.


    Ghrelin, an octanoylated peptide hormone produced in the stomach, rises dramatically in mouse plasma during chronic severe calorie deprivation, an event that is essential to maintain life. The mechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene. We found that the ghrelin-secreting cells express high levels of mRNA encoding β1-adrenergic receptors. Addition of norepinephrine or epinephrine to the culture medium stimulated ghrelin secretion, and this effect was blocked by atenolol, a selective β1-adrenergic antagonist. When WT mice were treated with reserpine to deplete adrenergic neurotransmitters from sympathetic neurons, the fasting-induced increase in plasma ghrelin was blocked. Inhibition was also seen following atenolol administration. We conclude that ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons and acting directly on β1 receptors on the ghrelin-secreting cells of the stomach. PMID:20713709

  1. In utero Exposure to beta-2-Adrenergic Receptor Agonist Drugs and Risk for Autism Spectrum Disorders

    DEFF Research Database (Denmark)

    Gidaya, Nicole B.; Lee, Brian K.; Burstyn, Igor


    OBJECTIVES: The purpose of this study was to investigate associations between use of β-2-adrenergic receptor (B2AR) agonist drugs during pregnancy and risk for autism spectrum disorders (ASD). METHODS: A case-control study was conducted by using Denmark’s health and population registers. Among...

  2. Ghrelin secretion stimulated by {beta}1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice. (United States)

    Zhao, Tong-Jin; Sakata, Ichiro; Li, Robert Lin; Liang, Guosheng; Richardson, James A; Brown, Michael S; Goldstein, Joseph L; Zigman, Jeffrey M


    Ghrelin, an octanoylated peptide hormone produced in the stomach, rises dramatically in mouse plasma during chronic severe calorie deprivation, an event that is essential to maintain life. The mechanism for this increase is not understood. Here, we study the control of ghrelin secretion in tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene. We found that the ghrelin-secreting cells express high levels of mRNA encoding beta(1)-adrenergic receptors. Addition of norepinephrine or epinephrine to the culture medium stimulated ghrelin secretion, and this effect was blocked by atenolol, a selective beta(1)-adrenergic antagonist. When WT mice were treated with reserpine to deplete adrenergic neurotransmitters from sympathetic neurons, the fasting-induced increase in plasma ghrelin was blocked. Inhibition was also seen following atenolol administration. We conclude that ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons and acting directly on beta(1) receptors on the ghrelin-secreting cells of the stomach.

  3. β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus. (United States)

    O'Dell, Thomas J; Connor, Steven A; Guglietta, Ryan; Nguyen, Peter V


    Encoding new information in the brain requires changes in synaptic strength. Neuromodulatory transmitters can facilitate synaptic plasticity by modifying the actions and expression of specific signaling cascades, transmitter receptors and their associated signaling complexes, genes, and effector proteins. One critical neuromodulator in the mammalian brain is norepinephrine (NE), which regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express β-adrenergic receptors, which are known to play important roles in gating the induction of long-lasting forms of synaptic potentiation. These forms of long-term potentiation (LTP) are believed to importantly contribute to long-term storage of spatial and contextual memories in the brain. In this review, we highlight the contributions of noradrenergic signaling in general and β-adrenergic receptors in particular, toward modulating hippocampal LTP. We focus on the roles of NE and β-adrenergic receptors in altering the efficacies of specific signaling molecules such as NMDA and AMPA receptors, protein phosphatases, and translation initiation factors. Also, the roles of β-adrenergic receptors in regulating synaptic "tagging" and "capture" of LTP within synaptic networks of the hippocampus are reviewed. Understanding the molecular and cellular bases of noradrenergic signaling will enrich our grasp of how the brain makes new, enduring memories, and may shed light on credible strategies for improving mental health through treatment of specific disorders linked to perturbed memory processing and dysfunctional noradrenergic synaptic transmission.

  4. Preserved alpha-adrenergic tone in the leg vascular bed of spinal cord-injured individuals.

    NARCIS (Netherlands)

    Kooijman, H.M.; Rongen, G.A.P.J.M.; Smits, P.; Hopman, M.T.E.


    BACKGROUND: Supraspinal sympathetic control of leg vascular tone is lost in spinal cord-injured individuals, but this does not result in a reduced leg vascular tone: Leg vascular resistance is even increased. The aim of this study was to assess the alpha-adrenergic contribution to the increased vasc

  5. Alpha-1 adrenergic receptor: Binding and phosphoinositide breakdown in human myometrium

    Energy Technology Data Exchange (ETDEWEB)

    Breuiller-Fouche, M.; Doualla-Bell Kotto Maka, F.; Geny, B.; Ferre, F. (INSERM U.166 Groupe de recherches sur l' Endocrinologie de la Reproduction, Maternite Baudelocque, Paris (France))


    Alpha-1 adrenergic receptors were examined in both inner and outer layers of human pregnant myometrium using radioligand binding of (3H)prazosin. (3H)prazosin bound rapidly and reversibly to a single class of high affinity binding sites in myometrial membrane preparations. Scatchard analysis gave similar values of equilibrium dissociation constants in both myometrial layers. In contrast, more alpha-1 adrenergic receptors were detected in the outer layer than in the inner layer. Antagonist inhibited (3H)prazosin binding with an order of potency of prazosin greater than phentolamine greater than idazoxan. Competition experiments have also revealed that a stable guanine nucleotide decreases the apparent affinity of norepinephrine for myometrial (3H)prazosin binding sites. The functional status of these alpha-1 adrenergic receptors was also assessed by measuring the norepinephrine-induced accumulation of inositol phosphates in myometrial tissue. Norepinephrine produced a concentration-dependent accumulation of inositol phosphates in both myometrial layers. However, norepinephrine-induced increases in inositol 1,4,5-triphosphate were only observed in the outer layer. These results indicate that alpha-1 adrenergic receptors in human myometrium at the end of pregnancy are linked to phosphoinositide hydrolysis and that this response occurs mainly in the outer layer.

  6. The role of the alpha-adrenergic receptor in the leg vasoconstrictor response to orthostatic stress.

    NARCIS (Netherlands)

    Kooijman, M.; Rongen, G.A.P.J.M.; Smits, P.; Kuppevelt, H.J.M. van; Hopman, M.T.E.


    AIM: The prompt increase in peripheral vascular resistance, mediated by sympathetic alpha-adrenergic stimulation, is believed to be the key event in blood pressure control during postural stress. However, despite the absence of central sympathetic control of the leg vasculature, postural leg vasocon

  7. Effects of Adrenergic Blockade on Postpartum Adaptive Responses Induced by Labor Contractions (United States)

    Ronca, April E.; Mills, N. A.; Lam, K. P.; Hayes, L. E.; Bowley, Susan M. (Technical Monitor)


    Prenatal exposure to labor contractions augments the expression of postnatal adaptive responses in newborn rats. Near-term rat fetuses exposed prenatally to simulated labor contractions and delivered by cesarean section breath and attach to nipples at greater frequencies than non-stimulated fetuses. Plasma NE (norepinephrine) and EPI (epinephrine) was significantly elevated in newborn rats exposed to vaginal birth or simulated labor contractions (compressions) with cesarean delivery as compared to non-compressed fetuses. In the present study, we investigated adrenergic mechanisms underlying labor-induced postnatal adaptive responses. Following spinal transection of late pregnant rat dams, fetuses were administered neurogenic or non-neurogenic adrenergic blockade: 1) bretylium (10 mg/kg sc) to prevent sympathetic neuronal release, 2) hexamethonium (30 mg/kg) to produce ganglionic blockade, 3) phenoxybenzanune (10mg/kg sc), an a- adrenergic receptor antagonist, 4) ICI-118551, 10 mg/kg sc), a b receptor antagonist, or 5) vehicle alone. Fetuses were either compressed (C) or non-compressed (NC) prior to cesarean delivery. a- and b- adrenergic antagonists reduced respiration and nipple attachment rates while sympathetic and vehicle alone did not. These results provide additional support for the hypothesis that adaptive neonatal effects of labor contractions are mediated by adrenal and extra-adrenal catecholamines.

  8. Modulation of nicotinic receptor channels by adrenergic stimulation in rat pinealocytes (United States)

    Yoon, Jin-Young; Jung, Seung-Ryoung; Hille, Bertil


    Melatonin secretion from the pineal gland is triggered by norepinephrine released from sympathetic terminals at night. In contrast, cholinergic and parasympathetic inputs, by activating nicotinic cholinergic receptors (nAChR), have been suggested to counterbalance the noradrenergic input. Here we investigated whether adrenergic signaling regulates nAChR channels in rat pinealocytes. Acetylcholine or the selective nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) activated large nAChR currents in whole cell patch-clamp experiments. Norepinephrine (NE) reduced the nAChR currents, an effect partially mimicked by a β-adrenergic receptor agonist, isoproterenol, and blocked by a β-adrenergic receptor antagonist, propranolol. Increasing intracellular cAMP levels using membrane-permeable 8-bromoadenosine (8-Br)-cAMP or 5,6-dichlorobenzimidazole riboside-3′,5′-cyclic monophosphorothioate (cBIMPS) also reduced nAChR activity, mimicking the effects of NE and isoproterenol. Further, removal of ATP from the intracellular pipette solution blocked the reduction of nAChR currents, suggesting involvement of protein kinases. Indeed protein kinase A inhibitors, H-89 and Rp-cAMPS, blocked the modulation of nAChR by adrenergic stimulation. After the downmodulation by NE, nAChR channels mediated a smaller Ca2+ influx and less membrane depolarization from the resting potential. Together these results suggest that NE released from sympathetic terminals at night attenuates nicotinic cholinergic signaling. PMID:24553185

  9. Effects of thyroid hormone on. beta. -adrenergic responsiveness of aging cardiovascular systems

    Energy Technology Data Exchange (ETDEWEB)

    Tsujimoto, G.; Hashimoto, K.; Hoffman, B.B.


    The authors have compared the effects of ..beta..-adrenergic stimulation on the heart and peripheral vasculature of young (2-mo-old) and older (12-mo-old) rats both in the presence and absence of triiodothyronine (T/sub 3/)-induced hyperthyroidism. The hemodynamic consequences of T/sub 3/ treatment were less prominent in the aged hyperthyroid rats compared with young hyperthyroid rats (both in intact and pithed rats). There was a decrease in sensitivity of chronotropic responsiveness to isoproterenol in older pithed rats, which was apparently reversed by T/sub 3/ treatment. The number and affinity of myocardial ..beta..-adrenergic receptor sites measured by (/sup 125/I)cyanopindolol were not significantly different in young and older control rats; also, ..beta..-receptor density increased to a similar extent in both young and older T/sub 3/-treated rats. The ability of isoproterenol to relax mesenteric arterial rings, markedly blunted in older rats, was partially restored by T/sub 3/ treatment without their being any change in isoproterenol-mediated relaxation in the arterial preparation from young rats. The number and affinity of the ..beta..-adrenergic receptors measured in the mesenteric arteries was unaffected by either aging or T/sub 3/ treatment. The data suggest that effects of thyroid hormone and age-related alterations of cardiovascular responsiveness to ..beta..-adrenergic stimulation are interrelated in a complex fashion with a net result that the hyperkinetic cardiovascular manifestations in hyperthyroidism are attenuated in the older animals.

  10. Characterization and regulation of. beta. /sub 2/-adrenergic receptors in rat vas deferens

    Energy Technology Data Exchange (ETDEWEB)

    May, J.M.


    ..beta../sub 2/-Adrenergic receptors in rat vas deferens were examined by measuring the binding of /sup 125/I-pindolol (/sup 125/IPIN) to membrane preparations and the inhibition of evoked contractions in intact tissues. /sup 125/IPIN labeled a single class of binding sites with mass action kinetics. Affinity constants for ..beta..-adrenergic receptor antagonists calculated from both binding and functional experiments agreed well, suggesting that /sup 125/IPIN labels the functional ..beta../sub 2/-adrenergic receptor. n-Bromoacetylalprenololmenthane (BAAM) was used to decrease receptor density so that agonist affinity constants could be determined functionally. Treatment of tissues with BAAM decreased the functional potencies of agonists. Higher concentrations of BAAM decreased the maximum tissue response. Affinity constants for agonists calculated after BAAM treatment were compared to affinity constants determined from binding studies done under conditions designed to promote high or low affinity agonist binding. Functional affinity constants for isoproterenol and salbutamol agreed with the low affinity binding constants, suggesting that the low affinity form of the receptor initiates the functional response. Because acute denervation of vasa deferentia did not alter the density of /sup 125/IPIN binding sites, the sites are probably post-junctional. Chronic infusion of isoproterenol reduced the potency of isoproterenol, the maximum tissue response, and the receptor density. These results suggest that ..beta..-adrenergic receptor density and responsiveness in rat vas deferens are not affected by removing catecholamine sources, but receptor density and responsiveness can be decreased by increasing agonist concentration at the receptor.

  11. Hypoxia increases exercise heart rate despite combined inhibition of β-adrenergic and muscarinic receptors

    DEFF Research Database (Denmark)

    Siebenmann, Christoph; Rasmussen, Peter; Sørensen, Henrik;


    Hypoxia increases the heart rate (HR) response to exercise but the mechanism(s) remain unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate but not combined inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exerci...

  12. Vasoconstriction induced by ouabain in the canine coronary artery: contribution of adrenergic and nonadrenergic responses. (United States)

    Cooke, J P; Shepherd, J T; Vanhoutte, P M


    Ouabain, when applied to rings of the left circumflex coronary artery of the dog (which contains both alpha 1-adrenoceptors leading to contraction and beta 1-adrenoceptors leading to relaxation) caused an initial contraction which peaked within 15 minutes and a later secondary increase in tension which peaked within 60 minutes. These contractions were prevented by Ca2+ removal or by verapamil. Adrenergic denervation with 6-hydroxydopamine did not affect the initial contraction. Thus it is due to a nonadrenergic effect of the glycoside. Since the secondary increase in tension was prevented by adrenergic denervation and prazosin, it is likely to be due to norepinephrine released from adrenergic nerves acting on alpha-adrenoceptors. This interpretation was confirmed by the finding that ouabain, after a latent period of about 35 minutes, augmented the output of 3H-norepinephrine from helical strips of the artery previously incubated with tritiated transmitter. In rings contracted with prostaglandin F2 alpha, ouabain reduced beta-adrenergic relaxations caused by isoproterenol or exogenous norepinephrine, but not those caused by sodium nitroprusside. Thus, in this artery, ouabain depresses the responses of the beta-adrenoceptors to the norepinephrine which it releases, thereby permitting the neurotransmitter to cause contraction by activating postjunctional alpha 1-adrenoceptors.

  13. [Adrenergic innervation of the uterus of the rat in various phases of the estrous cycle]. (United States)

    Rakitskaia, V V; Proimina, F I; Chudinov, Iu V


    Adrenergic innervation of the rat uterus is connected chiefly with vessel innervation. The highest density of fibers and the highest intensity of specific fluorescence is shown in the stage of dioestrus, the least those--in oestrus. These indices correlated with the estradiol and progesterone level in the plasma.

  14. Effects of adrenergic and nitrergic blockade on theophylline-induced increase in peripheral blood flow in rat ear. (United States)

    Sanae, F; Hayashi, H


    A bolus injection of theophylline produced a significant increase in peripheral blood flow in anesthetized rat ear, monitored by laser-Doppler flowmetry, with increases in arterial blood pressure and heart rate. These effects were attenuated by previous treatment with reserpine, but reserpine had no effect on the blood flow increase produced by acetylcholine. A dose of propranolol, which caused attenuation of the theophylline-induced increase in heart rate, did not change the peripheral blood flow. The higher dose of propranolol, which nearly canceled the increases in blood pressure and heart rate, caused attenuation of the blood flow increase but did not cancel it. However, the theophylline-induced flow increase was completely reversed by a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester, which alone had no effect, without any change in arterial blood pressure and heart rate. Treatment of the rats with the dose of inhibitor slightly and significantly reduced the response of peripheral blood flow to acetylcholine. The other isomer, NG-nitro-D-arginine methyl ester, and the other inhibitor, NG-monomethyl-L-arginine, did not have such an effect. These results suggest that the flow increase is due to an independent effect on the heart with modification by autonomic reflexes and involves the adrenergic and nitrergic pathways.

  15. Activation of α2A-adrenergic signal transduction in chondrocytes promotes degenerative remodelling of temporomandibular joint (United States)

    Jiao, Kai; Zeng, Guang; Niu, Li-Na; Yang, Hong-xu; Ren, Gao-tong; Xu, Xin-yue; Li, Fei-fei; Tay, Franklin R.; Wang, Mei-qing


    This study tested whether activation of adrenoreceptors in chondrocytes has roles in degenerative remodelling of temporomandibular joint (TMJ) and to determine associated mechanisms. Unilateral anterior crossbite (UAC) was established to induce TMJ degeneration in rats. Saline vehicle, α2- and β-adrenoreceptor antagonists or agonists were injected locally into the TMJ area of UAC rats. Cartilage degeneration, subchondral bone microarchitecture and the expression of adrenoreceptors, aggrecans, matrix metalloproteinases (MMPs) and RANKL by chondrocytes were evaluated. Chondrocytes were stimulated by norepinephrine to investigate signal transduction of adrenoreceptors. Increased α2A-adrenoreceptor expression was observed in condylar cartilage of UAC rats, together with cartilage degeneration and subchondral bone loss. Norepinephrine depresses aggrecans expression but stimulates MMP-3, MMP-13 and RANKL production by chondrocytes through ERK1/2 and PKA pathway; these effects were abolished by an α2A-adrenoreceptor antagonist. Furthermore, inhibition of α2A-adrenoreceptor attenuated degenerative remodelling in the condylar cartilage and subchondral bone, as revealed by increased cartilage thickness, proteoglycans and aggrecan expression, and decreased MMP-3, MMP-13 and RANKL expressions in cartilage, increased BMD, BV/TV, and decreased Tb.Sp in subchondral bone. Conversely, activation of α2A-adrenoreceptor intensified aforementioned degenerative changes in UAC rats. It is concluded that activation of α2A-adrenergic signal in chondrocytes promotes TMJ degenerative remodelling by chondrocyte-mediated pro-catabolic activities. PMID:27452863

  16. Nebivolol protects against myocardial infarction injury via stimulation of beta 3-adrenergic receptors and nitric oxide signaling.

    Directory of Open Access Journals (Sweden)

    Zheng Zhang

    Full Text Available Nebivolol, third-generation β-blocker, may activate β3-adrenergic receptor (AR, which has been emerged as a novel and potential therapeutic targets for cardiovascular diseases. However, it is not known whether nebivolol administration plays a cardioprotective effect against myocardial infarction (MI injury. Therefore, the present study was designed to clarify the effects of nebivolol on MI injury and to elucidate the underlying mechanism. MI model was constructed by left anterior descending (LAD artery ligation. Nebivolol, β3-AR antagonist (SR59230A, Nitro-L-arginine methylester (L-NAME or vehicle was administered for 4 weeks after MI operation. Cardiac function was monitored by echocardiography. Moreover, the fibrosis and the apoptosis of myocardium were assessed by Masson's trichrome stain and TUNEL assay respectively 4 weeks after MI. Nebivolol administration reduced scar area by 68% compared with MI group (p<0.05. Meanwhile, nebivolol also decreased the myocardial apoptosis and improved the heart function after MI (p<0.05 vs. MI. These effects were associated with increased β3-AR expression. Moreover, nebivolol treatment significantly increased the phosphorylation of endothelial NOS (eNOS and the expression of neuronal NOS (nNOS. Conversely, the cardiac protective effects of nebivolol were abolished by SR and L-NAME. These results indicate that nebivolol protects against MI injury. Furthermore, the cardioprotective effects of nebivolol may be mediated by β3-AR-eNOS/nNOS pathway.

  17. Astrocytic β2 Adrenergic Receptor Gene Deletion Affects Memory in Aged Mice (United States)

    Jensen, Cathy Joanna; Demol, Frauke; Bauwens, Romy; Kooijman, Ron; Massie, Ann; Villers, Agnès; Ris, Laurence; De Keyser, Jacques


    In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the β2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific β2-adrenergic receptor knock-out mice were generated by crossing homozygous β2-adrenergic receptor floxed mice (Adrb2flox) and mice with heterozygous tamoxifen-inducible Cre recombinase-expression driven by the astrocyte specific L-glutamate/L-aspartate transporter promoter (GLAST-CreERT2). Assessments using the modified SHIRPA (SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment) test battery, swimming ability test, and accelerating rotarod test, performed at 1, 2 and 4 weeks, 6 and 12 months after tamoxifen (or vehicle) administration did not reveal any differences in physical health or motor functions between the knock-out mice and controls. However deficits were found in the cognitive ability of aged, but not young adult mice, reflected in impaired learning in the Morris Water Maze. Similarly, long-term potentiation (LTP) was impaired in hippocampal brain slices of aged knock-out mice maintained in low glucose media. Using microdialysis in cerebellar white matter we found no significant differences in extracellular lactate or glucose between the young adult knock-out mice and controls, although trends were detected. Our results suggest that β2-adrenergic receptor expression on astrocytes in mice may be important for maintaining cognitive health at advanced age, but is dispensable for motor function. PMID:27776147

  18. Beta-adrenergic stimulation reverses the IKr–IKs dominant pattern during cardiac action potential (United States)

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T.; Chen-Izu, Ye


    β-adrenergic stimulation differentially modulates different K+ channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of IKs, IKr, and IK1 current in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K+ current to the total repolarization reserve. In this study we used an innovative AP-clamp Sequential Dissection technique to directly record the dynamic –IKs, IKr, IK1– currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of IKs, IKr, IK1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca2+ homeostasis. We found that isoproterenol treatment significantly enhanced IKs, moderately increased IK1, but slightly decreased IKr in a dose-dependent manner. The dominance pattern of the K+ currents was IKr>IK1>IKs at the control condition, but reversed to IKradrenergic stimulation. We systematically determined the changes in the relative contribution of IKs, IKr, IK1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K+ currents in a dose-dependent manner. This Knowledge is important for designing anti-arrhythmic drug strategies to treat the hearts exposed to various sympathetic tones. PMID:24535581

  19. Association of the beta-1 adrenergic receptor carboxyl terminal variants with left ventricular hypertrophy among diabetic and non-diabetic survivors of acute myocardial infarction

    Directory of Open Access Journals (Sweden)

    Hakalahti Anna E


    Full Text Available Abstract Background The beta-1 adrenergic receptor (β1AR plays a fundamental role in the regulation of cardiovascular functions. It carries a nonsynonymous single nucleotide polymorphism in its carboxyl terminal tail (Arg389Gly, which has been shown to associate with various echocardiographic parameters linked to left ventricular hypertrophy (LVH. Diabetes mellitus (DM, on the other hand, represents a risk factor for LVH. We investigated the possible association between the Arg389Gly polymorphism and LVH among non-diabetic and diabetic acute myocardial infarction (AMI survivors. Methods The study population consisted of 452 AMI survivors, 20.6% of whom had diagnosed DM. Left ventricular parameters were measured with two-dimensional guided M-mode echocardiography 2-7 days after AMI, and the Arg389Gly polymorphism was determined using a polymerase chain reaction-restriction fragment length polymorphism assay. Results The Arg389 homozygotes in the whole study population had a significantly increased left ventricular mass index (LVMI when compared to the Gly389 carriers (either Gly389 homozygotes or Arg389/Gly389 heterozygotes [62.7 vs. 58.4, respectively (p = 0.023]. In particular, the Arg389 homozygotes displayed thicker diastolic interventricular septal (IVSd measures when compared to the Gly389 carriers [13.2 vs. 12.3 mm, respectively (p = 0.004]. When the euglycemic and diabetic patients were analyzed separately, the latter had significantly increased LVMI and diastolic left ventricular posterior wall (LVPWd values compared to the euglycemic patients [LVMI = 69.1 vs. 58.8 (p = 0.001 and LVPWd = 14.2 vs. 12.3 mm (p Conclusions The data suggest an association between the β1AR Arg389Gly polymorphism and LVH, particularly the septal hypertrophy. The Arg389 variant appears to confer a higher risk of developing LVH than the corresponding Gly389 variant among patients who have suffered AMI. This association cannot be considered to be universal

  20. Association Between the 1291-C/G Polymorphism in the Adrenergic alpha-2a Receptor and the Metabolic Syndrome

    NARCIS (Netherlands)

    Risselada, Arne J.; Vehof, Jelle; Bruggeman, Richard; Wilffert, Bob; Cohen, Dan; Al Hadithy, Asmar F.; Arends, Johan; Mulder, Hans


    The prevalence of the metabolic syndrome is increased in patients with schizophrenia compared with the general population. The strong interindividual differences in susceptibility to developing the metabolic syndrome suggests that the genetic makeup is a modulating factor. Part of the genetic puzzle

  1. MTHFR Gene C677T Polymorphism in Autism Spectrum Disorders

    Directory of Open Access Journals (Sweden)

    Elif Funda Sener


    Full Text Available Aim. Autism is a subgroup of autism spectrum disorders, classified as a heterogeneous neurodevelopmental disorder and symptoms occur in the first three years of life. The etiology of autism is largely unknown, but it has been accepted that genetic and environmental factors may both be responsible for the disease. Recent studies have revealed that the genes involved in the folate/homocysteine pathway may be risk factors for autistic children. In particular, C677T polymorphism in the MTHFR gene as a possible risk factor for autism is still controversial. We aimed to investigate the possible effect of C677T polymorphism in a Turkish cohort. Methods. Autism patients were diagnosed by child psychiatrists according to DSM-IV and DSM-V criteria. A total of 98 children diagnosed as autistic and 70 age and sex-matched children who are nonautistic were tested for C677T polymorphism. This polymorphism was studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP methods. Results. MTHFR 677T-allele frequency was found to be higher in autistic children compared with nonautistic children (29% versus 24%, but it was not found statistically significant. Conclusions. We conclude that other MTHFR polymorphisms such as A1298C or other folate/homocysteine pathway genes may be studied to show their possible role in autism.

  2. Deadly proposal: a case of catecholaminergic polymorphic ventricular tachycardia. (United States)

    Heiner, Jason D; Bullard-Berent, Jeffrey H; Inbar, Shmuel


    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare adrenergically mediated arrhythmogenic disorder classically induced by exercise or emotional stress and found in structurally normal hearts. It is an important cause of cardiac syncope and sudden death in childhood. Catecholaminergic polymorphic ventricular tachycardia is a genetic cardiac channelopathy with known mutations involving genes affecting intracellular calcium regulation. We present a case of a 14-year-old boy who had cardiopulmonary arrest after an emotionally induced episode of CPVT while attempting to invite a girl to the school dance. Review of his presenting cardiac rhythm, induction of concerning ventricular arrhythmias during an exercise stress test, and genetic testing confirmed the diagnosis of CPVT. He recovered fully and was treated with β-blocker therapy and placement of an implantable cardioverter-defibrillator. In this report, we discuss this rare but important entity, including its molecular foundation, clinical presentation, basics of diagnosis, therapeutic options, and implications of genetic testing for family members. We also compare CPVT to other notable cardiomyopathic and channelopathic causes of sudden death in youth including hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, long QT syndrome, short QT syndrome, and Brugada syndrome.

  3. Effect of CYP2C19 genetic polymorphism on pharmacokinetic characterstics and 5-hydroxyl metabolic pathway of lansoprazole in Chinese volunteers%CYP2C19基因多态性对中国人体内兰索拉唑药代动力学及其5-羟基代谢通路的影响

    Institute of Scientific and Technical Information of China (English)

    严非; 夏春华; 熊玉卿


    AIM: To investigate the effect of CYP2C19 polymorphism on pharmacokinetic characteristics and 5-hydroxyl metabolic pathway of lansoprazole in Chinese subjects. METH-ODS: Twelve healthy subjects were typed by u-sing RFLP-PCR method. After intravenous drip 30 mg lansoprazole, the plasma concentrations of lansoprazole in subjects were determined byLC-MS method. The pharmacokinetic parameters of lansoprazole and AUClpz/AUC5-Ohlpz were calculated and compared between different groups. RESULTS-. After all the subjects were given 30 mg lansoprazole, it found that the AUCo-,, AUCo-(x), CLz, ( AUCLpz/ AUC5-oh)0-t, and (AUCLpZ/AUC5-oh)0-∞ of the mutant types were equivalent to 2.381, 2.572, 0. 428, 3. 602 and 4. 083-fold as those of the wild types, respectively. CONCLUSION: The CYP2C19 genetic polymorphism, which has significant influence on the pharmacokinetic characteristics of the lansoprazole in Chinese volun-teers (P<0. 05), has very significant influence on the 5-hydroxyl metabolic pathway of the lansoprazole (P<0. 01). The result suggests that CYP2C19 genetic polymorphism is one of the important factors leading to individual concentration differences of the lansoprazole and has a better relevance with the 5-hydroxyl metabolic pathway.%目的:研究CYP2C19基因多态性对中国人体内兰索拉唑药代动力学及其5-羟基代谢通路的影响.方法:采用RFLP-PCR方法对12名健康受试者进行CYP2C19基因多态性检测,并采用液相色谱-质谱法(LC-MS)检测兰索拉唑体内血药浓度并计算相关的药代动力学参数,比较不同基因型受试者之间主要药代动力学参数以及AUCLpz/AUC5-oH LPZ 比 值(AUGansoprazole/AUC5-hydroxylansoprazole,此参数用以评价5-羟基代谢的标准)的差异.结果:12名健康受试者在给予30 mg兰索拉唑后,发现突变型个体AUC0-t、AUC0-∞、CLz、(AUCLPZ/AUC5-OHLPZ)0-t、(AUCLPZ/AUC5-OH LPZ)0-.∞分别相当于野生型个体的2.381、2.572、0.428、3.602、4.083

  4. Interação entre as vias de sinalização de receptores serotoninérgicos e Β-adrenérgicos em artéria femoral de ratos Interacción entre las vías de señalización de receptores serotoninérgicos y β-adrenégicos en la arteria femoral de ratones Interaction between serotoninergic-and β-adrenergic receptors signaling pathways in rat femoral artery

    Directory of Open Access Journals (Sweden)

    Maria Andréia Delbin


    responses, tissues were precontracted with PE or 5-HT. RESULTS: The order rank potency in femoral artery was 5-HT > PE for contractile responses. In tissues precontracted with 5-HT, relaxing responses to isoproterenol was virtually abolished as compared to PE-contracted tissues. Forskolin, a stimulant of adenylyl cyclase, partially restored the relaxing response to ISO in 5-HT-precontracted tissues. CONCLUSION: An interaction between β-adrenergic- and serotoninergic- receptors signaling pathway occurs in femoral artery. Moreover, this study provides a new model to study serotoninergic signaling pathway under normal and pathological conditions which can help understanding clinical outcomes in the PAD.

  5. Study on the relationship between single-nucleotide polymorphisms in DNA repair pathway and the clinicopathological characteristics of primary liver cancer%广西人群DNA修复途径部分基因多态性与肝癌临床病理特征的关联研究

    Institute of Scientific and Technical Information of China (English)

    潘冬香; 仇小强; 刘顺; 谭超; 黄慧


    Objective To investigate the association between single-nucleotide polymorphisms in DNA repair genes XRCC1, APE1, hOGGl, XPC, XPD, XPG, XRCC3 and clinicopathological characteristics of primary liver cancer. Methods Materials of clinical pathology, blood DNA of 257 new-onset primary liver cancer patients who were hospitalized at Guangxi medical university first affiliated hospital between February 2007 and October 2008 were collected. Genotypes of 499, 939 site of XPC, 312 site of XPD, 1104 site of XPG, 194, 280, 399 site of XRCC1, 324 site of XRCC3 were determined by real-time polymorphism chain reaction, χ2 test and unconditional Logistic regression were used to explore the association between single-nucleotide polymorphisms in DNA repair genes and clinicopathological characteristics of primary liver cancer. Results Significant positive correlations were revealed between polymorphisms of XRCC1-399 and portal vein tumor thrombosis (P =0.036), hOOGl-326 and envelope evasion ( P = 0. 036), XPC499 and gross classification (P = 0.047). The stratified analysis showed that XPD312 polymorphisms associated with tumor number in the onset below 47 years old group (P =0.025). There were significant differences between polymorphisms of XPD312 site and tumor size (P=0. 009) , XRCC1-280 site and portal vein tumor thrombosis (P =0.024) , XRCC1-280 site and pathological stage (P =0. 050) in the onset over 47 years old group. The combined effects of different repair pathway gene polymorphism genotype distribution frequency were significantly correlated with satellite nodules of primary liver cancer ( P = 0. 037). No significant correlation was observed between-148 site of APElgene, -939 site of XPC gene, -1104 site of XPG gene, -241 site of XRCC3 gene and primary liver cancer ( all P > 0. 05). Conclusions Polymorphisms of XRCC1-280, XRCC1-399, hOGGl-326, XPC499, XPD312 may be correlated with the clinicobiological characteristics of primary liver cancer.%目的 探讨广西

  6. Functional and pharmacological characterization of the natriuretic peptide-dependent lipolytic pathway in human fat cells. (United States)

    Moro, Cedric; Galitzky, Jean; Sengenes, Coralie; Crampes, François; Lafontan, Max; Berlan, Michel


    A lipolytic pathway involving natriuretic peptides has recently been discovered in human fat cells. Its functional characteristics and the interactions of the atrial natriuretic peptide (ANP)-induced effects with adrenergic and insulin pathways were studied. Characterization of the action of ANP antagonists, i.e., A71915, anantin, S-28-Y (Ser-28-Tyr, a synthesized peptide), and HS-142-1 (a microbial polysaccharide), was performed. Lipolytic assays and intracellular cGMP and cAMP determinations were performed on isolated fat cells. Cell membranes were used for binding studies. At low concentrations ANP and isoproterenol [beta-adrenergic receptor (beta-AR) agonist] exerted additive lipolytic effects. The alpha(2)-AR pathway did not interfere with that of ANP. Lipolytic effects of ANP were unaltered by a 2-h pretreatment of fat cells with insulin, whereas beta-AR-induced lipolysis was reduced. Homologous desensitization occurred for ANP-dependent lipolytic pathways. Dendroapsis natriuretic peptide exhibited a similar maximal effect but a 10-fold higher lipolytic potency than ANP and mini-ANP (the shortest form of ANP). The antagonist A71915 exhibited competitive antagonistic properties with a pA(2) value of 7.51. Anantin displayed noncompetitive antagonism and exerted an inhibitory action on basal and beta-adrenergic receptor-induced lipolytic response. S-28-Y exhibited antagonist potencies toward ANP-induced lipolysis and behaved as a partial lipolytic agonist with a lower pD(2) value (7.4 +/- 0.2) than ANP (9.4 +/- 0.3). HS-142-1 exerted the weakest antagonistic effects. The results demonstrate that ANP-dependent effects do not interfere with beta- and alpha(2)-adrenergic pathways in human fat cells. They are unaffected by insulin pretreatments of fat cells but undergo desensitization. In the search of potent and specific natriuretic peptide receptor-A antagonist, in the human fat cell, A71915 was the only reliable one found.

  7. Assessment of myocardial adrenergic innervation in patients with sick sinus syndrome: effect of asynchronous ventricular activation from ventricular apical stimulation


    Marketou, M E; Simantirakis, E N; Prassopoulos, V K; Chrysostomakis, S I; Velidaki, A A; Karkavitsas, N S; Vardas, P.E.


    Objective: To investigate ventricular sympathetic innervation in patients with sick sinus syndrome and to detect regional deterioration of adrenergic innervation caused by asynchronous ventricular activation from right ventricular pacing.

  8. Hypocaloric diet reduces exercise-induced alpha 2-adrenergic antilipolytic effect and alpha 2-adrenergic receptor mRNA levels in adipose tissue of obese women. (United States)

    Stich, V; Marion-Latard, F; Hejnova, J; Viguerie, N; Lefort, C; Suljkovicova, H; Langin, D; Lafontan, M; Berlan, M


    Previous investigations have shown that alpha 2-adrenoceptor (alpha 2-AR) stimulation blunts lipid mobilization during physiological activation of the sympathetic nervous system promoted by exercise in sc abdominal adipose tissue (SCAAT) in obese men. To investigate the effect of a low calorie diet (LCD) on the alpha 2-adrenergic responsiveness and on the expression of alpha 2-AR and beta 2-adrenoceptor (beta 2-AR) in SCAAT, 11 obese women (weight: 99.1 +/- 4.6 kg; body mass index: 34.3 +/- 1.1 kg/m(2)) received a 12-wk diet providing 500 kcal/d less than their usual diet. The exercise-induced alpha 2-adrenergic antilipolytic effect was investigated in SCAAT before and at the end of LCD. Changes in extracellular glycerol concentration and local blood flow were measured in SCAAT during a 45-min exercise bout (50% of heart rate reserve) using a control microdialysis probe and a probe supplemented with the alpha2-AR antagonist phentolamine. SCAAT biopsies were performed for determination of mRNA levels using RT-competitive PCR. Plasma catecholamine responses to exercise bout were not different before and at the end of LCD. Before LCD, the exercise-induced increase in extracellular glycerol concentration was potentiated by phentolamine supplementation, while this potentiating effect of the alpha-antagonist was not observed at the end of LCD. No changes were observed for beta 2-AR and hormone-sensitive lipase mRNA levels, while alpha 2-AR mRNA level was significantly decreased in adipose tissue during LCD. These findings show that alpha 2-AR-mediated antilipolytic action is reduced by a moderate hypocaloric diet and that down-regulation of alpha 2-AR mRNA levels may participate in the decrease of the alpha 2-adrenergic effect revealed by microdialysis.

  9. Interactions between an alpha2-adrenergic antagonist and a beta3-adrenergic agonist on the expression of UCP2 and UCP3 in rats.



    This experimental trial was devised to assess whether selective β3-adrenergic receptor (AR) stimulation and simultaneous blockade of α2-AR would affect thermoregulation. With this purpose, the individual and combined administration of a β3-AR agonist, trecadrine, and an α2-AR antagonist, yohimbine, were evaluated. Yohimbine produced a marked decrease (p < 0.001) in body temperature one hour after administration (5 mg kg−1, i.p.) and blocked the thermogenic effect of trecadrine (1 mg kg−1, i.p...

  10. Impact of alpha 1-adrenergic antagonist use for benign prostatic hypertrophy on outcomes in patients with heart failure. (United States)

    Dhaliwal, Amandeep S; Habib, Gabriel; Deswal, Anita; Verduzco, Melinda; Souchek, Julianne; Ramasubbu, Kumudha; Aguilar, David; Ma, Tony S; Jneid, Hani M; Bolos, Mariana; Bozkurt, Biykem


    Previous clinical trials have shown that alpha(1)-adrenergic antagonists are not effective in subjects with heart failure (HF) and might increase HF rates when used for hypertension. However, alpha(1)-adrenergic antagonists may be prescribed to subjects with HF who have symptomatic benign prostatic hyperplasia. We sought to determine any association between alpha(1)-adrenergic antagonist use, commonly prescribed for benign prostatic hyperplasia, and the clinical outcomes of subjects with HF receiving contemporary therapy. An existing database of 388 subjects with decompensated HF admissions from 2002 to 2004 at the Veterans Affairs Hospital was analyzed according to the use of alpha(1)-adrenergic antagonists at discharge. Covariate-adjusted Cox proportional hazard models were used to examine any association with future admissions for decompensated HF and total mortality. Alpha-1-adrenergic antagonist therapy was prescribed in 25% of our HF population, predominantly for benign prostatic hyperplasia, and was not associated with significant increases in the combined risk of all-cause mortality and rehospitalization for HF (hazard ratio 1.24, 95% confidence interval 0.93 to 1.65, p = 0.14), HF hospitalization (hazard ratio 1.20, 95% confidence interval 0.85 to 1.70, p = 0.31), or all-cause mortality (hazard ratio 1.10, 95% confidence interval 0.78 to 1.56, p = 0.57). In patients not receiving beta-blocker therapy, alpha(1)-adrenergic antagonist therapy was significantly associated with increased HF hospitalizations (hazard ratio 1.94, 95% confidence interval 1.14 to 3.32, p = 0.015). In conclusion, in patients with chronic HF, the use of alpha(1)-adrenergic antagonists was significantly associated with more HF hospitalizations when prescribed without concomitant beta blockade. Thus, background beta-blocker therapy appears to be protective against the potential harmful effects of alpha(1)-adrenergic antagonist therapy in patients with HF.

  11. cAMP-synthesis in a medullary thyroid carcinoma cell line: response to adrenergic agents and prostaglandines. (United States)

    Mertens, P R; Goretzki, P E; Keck, E


    Calcitonin secretion by C-cells is mediated through intracellular 3'5'-cyclic adenosine monophosphate (cAMP) and calcium signaling. Calcitonin release stimulation tests may take advantage of both signaling cascades in screening for medullary thyroid carcinomas (MTC). To elucidate the regulation of the adenylyl cyclase system we have determined cAMP levels of a calcitonin-expressing MTC cell line (RG) after exposure to adrenergic agents and prostaglandines. In early passages (20-30) cAMP concentrations were significantly elevated in RG cells after exposure to beta-adrenergic agents and prostaglandines E1 and E2. In advanced passages (60-80) the beta-adrenergic response was no longer detectable and adrenergic receptors were uncoupled from the adenylyl cyclase complex; while the effect of prostaglandines E1 and E2 remained unaffected. Preincubation with dexamethasone, in a process requiring protein new synthesis, re-established the adrenergic response in later passages, indicating that RG cells dedifferentiated in culture over time. Our in vitro findings suggest that MTC cell dedifferentiation may be accompanied by adrenergic receptor-uncoupling from the adenylate cyclase system and that this process may be reversed by dexamethasone incubation.

  12. Altered beta-adrenergic receptor-stimulated cAMP formation in cultured skin fibroblasts from Alzheimer donors. (United States)

    Huang, H M; Gibson, G E


    An alteration in signal transduction systems in Alzheimer's disease would likely be of pathophysiological significance, because these steps are critical to normal brain function. Since dynamic processes are difficult to study in autopsied brain, the current studies utilized cultured skin fibroblasts. The beta-adrenergic-stimulated increase in cAMP was reduced approximately 80% in fibroblasts from Alzheimer's disease compared with age-matched controls. The deficit in Alzheimer fibroblasts in response to various adrenergic agonists paralleled their beta-adrenergic potency, and enhancement of cAMP accumulation by a non-adrenergic agonist, such as prostaglandin E1, was similar in Alzheimer and control fibroblasts. Diminished adenylate cyclase activity did not underlie these abnormalities, since direct stimulation of adenylate cyclase by forskolin elevated cAMP production equally in Alzheimer and control fibroblasts. Cholera toxin equally stimulated cAMP formation in Alzheimer and control fibroblasts. Moreover, cholera toxin partially reduced isoproterenol-induced cAMP deficit in Alzheimer fibroblasts. Pertussis toxin, on the other hand, did not alter the Alzheimer deficits. The results suggest either that the coupling of the GTP-binding protein(s) to the beta-adrenergic receptor is abnormal or that the sensitivity of receptor is altered with Alzheimer's disease. Further, any hypothesis about Alzheimer's disease must explain why a reduced beta-adrenergic-stimulated cAMP formation persists in tissue culture.

  13. The Effects of Inhaled β-Adrenergic Agonists in Transient Tachypnea of the Newborn

    Directory of Open Access Journals (Sweden)

    Esengul Keleş MD


    Full Text Available Aim. To investigate the efficacy of an inhaled β-adrenergic agonists in transient tachypnea of the newborn (TTN. Method. We retrospectively analyzed a cohort of 51 term infants (Group 1 and 37 term infants (Group 2 monitored in the newborn intensive care unit diagnosed with TTN. Infants in Group 1 received humidified oxygen alone, and infants in Group 2 were administered the inhaled β-2 agonist plus humidified oxygen. Results. TTN clinical respiratory assessment, respiratory rate, oxygen saturation values, need for supplemental oxygen therapy, blood gas PH, PO2, and duration of hospitalization were significantly improved in infants in Group 2 as compared with infants in Group 1 (P .05. Conclusion. Inhaled β-adrenergic agonist added to humidified oxygen was found to improve clinical and laboratory parameters. We believe that further studies should be conducted with larger groups to demonstrate the efficacy of β-2 agonists in TTN patients.

  14. Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth (United States)

    Armaiz-Pena, Guillermo N.; Gonzalez-Villasana, Vianey; Nagaraja, Archana S.; Rodriguez-Aguayo, Cristian; Sadaoui, Nouara C.; Stone, Rebecca L.; Matsuo, Koji; Dalton, Heather J.; Previs, Rebecca A.; Jennings, Nicholas B.; Dorniak, Piotr; Hansen, Jean M.; Arevalo, Jesusa M.G.; Cole, Steve W.; Lutgendorf, Susan K.; Sood, Anil K.; Lopez-Berestein, Gabriel


    Increased adrenergic signaling facilitates tumor progression, but the underlying mechanisms remain poorly understood. We examined factors responsible for stress-mediated effects on monocyte/macrophage recruitment into the tumor microenvironment, and the resultant effects on tumor growth. In vitro, MCP1 was significantly increased after catecholamine exposure, which was mediated by cAMP and PKA. Tumor samples from mice subjected to daily restraint stress had elevated MCP1 gene and protein levels, increased CD14+ cells, and increased infiltration of CD68+ cells. hMCP1 siRNA-DOPC nanoparticles significantly abrogated daily restraint stress-induced tumor growth and inhibited infiltration of CD68+ and F4/80+ cells. In ovarian cancer patients, elevated peripheral blood monocytes and tumoral macrophages were associated with worse overall survival. Collectively, we demonstrate that increased adrenergic signaling is associated with macrophage infiltration and mediated by tumor cell-derived MCP1 production. PMID:25738355

  15. Expression of hippocampal adrenergic receptor mRNA in a rat model of depression

    Institute of Scientific and Technical Information of China (English)

    Jianbin Zhang; Lingling Wang; Xinjun Wang; Jingfeng Jiang; Xiaoren Xiang; Tianjun Wang


    Adrenergic receptor dysfunction is suggested as a potential cause of hippocampal vulnerability to stress-related pathology. We examined mRNA expression of adrenergic receptor (AR) subtypes α1-AR, α2-AR, and β1-AR in hippocampal subregions (CA1, CA3, dentate gyrus) using in situ hybridization in a depression model induced by chronic unpredictable mild stress and social isolation. α1-AR mRNA expression was significantly increased in the CA3 and dentate gyrus, β1-AR mRNA was significantly increased in the CA1, and α2-AR mRNA remained unchanged in all regions of depression rats compared with controls. Thus, different AR subtypes exhibit a differing pattern of mRNA expression in various hippocampal subregions following depression.

  16. Significance of adrenergic receptors for the development of nevus flammeus and nevus anemicus

    Energy Technology Data Exchange (ETDEWEB)

    Raff, M. (Vienna Univ. (Austria). 2. Hautklinik)


    Examination of patients with nevus flammeus or nevus anemicus showed disturbed sensibility in the area of the nevus in the majority of cases. Histologically and with special technique of histochemistry and fluorescence microscopy there was no evidence for neurogenic lesions. However, signs of vegetative disfunction were present: hyperhidrosis and absent reactivity of vasculature in the nevus area to vasoconstrictive and vasodilatatory stimuli. Based on these findings a disturbed regulation of vascular intramural adrenergic receptors seemed possible and really could be demonstrated by means of autoradiography. In both types of nevi only one of the adrenergic receptors could be marked with specific antagonists. Therefore, the persistent vascular dilatation and constriction can be accounted for by the absence of one of these receptors. This abnormal distribution of receptors could be due to a developmental defect influenced by the ''nerve growth factor''.

  17. The influence of adrenergic agonists and their antagonists on isolated salivary glands of ixodid ticks. (United States)

    Kaufman, W R


    Various drugs elicit fluid secretion by isolated salivary glands of two species of ixodid ticks (Dermacentor andersoni Stiles and Amblyomma hebraeum Koch). Among catecholamines, the following order of potency was observed: dopamine, epinine, noradrenaline = adrenaline and isoprenaline. The following drugs, in order of potency, were also agonists on this preparation: ergonovine, ergotamine, 6-hydroxydopamine, apomorphine, phenylephrine, norphenylephrine, beta-phenylethylamine, tyramine, D, L-dopa and octopamine. Nialamide increased the response to near-threshold concentrations of dopamine but had no intrinsic activity. Dopamine-induced secretion was depressed by phenoxybenzamine, alpha-flupenthixol, phentolamine, propranolol and dichloroisoprenaline, but only at conce,trations 10- to 1000-fold that of the agonist. Pimozide and spiperone (10(-6) M) augmented the maximum response of dopamine. The tick salivary gland, thus appears to contain one or several receptors differing pharmacologically from mammalian alpha-adrenergic, beta-adrenergic and dopamine receptors.

  18. Nitric Oxide Synthase 1 Modulates Basal and β-Adrenergic-Stimulated Contractility by Rapid and Reversible Redox-Dependent S-Nitrosylation of the Heart. (United States)

    Vielma, Alejandra Z; León, Luisa; Fernández, Ignacio C; González, Daniel R; Boric, Mauricio P


    S-nitrosylation of several Ca2+ regulating proteins in response to β-adrenergic stimulation was recently described in the heart; however the specific nitric oxide synthase (NOS) isoform and signaling pathways responsible for this modification have not been elucidated. NOS-1 activity increases inotropism, therefore, we tested whether β-adrenergic stimulation induces NOS-1-dependent S-nitrosylation of total proteins, the ryanodine receptor (RyR2), SERCA2 and the L-Type Ca2+ channel (LTCC). In the isolated rat heart, isoproterenol (10 nM, 3-min) increased S-nitrosylation of total cardiac proteins (+46±14%) and RyR2 (+146±77%), without affecting S-nitrosylation of SERCA2 and LTCC. Selective NOS-1 blockade with S-methyl-L-thiocitrulline (SMTC) and Nω-propyl-l-arginine decreased basal contractility and relaxation (-25-30%) and basal S-nitrosylation of total proteins (-25-60%), RyR2, SERCA2 and LTCC (-60-75%). NOS-1 inhibition reduced (-25-40%) the inotropic response and protein S-nitrosylation induced by isoproterenol, particularly that of RyR2 (-85±7%). Tempol, a superoxide scavenger, mimicked the effects of NOS-1 inhibition on inotropism and protein S-nitrosylation; whereas selective NOS-3 inhibitor L-N5-(1-Iminoethyl)ornithine had no effect. Inhibition of NOS-1 did not affect phospholamban phosphorylation, but reduced its oligomerization. Attenuation of contractility was abolished by PKA blockade and unaffected by guanylate cyclase inhibition. Additionally, in isolated mouse cardiomyocytes, NOS-1 inhibition or removal reduced the Ca2+-transient amplitude and sarcomere shortening induced by isoproterenol or by direct PKA activation. We conclude that 1) normal cardiac performance requires basal NOS-1 activity and S-nitrosylation of the calcium-cycling machinery; 2) β-adrenergic stimulation induces rapid and reversible NOS-1 dependent, PKA and ROS-dependent, S-nitrosylation of RyR2 and other proteins, accounting for about one third of its inotropic effect.

  19. Beta2-adrenergic signaling affects the phenotype of human cardiac progenitor cells through EMT modulation. (United States)

    Pagano, Francesca; Angelini, Francesco; Siciliano, Camilla; Tasciotti, Julia; Mangino, Giorgio; De Falco, Elena; Carnevale, Roberto; Sciarretta, Sebastiano; Frati, Giacomo; Chimenti, Isotta


    Human cardiac progenitor cells (CPCs) offer great promises to cardiac cell therapy for heart failure. Many in vivo studies have shown their therapeutic benefits, paving the way for clinical translation. The 3D model of cardiospheres (CSs) represents a unique niche-like in vitro microenvironment, which includes CPCs and supporting cells. CSs have been shown to form through a process mediated by epithelial-to-mesenchymal transition (EMT). β2-Adrenergic signaling significantly affects stem/progenitor cells activation and mobilization in multiple tissues, and crosstalk between β2-adrenergic signaling and EMT processes has been reported. In the present study, we aimed at investigating the biological response of CSs to β2-adrenergic stimuli, focusing on EMT modulation in the 3D culture system of CSs. We treated human CSs and CS-derived cells (CDCs) with the β2-blocker butoxamine (BUT), using either untreated or β2 agonist (clenbuterol) treated CDCs as control. BUT-treated CS-forming cells displayed increased migration capacity and a significant increase in their CS-forming ability, consistently associated with increased expression of EMT-related genes, such as Snai1. Moreover, long-term BUT-treated CDCs contained a lower percentage of CD90+ cells, and this feature has been previously correlated with higher cardiogenic and therapeutic potential of the CDCs population. In addition, long-term BUT-treated CDCs had an increased ratio of collagen-III/collagen-I gene expression levels, and showed decreased release of inflammatory cytokines, overall supporting a less fibrosis-prone phenotype. In conclusion, β2 adrenergic receptor block positively affected the stemness vs commitment balance within CSs through the modulation of type1-EMT (so called "developmental"). These results further highlight type-1 EMT to be a key process affecting the features of resident cardiac progenitor cells, and mediating their response to the microenvironment.

  20. Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction. (United States)

    Goldstein, I


    Phentolamine mesylate is an alpha-1 and alpha-2 selective adrenergic receptor antagonist which has undergone clinical trials for erectile dysfunction treatment. Biochemical and physiological studies in human erectile tissue have revealed a high affinity of phentolamine for alpha-1 and alpha-2 adrenergic receptors. Based on pharmacokinetic studies, it is suggested that 30-40 min following oral ingestion of 40 or 80 mg of phentolamine (Vasomax), the mean plasma phentolamine concentrations are sufficient to occupy the alpha-1 and -2 adrenergic receptors in erectile tissue and thereby result in inhibition of adrenergic-mediated physiologic activity. In large multi-center, placebo-controlled pivotal phase III clinical trials, the mean change in the erectile function domain of the International Index of Erectile Function scores (Questions 1-5 and 15) from screening to the end of treatment was significantly higher following use of active drug (40 mg and 80 mg) compared to placebo. Three to four times as many patients receiving phentolamine reported being satisfied or very satisfied compared with those receiving placebo. At doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration with 51% and 53% achieving penetration on 75% of attempts. The correction of erectile dysfunction or improvement to a less severe category of dysfunction was experienced by 53% of men with the 80 mg dose and 40% with the 40 mg dose of phentolamine. All trends of response were the same regardless of any concomitant medication. There were no severe adverse events. At 40 mg, 7.7% experienced rhinitis and fewer than 3.1% experienced any other side effect of treatment. Phentolamine is safe, well tolerated and efficacious for the treatment of erectile dysfunction.

  1. Alpha-Adrenergic receptors in cerebral microvessels of normotensive and spontaneously hypertensive rats

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    Kobayashi, H.; Wada, A.; Izumi, F.; Magnoni, M.S.; Trabucchi, M.


    In rat cerebral microvessels, we characterized alpha 1- and alpha 2-adrenergic receptors, using (/sup 3/H)prazosin and (/sup 3/H)-p-amino-clonidine as radioligands. (/sup 3/H)Prazosin binding to the cerebral microvessels was saturable and of high affinity (dissociation constant of 78 pM), with a maximum binding of 48 fmol/mg protein. (/sup 3/H)Prazosin binding reached equilibrium within 15 minutes and was dissociated by the addition of 10 microM phentolamine. The inhibitory effects of isomers of norepinephrine and epinephrine on the binding showed that l-isomers were over 10 times more potent than d-isomers. (/sup 3/H)-p-Amino-clonidine binding to the cerebral microvessels was saturable and of high affinity (K/sub D/ . 0.61 nM) with a B/sub max/ of 73 fmol/mg protein. The binding reached equilibrium within 30 minutes, and was dissociated by the addition of 100 microM l-norepinephrine. l-Isomers of norepinephrine and epinephrine were over 10 times more potent than d-isomers in displacing the binding. Thus, both (/sup 3/H)prazosin and (/sup 3/H)-p-amino-clonidine bindings to the cerebral microvessels were characterized by saturability, high affinity, reversibility, and stereo-specificity. Furthermore, the specificity of both binding sites was pharmacologically evaluated by the inhibitory effects of various adrenergic agonists and antagonists on the bindings. These data indicate the existence of alpha-adrenergic receptors in the cerebral microvessels and are consistent with the hypothesis that the cerebral microcirculation is regulated by adrenergic innervation. Furthermore, the receptors were measured in cerebral microvessels of spontaneously hypertensive rats and Wistar-Kyoto controls.

  2. alpha-adrenergic Blockade Unmasks a Greater Compensatory Vasodilation in Hypoperfused Contracting Muscle

    Directory of Open Access Journals (Sweden)

    Darren P. Casey


    Full Text Available We previously demonstrated that acute hypoperfusion in exercising human muscle causes an immediate increase in vascular resistance that is followed by a partial restoration (less than 100% recovery of flow. In the current study we examined the contribution of alpha-adrenergic vasoconstriction in the initial changes in vascular resistance at the onset of hypoperfusion as well as in the recovery of flow over time. Nine healthy male subjects (29 ± 2 performed rhythmic forearm exercise (20% of maximum during hypoperfusion evoked by intra-arterial balloon inflation. Each trial included; baseline, exercise prior to inflation, exercise with inflation, and exercise after deflation (3 min each. Forearm blood flow (FBF; ultrasound, local (brachial artery, and systemic arterial pressure (MAP; Finometer were measured. The trial was repeated during phentolamine infusion (alpha-adrenergic receptor blockade. Forearm vascular conductance (FVC; ml min-1 100 mmHg-1 and resistance (mmHg ml min-1 was calculated from BF (ml min-1 and local MAP (mmHg. Recovery of FBF and FVC (steady state inflation plus exercise value – nadir/ [steady state exercise (control value-nadir] with phentolamine was enhanced compared with the respective control (no drug trial (FBF = 97 ± 5% vs. 81 ± 6%, P < 0.05; FVC = 126 ± 9% vs. 91 ± 5%, P < 0.01. However, the absolute (0.05 ± 0.01 vs. 0.06 ± 0.01 mmHg ml min-1; P = 0.17 and relative (35 ± 5% vs. 31 ± 2%; P = 0.41 increase in vascular resistance at the onset of balloon inflation was not different between the alpha-adrenergic receptor inhibition and control (no drug trials. Therefore, our data indicate that alpha-adrenergic mediated vasoconstriction restricts compensatory vasodilation during forearm exercise with hypoperfusion, but is not responsible for the initial increase in vascular resistance at the onset of hypoperfusion.

  3. α1A-adrenergic receptor mediated pressor response to phenylephrine in anesthetized rat

    Institute of Scientific and Technical Information of China (English)

    XU Qi; ZHU Weizhong; L(U) Zhizhen; ZHANG Youyi; HAN Qide


    To determine which subtype of α1A-adrenergic receptors plays a role in the regulation of blood pressure, with α1A-adrenergic receptor-mediated vasoconstriction in perfused hindlimb as a control, we compared the inhibitory effects of various α1A-adrenergic receptor selective antagonists on the vasopressure responses to phenylephrine between the mean arterial pressure and hindlimb perfusion pressure in anesthetized rats. In Normotensive Wistar rats, the results showed that the inhibitory effects (dose ratios of ED50, Dr) of α1A-adrenoceptor selective antagonist (prazosin, Dr 13.5 ± 3.6 vs.15.1 ± 4.3, n = 11), α1A-adrenoceptor selective antagonist (5- methyl-urapidil, Dr 2.4 ± 0.9 vs. 3.7 ± 2.3, n = 12; RS-17053, Dr 3.2 ± 1.6 vs. 4.4 ± 3.3, n =12) and α1D- adrenoceptor selective antagonist (BMY7378, Dr 1.9 ± 0.9 vs. 2.2 ± 0.8, n = 8) on phenylephrine- induced increases of perfusion pressure in the autoperfused femoral beds were the same as that in the mean arterial blood pressure in normotensive Wistar rats. The inhibitory effects of antagonists (RS-17053, Dr 3.4 ± 0.6 vs. 4.3 ± 0.9, n = 5; BMY7378, Dr 1.7±0.5 vs. 1.7 ± 0.5, n = 8) in spontaneous hypertensive rats were similar with the Wistar rats. These results suggest that the mean arterial pressure induced by phenylephrine was mainly mediated by α1A-adrenergic receptor in both the anesthetized Wistar rats and spontaneous hypertensive rats.

  4. Adrenergic signaling elements in the bladder wall of the adult rat. (United States)

    Persyn, Sara; Eastham, Jane; De Wachter, Stefan; Gillespie, James


    A growing body of work is describing the absence of a significant sympathetic innervation of the detrusor implying little sympathetic regulation of bladder contractility. However, low doses of adrenergic agonists are capable of relaxing the bladder smooth muscle. If these effects underpin a physiological response then the cellular nature and operation of this system are currently unknown. The present immunohistochemistry study was done to explore the existence of alternative adrenergic signaling elements in the rat bladder wall. Using antibodies to tyrosine hydroxylase (TH) and vesicular mono-amine transporter (vmat), few adrenergic nerves were found in the detrusor although TH immunoreactive (IR) nerves were apparent in the bladder neck. TH-IR and vmat-IR nerves were however abundant surrounding blood vessels. A population of vmat-IR cells was found within the network of interstitial cells that surround the detrusor muscle bundles. These vmat-IR cells were not or only weakly TH-IR. This suggests that these interstitial cells have the capacity to store and release catecholamines that may involve noradrenaline. Cells expressing the β1-adrenoceptor (β1AR-IR) were also detected within the interstitial cell network. Double staining with antibodies to β1AR and vmat suggests that the majority of vmat-IR interstitial cells show β1AR-IR indicative of an autocrine signaling system. In conclusion, a population of interstitial cells has the machinery to store, release and respond to catecholamines. Thus, there might exist a non-neuronal β-adrenergic system operating in the bladder wall possibly linked to one component of motor activity, micro-contractions, a system that may be involved in mechanisms underpinning bladder sensation.

  5. β2 adrenergic agonists in acute lung injury? The heart of the matter


    Lee, Jae W


    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of β2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to in...

  6. [The adrenergic innervation of the normal rat uterus and during pregnancy]. (United States)

    Rakitskaia, V V; Chudinov, Iu V; Shaliapina, V G


    Histochemical analysis revealed that, normally, the main amount of adrenergic fibers in the rat uterus is connected with vascular innervation. The amount of neural elements projecting to the muscle cells in insignificant. In pregnancy, the amount of fibers with the specific fluorescence decreases and they completely disappear from the myometrium in parturient rats. Biochemical analysis corroborated the finding that the noradrenaline level is considerably decreased at the time in sympathetic neurons innervating the uterus thus leading to a physiological "desympathization" of the organ.

  7. [Sleep disturbances in Smith-Magenis syndrome: treatment with melatonin and beta-adrenergic antagonists]. (United States)

    Van Thillo, A; Devriendt, K; Willekens, D


    Smith-Magenis syndrome is a generic disorder, characterised by physical, neurological and behavioural features and caused by a 17p11.2 deletion. Patients with this syndrome typically display an inversion of the sleep-wake cycle. In this article we describe clinical developments in a two-year-old girl with Smith-Magenis syndrome whose sleep problems were successfully treated with melatonin and beta-adrenergic blockers. We also mention relevant data obtained in our literature search.

  8. Minimum Alveolar Concentration for Blunting Adrenergic Responses (MAC-BAR) of Sevoflurane in Dogs


    YAMASHITA, Kazuto; FURUKAWA, Erika; ITAMI, Takaharu; ISHIZUKA, Tomohito; TAMURA, Jun; MIYOSHI, Kenjirou


    It is well known that heart rate or arterial blood pressure may increase in response to surgical stimulation despite the absence of a purposeful movement. However, there is limited information regarding anesthetic requirement for blunting adrenergic response in dogs. This study was designed to compare the minimum alveolar concentrations of sevoflurane required to prevent autonomic response (MAC-BAR) and purposeful movement (MAC) in dogs. Sevoflurane MAC-BAR and MAC were determined in 5 beagle...

  9. β3-adrenergic receptor gene, body mass index, bone mineral density and fracture risk in elderly men and women: the Dubbo Osteoporosis Epidemiology Study (DOES

    Directory of Open Access Journals (Sweden)

    Center Jacqueline R


    Full Text Available Abstract Background Recent studies have suggested that the Arg allele of β3-adrenergic receptor (ADRB3 gene is associated with body mass index (BMI, which is an important predictor of bone mineral density (BMD and fracture risk. However, whether the ADRB3 gene polymorphism is associated with fracture risk has not been investigated. The aim of study was to examine the inter-relationships between ADRB3 gene polymorphisms, BMI, BMD and fracture risk in elderly Caucasians. Methods Genotypes of the ADRB3 gene were determined in 265 men and 446 women aged 60+ in 1989 at entry into the study, whose BMD were measured by DXA (GE Lunar, WI USA at baseline. During the follow-up period (between 1989 and 2004, fractures were ascertained by reviewing radiography reports and personal interviews. Results The allelic frequencies of the Trp and the Arg alleles were 0.925 and 0.075 respectively, and the relative frequencies of genotypes Trp/Trp, Trp/Arg and Arg/Arg 0.857, 0.138 and 0.006 respectively. There was no significant association between BMI and ADRB3 genotypes (p = 0.10 in women and p = 0.68 in men. There was also no significant association between ADRB3 genotypes and lumbar spine or femoral neck BMD in either men and women. Furthermore, there were no significant association between ADRB3 genotypes and fracture risk in both women and men, either before or after adjusting for and, BMD and BMI. Conclusion The present data suggested that in Caucasian population the contribution of ADRB3 genotypes to the prediction of BMI, BMD and fracture risk is limited.

  10. The Relationship between Birthweight and Longitudinal Changes of Blood Pressure Is Modulated by Beta-Adrenergic Receptor Genes: The Bogalusa Heart Study

    Directory of Open Access Journals (Sweden)

    Wei Chen


    Full Text Available This study examines the genetic influence of β-adrenergic receptor gene polymorphisms (β2-AR Arg16Gly and β3-AR Trp64Arg on the relationship of birthweight to longitudinal changes of blood pressure (BP from childhood to adulthood in 224 black and 515 white adults, aged 21–47 years, enrolled in the Bogalusa Heart Study. Blacks showed significantly lower birthweight and frequencies of β2-AR Gly16 and β3-AR Trp64 alleles and higher BP levels and age-related trends than whites. In multivariable regression analyses using race-adjusted BP and birthweight, low birthweight was associated with greater increase in age-related trend of systolic BP (standardized regression coefficient β=−0.09, P=.002 and diastolic BP (β=−0.07, P=.037 in the combined sample of blacks and whites, adjusting for the first BP measurement in childhood, sex, age, and gestational age. Adjustment for the current body mass index strengthened the birthweight-BP association. Importantly, the strength of the association, measured as regression coefficients, was modulated by the combination of β2-AR and β3-AR genotypes for systolic (P=.042 for interaction and diastolic BP age-related trend (P=.039 for interaction, with blacks and whites showing a similar trend in the interaction. These findings indicate that the intrauterine programming of BP regulation later in life depends on β-AR genotypes.

  11. Polymorphism in Energetic Materials (United States)


    salicylic acid ) was first prepared by Charles Frederic Gerhardt in 1853, a second polymorph of this drug was not discovered until 2005. Studies have...the crystallization conditions post- synthesis were not recorded, reproducing the condi- tions resulting in the analyzed sample was not possible. All

  12. Investigation of Uranium Polymorphs

    Energy Technology Data Exchange (ETDEWEB)

    Sweet, Lucas E.; Henager, Charles H.; Hu, Shenyang Y.; Johnson, Timothy J.; Meier, David E.; Peper, Shane M.; Schwantes, Jon M.


    The UO3-water system is complex and has not been fully characterized, even though these species are common throughout the nuclear fuel cycle. As an example, most production schemes for UO3 result in a mixture of up to six or more different polymorphic phases, and small differences in these conditions will affect phase genesis that ultimately result in measureable changes to the end product. As a result, this feature of the UO3-water system may be useful as a means for determining process history. This research effort attempts to better characterize the UO3-water system with a variety of optical techniques for the purpose of developing some predictive capability for estimating process history in polymorphic phases of unknown origin. Three commercially relevant preparation methods for the production of UO3 were explored. Previously unreported low temperature routes to β- and γ-UO3 were discovered. Raman and fluorescence spectroscopic libraries were established for pure and mixed polymorphic forms of UO3 in addition to the common hydrolysis products of UO3. An advantage of the sensitivity of optical fluorescence microscopy over XRD has been demonstrated. Preliminary aging studies of the α and γ forms of UO3 have been conducted. In addition, development of a 3-D phase field model used to predict phase genesis of the system was initiated. Thermodynamic and structural constants that will feed the model have been gathered from the literature for most of the UO3 polymorphic phases.

  13. Single Nucleotide Polymorphism

    DEFF Research Database (Denmark)

    Børsting, Claus; Pereira, Vania; Andersen, Jeppe Dyrberg;


    Single nucleotide polymorphisms (SNPs) are the most frequent DNA sequence variations in the genome. They have been studied extensively in the last decade with various purposes in mind. In this chapter, we will discuss the advantages and disadvantages of using SNPs for human identification and bri...

  14. Teaching polymorphism early

    DEFF Research Database (Denmark)


    Is it possible to teach dynamic polymorphism early? What techniques could facilitate teaching it in Java. This panel will bring together people who have considered this question and attempted to implement it in various ways, some more completely than others. It will also give participants an oppo...

  15. Polymorphous Perversity in Texts (United States)

    Johnson-Eilola, Johndan


    Here's the tricky part: If we teach ourselves and our students that texts are made to be broken apart, remixed, remade, do we lose the polymorphous perversity that brought us pleasure in the first place? Does the pleasure of transgression evaporate when the borders are opened?

  16. Polymorphism of sorbitol (United States)

    Nezzal, Amale; Aerts, Luc; Verspaille, Marleen; Henderickx, Geert; Redl, Andreas


    The polymorphism of sorbitol was investigated, confirming the existence of four anhydrous crystalline phases plus the hydrate. The crystallised melt (CM), the alpha form, and the gamma form were obtained via a dry route. The CM was confirmed to be a crystalline state with a spherulite morphology. The alpha form was obtained via direct conversion from the CM, in contrast to more complicated routes previously reported, and was found to have a very high crystallinity. Gamma crystals were obtained by seeding the melt at high temperature; however, crystallinity was clearly less than for alpha crystals. Despite its lower crystallinity, the gamma polymorph was found to be the most stable of the anhydrous crystalline forms; this was confirmed by its high melting point and low hygroscopicity. In contrast, the alpha polymorph has a relatively high melting point but lacks moisture stability at high relative humidity. The hydrate form has the same resistance to moisture as the gamma form, but melts at a lower temperature. The combination of both a high melting point and high stability in the presence of water makes the gamma polymorph best suited for confectionary applications.

  17. Effects of central imidazolinergic and alpha2-adrenergic activation on water intake

    Directory of Open Access Journals (Sweden)

    Sugawara A.M.


    Full Text Available Non-adrenergic ligands that bind to imidazoline receptors (I-R, a selective ligand that binds to alpha2-adrenoceptors (alpha2-AR and mixed ligands that bind to both receptors were tested for their action on water intake behavior of 24-h water-deprived rats. All drugs were injected into the third cerebral ventricle. Except for agmatine (80 nmol, mixed ligands binding to I-R/alpha2-AR such as guanabenz (40 nmol and UK 14304 (20 nmol inhibited water intake by 65% and up to 95%, respectively. The selective non-imidazoline alpha2-AR agonist, alpha-methylnoradrenaline, produced inhibition of water intake similar to that obtained with guanabenz, but at higher doses (80 nmol. The non-adrenergic I-R ligands histamine (160 nmol, mixed histaminergic and imidazoline ligand and imidazole-4-acetic acid (80 nmol, imidazoline ligand did not alter water intake. The results show that selective, non-imidazoline alpha2-AR activation suppresses water intake, and suggest that the action on imidazoline sites by non-adrenergic ligands is not sufficient to inhibit water intake.

  18. Alpha adrenergic modulation of the Na/sup +/ pump of canine vascular smooth muscle

    Energy Technology Data Exchange (ETDEWEB)

    Navran, S.S.; Adair, S.E.; Allen, J.C.; Seidel, C.L.


    Some vasoactive agents, eg. beta adrenergic agonists and forskolin, stimulate the Na/sup 7/ pump by a cAMP- dependent mechanism. The authors have now demonstrated that phenylephrine (PE) stimulates the Na/sup 7/ pump in intact blood vessels as quantitated by an increased ouabain-sensitive /sup 86/Rb uptake. The stimulation is dose-dependent (ED/sub 50/, 3 x 10/sup -6/M) and blocked by phentolamine (I/sub 50/, 10/sup -7/M), prazosin (I/sub 50/, 10/sup -8/M) yohimbine (I/sub 50/, 10/sup -6/M) or elevated intracellular Na/sup +/. These data suggest that the Na/sup +/ pump stimulation is mediated through alpha/sub 1/ receptors which produce an influx of extracellular Na/sup +/. In vascular smooth muscle cell cultures PE stimulates the Na/sup +/ pump, but only when cells have been deprived of fetal calf serum (FCS). Since FCS is known to stimulate Na/sup +/influx, in the continuous presence of FCS, these cells may already be Na/sup +/-loaded and therefore refractory to further stimulation by alpha-adrenergic agents. Unlike those vasorelaxants whose mechanism involves stimulation of the Na/sup +/ pump, alpha adrenergic agents are vasoconstrictors and therefore the role of Na/sup +/ pump stimulation in this case may be as a mechanism of feedback inhibition of contractility.

  19. Alpha-1 adrenergic antagonists in aircrew for the treatment of benign prostatic hypertrophy. (United States)

    Matthies, Andrew K; Tachikawa, Nina J


    Benign prostatic hypertrophy (BPH) affects the majority of men later in life. Other than surgery, finasteride (Proscar) is currently the only pharmacologic option available for U.S. Air Force (USAF) aircrew. This article will evaluate the current literature regarding the treatment of benign prostatic hypertrophy with FDA approved tamsulosin (Flomax) and alfuzosin (Uroxatrol), third-generation alpha-1 adrenergic antagonists. Current literature supports the fact that some third-generation alpha blockers limit the side effects of hypotension when compared to other alpha blockers as a result of the specificity of subtype binding of the receptors and the sustained release formulation. Alpha blockers are currently used almost universally for the treatment of BPH; however, they are currently not approved for USAF aircrew. This article will review the aeromedical implications of the side effects of alpha-1 adrenergic antagonists (alfuzosin, tamsulosin), which affect aircrew while performing aeronautical duties, and examine whether alpha-1 adrenergic antagonists should be acceptable medications in certain situations depending on airframe and aeronautical duties.

  20. Brain beta-adrenergic receptor binding in rats with obesity induced by a beef tallow diet. (United States)

    Matsuo, T; Suzuki, M


    We have previously reported that compared with safflower oil diet, feeding a beef tallow diet leads to a greater accumulation of body fat by reducing sympathetic activities. The present study examined the effects of dietary fats consisting of different fatty acids on alpha1- and beta-adrenergic receptor binding in the hypothalamus and cerebral cortex. Male Sprague-Dawley rats were meal-fed isoenergetic diets based on safflower oil (rich in n-6 polyunsaturated fatty acids) or beef tallow (rich in saturated fatty acids) for 8 weeks. Binding affinities of the beta-adrenergic receptor in the hypothalamus and cortex were significantly lower in the beef tallow diet group, but those of the alpha1-receptor did not differ between the two groups. The polyunsaturated to saturated fatty acid (P/S) ratio and fluidities of plasma membranes in the hypothalamus and cortex were lower in the beef tallow diet group than in the safflower oil diet group. These results suggest that the beef tallow diet decreases membrane fluidity by altering the fatty acid composition of plasma membranes in the hypothalamus and cerebral cortex of rat. Consequently, beta-adrenergic receptor binding affinities in the brain were lower in rats fed the beef tallow diet than in rats fed the safflower oil diet. We recognized that there is possible link between the membrane fluidity and the changes in affinity of beta-adrenoceptors in rat brain.

  1. Adrenergic mechanism responsible for pathological alteration in gastric mucosal blood flow in rats with ulcer bleeding (United States)

    Semyachkina-Glushkovskaya, O. V.; Pavlov, A. N.; Semyachkin-Glushkovskiy, I. A.; Gekalyuk, A. S.; Ulanova, M. V.; Lychagov, V. V.; Tuchin, V. V.


    The adrenergic system plays an important role in regulation of central and peripheral circulation in normal state and during hemorrhage. Because the impaired gastric mucosal blood flow (GMBF) is the major cause of gastroduodenal lesions, including ulcer bleeding (UB), we studied the adrenergic mechanism responsible for regulation of GMBF in rats with a model of stress-induced UB (SUB) using the laser Doppler flowmetry (LDF). First, we examined the effect of adrenaline on GMBF in rats under normal state and during UB. In all healthy animals the submucosal adrenaline injection caused a decrease in local GMBF. During UB the submucosal injection of adrenaline was accompanied by less pronounced GMBF suppression in 30,3% rats with SUB vs. healthy ones. In 69,7% rats with SUB we observed the increase in local GMBF after submucosal injection of adrenaline. Second, we studied the sensitivity of gastric β2-adrenoreceptors and the activity of two factors which are involved in β2-adrenomediated vasorelaxation-KATP -channels and NO. The effects of submucosal injection of isoproterenol, ICI118551 and glybenclamide on GMBF as well as NO levels in gastric tissue were significantly elevated in rats with SUB vs. healthy rats. Thus, our results indicate that high activation of gastric β2-adrenoreceptors associated with the increased vascular KATP -channels activity and elevated NO production is the important adrenergic mechanism implicated in the pathogenesis of UB.


    Adefurin, Abiodun; Ghimire, Laxmi V.; Kohli, Utkarsh; Muszkat, Mordechai; Sofowora, Gbenga G.; Li, Chun; Levinson, Rebecca T.; Paranjape, Sachin Y.; Stein, C. Michael; Kurnik, Daniel


    α1B- adrenergic receptors contribute to vasoconstriction in humans. We tested the hypothesis that variation in the ADRA1B gene contributes to interindividual variability and ethnic differences in adrenergic vasoconstriction. We measured dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 41 African-Americans and genotyped 34 ADRA1B variants. We validated findings in another model of catecholamine-induced vasoconstriction, the increase in mean arterial pressure (ΔMAP) during a cold pressor test (CPT). One ADRA1B variant, rs10070745, present in 14 African-American heterozygotes but not in Caucasians, was associated with a lower phenylephrine ED50 (geometric mean [95% CI], 144 [69–299] ng/ml) compared to 27 African-American non-carriers (208 [130–334] ng/ml; P=0.015) and contributed to the ethnic differences in ED50. The same variant was also associated with a greater ΔMAP during CPT (P=0.008). In conclusion, ADRA1B rs10070745 was significantly associated with vasoconstrictor responses after adrenergic stimulation and contributed to the ethnic difference in phenylephrine sensitivity. PMID:27089938

  3. Cholesterol modulates the dimer interface of the β₂-adrenergic receptor via cholesterol occupancy sites. (United States)

    Prasanna, Xavier; Chattopadhyay, Amitabha; Sengupta, Durba


    The β2-adrenergic receptor is an important member of the G-protein-coupled receptor (GPCR) superfamily, whose stability and function are modulated by membrane cholesterol. The recent high-resolution crystal structure of the β2-adrenergic receptor revealed the presence of possible cholesterol-binding sites in the receptor. However, the functional relevance of cholesterol binding to the receptor remains unexplored. We used MARTINI coarse-grained molecular-dynamics simulations to explore dimerization of the β2-adrenergic receptor in lipid bilayers containing cholesterol. A novel (to our knowledge) aspect of our results is that receptor dimerization is modulated by membrane cholesterol. We show that cholesterol binds to transmembrane helix IV, and cholesterol occupancy at this site restricts its involvement at the dimer interface. With increasing cholesterol concentration, an increased presence of transmembrane helices I and II, but a reduced presence of transmembrane helix IV, is observed at the dimer interface. To our knowledge, this study is one of the first to explore the correlation between cholesterol occupancy and GPCR organization. Our results indicate that dimer plasticity is relevant not just as an organizational principle but also as a subtle regulatory principle for GPCR function. We believe these results constitute an important step toward designing better drugs for GPCR dimer targets.

  4. The impact of beta-adrenergic blockade on daily rhythms of melatonin and body temperature of golden spiny mice Acomys russatus. (United States)

    Haim, A; Zisapel, N


    Beta-adrenergic stimulation induces melatonin synthesis and non-shivering thermogenesis (NST) in rodents. The golden spiny mouse, Acomys russatus is a nocturnal species capable of diurnal activity when coexisting with its congenitor the common spiny mouse A. cahirinus. We have investigated the impact of beta-adrenergic blockade on 6-sulphatoxymelatonin (6-SMT--a metabolite and index of melatonin production) and body temperature (Tb) daily rhythms in male A. russatus. Mice were acclimated to an ambient temperature (Ta) of 28 degrees C, under two photoperiod regimes (16L:8D; 8L:16D). The daily rhythms of Tb and urinary 6-SMT were measured for a period of 30 h at intervals of 4 h. Propranolol (4.5 mg/kg, i.p.) was administered one hour before lights went off (i.e. when beta blockade does not affect NST in this species) and both variables were measured for another 30 h. The beta blocker markedly augmented melatonin output of A. russatus under both photoperiod regimes. The elevation in melatonin secretion was accompanied with an increase in Tb of only 16L:8D-acclimated mice (i.e. shorten duration of melatonin peak). However, in 8L:16D-acclimated mice, a phase advance of about 4 h was noted in 6-SMT daily rhythm. These results indicate that the role of sympathetic innervation in regulation of melatonin synthesis in A. russatus differs from that in the rat. In addition, these data are compatible with the hyperthermic action of melatonin in this species. Therefore, it is suggested that in A. russatus, other neural pathways are involved in its pineal regulation.

  5. Loss of bone marrow adrenergic beta 1 and 2 receptors modifies transcriptional networks, reduces circulating inflammatory factors, and regulates blood pressure. (United States)

    Ahmari, Niousha; Schmidt, Jordan T; Krane, Gregory A; Malphurs, Wendi; Cunningham, Bruce E; Owen, Jennifer L; Martyniuk, Christopher J; Zubcevic, Jasenka


    Hypertension (HTN) is a prevalent condition with complex etiology and pathophysiology. Evidence exists of significant communication between the nervous system and the immune system (IS), and there appears to be a direct role for inflammatory bone marrow (BM) cells in the pathophysiology of hypertension. However, the molecular and neural mechanisms underlying this interaction have not been characterized. Here, we transplanted whole BM cells from the beta 1 and 2 adrenergic receptor (AdrB1(tm1Bkk)AdrB2(tm1Bkk)/J) knockout (KO) mice into near lethally irradiated C57BL/6J mice to generate a BM AdrB1.B2 KO chimera. This allowed us to evaluate the role of the BM beta 1 and beta 2 adrenergic receptors in mediating BM IS homeostasis and regulating blood pressure (BP) in an otherwise intact physiological setting. Fluorescence-activated cell sorting demonstrated that a decrease in systolic and mean BP in the AdrB1.B2 KO chimera is associated with a decrease in circulating inflammatory T cells, macrophage/monocytes, and neutrophils. Transcriptomics in the BM identified 7,419 differentially expressed transcripts between the C57 and AdrB1.B2 KO chimera. Pathway analysis revealed differentially expressed transcripts related to several cell processes in the BM of C57 compared with AdrB1.B2 KO chimera, including processes related to immunity (e.g., T-cell activation, T-cell recruitment, cytokine production, leukocyte migration and function), the cardiovascular system (e.g., blood vessel development, peripheral nerve blood flow), and the brain (e.g., central nervous system development, neurite development) among others. This study generates new insight into the molecular events that underlie the interaction between the sympathetic drive and IS in modulation of BP.

  6. Intracoronary genistein acutely increases coronary blood flow in anesthetized pigs through beta-adrenergic mediated nitric oxide release and estrogenic receptors. (United States)

    Grossini, Elena; Molinari, Claudio; Mary, David A S G; Uberti, Francesca; Caimmi, Philippe Primo; Surico, Nicola; Vacca, Giovanni


    Various studies have suggested that the phytoestrogen genistein has beneficial cardioprotective and vascular effects. However, there has been scarce information regarding the primary effect of genistein on coronary blood flow and its mechanisms including estrogen receptors, autonomic nervous system, and nitric oxide (NO). The present study was planned to determine the primary effect of genistein on coronary blood flow and the mechanisms involved. In anesthetized pigs, changes in left anterior descending coronary artery caused by intracoronary infusion of genistein at constant heart rate and arterial pressure were assessed using ultrasound flowmeters. In 25 pigs, genistein infused at 0.075 mg/min increased coronary blood flow by about 16.3%. This response was graded in a further five pigs by increasing the infused dose of the genistein between 0.007 and 0.147 mg/min. In the 25 pigs, blockade of cholinergic receptors (iv atropine; five pigs) and alpha-adrenergic receptors (iv phentolamine; five pigs) did not abolish the coronary response to genistein, whose effects were prevented by blockade of beta(2)-adrenergic receptors (iv butoxamine; five pigs), nitric oxide synthase (intracoronary N(omega)-nitro-L-arginine methyl ester; five pigs) and estrogenic receptors (ERs; ERalpha/ERbeta; intracoronary fulvestrant; five pigs). In porcine aortic endothelial cells, genistein induced the phosphorylation of endothelial nitric oxide synthase and NO production through ERK 1/2, Akt, and p38 MAPK pathways, which was prevented by the concomitant treatment by butoxamine and fulvestrant. In conclusion, genistein primarily caused coronary vasodilation the mechanism of which involved ERalpha/ERbeta and the release of NO through vasodilatory beta(2)-adrenoreceptor effects.

  7. Ischemia- and agonist-induced changes in. alpha. - and. beta. -adrenergic receptor traffic in guinea pig hearts

    Energy Technology Data Exchange (ETDEWEB)

    Maisel, A.S.; Motulsky, H.J.; Ziegler, M.G.; Insel, P.A. (Univ. of California, La Jolla (USA))


    The authors have used radioligand binding techniques and subcellular fraction to assess whether changes in expression of myocardial {alpha}{sub 1}- and {beta}-adrenergic receptors are mediated by a redistribution of receptors between various membrane fractions. Three fractions were prepared from the left ventricles of guinea pigs that underwent either 1 h of ischemia or injection of epinephrine a crude membrane, a purified sarcolemma, and a light vesicle fraction. In control animals {alpha}{sub 1}-adrenergic receptors (({sup 3}H)prazosin binding) in light vesicles was only 25% of the total {alpha}{sub 1}-receptor density found in sarcolemmal and light vesicle fractions as compared with 50% for {beta}-adrenergic receptors (({sup 125}I)iodocyanopindolol binding sites). Although ischemia was associated with a 53% decrease in the number of light vesicle {beta}-adrenergic receptors and a 42% increase in the number of sarcolemma {beta}-receptors there was no change in the number of light vesicle {alpha}{sub 1}-receptors, even though the number of sarcolemmal {alpha}{sub 1}-receptors increased 34%. Epinephrine treatment promoted internalization of {beta}-adrenergic receptors. These results indicate that {alpha}{sub 1} and {beta}{sub 1}-adrenergic receptors may undergo a different cellular itinerary in guinea pig myocardium. Agonist and ischemia-induced changes in surface {beta}-receptors, but not {alpha}{sub 1}-receptors, appear to result from entry and exit of receptors from an intracellular pool that can be isolated in a light vesicle fraction. Changes in expression of {alpha}{sub 1}-adrenergic receptors may represent changes in the properties of receptors found in the sarcolemma or in a membrane fraction other than the light vesicle fraction that they have isolated.

  8. Propranolol represses infantile hemangioma cell growth through the β2-adrenergic receptor in a HIF-1α-dependent manner. (United States)

    Li, Peng; Guo, Zhengtuan; Gao, Ya; Pan, Weikang


    Propranolol, as a non-selective blocker of the β-adrenergic receptor (AR), is utilised as the first-line treatment for infantile hemangiomas. However, the underlying mechanism remains poorly understood. The present study was designed to investigate the molecular basis of propranolol on the regression of infantile hemangiomas using a proliferating infantile hemangioma-derived endothelial cell line. In infantile hemangioma patients, we found that propranolol significantly decreased the expression levels of the hypoxia inducible factor (HIF)-1α in serum and urine, as well as in hemangioma tissues. In vitro analysis revealed that propranolol reduces the expression of HIF-1α in hemangioma cells in a dose- and time-dependent manner, mainly by acting on β2-AR. Interestingly, it was observed that overexpression of HIF-1α apparently abrogated the inhibitory effects of propranolol on vascular endothelial growth factor (VEGF) expression and cell growth. Our data further demonstrated that propranolol inhibited the signal transducer and activator of transcription 3 (STAT3), a critical oncogenic signaling molecule, and the anti-apoptotic protein Bcl-2. Additionally, overexpression of HIF-1α significantly reversed the inhibitory effects of propranolol on STAT3 signaling. In a mouse xenograft hemangioma model, overexpression of HIF-1α significantly attenuated the therapeutic effects of propranolol and inhibited propranolol-induced hemangioma cell apoptosis. Moreover, the protein levels of VEGF, phosphorylated STAT3, total STAT3 and Bcl-2 were significantly upregulated by HIF-1α overexpression in propranolol-treated nude mice bearing hemangiomas. Collectively, our data provide evidence that propranolol may regress infantile hemangiomas by suppressing VEGF and STAT3 signaling pathways in an HIF-1α-dependent manner.

  9. Leaf extract from Clusia nemorosa induces an antinociceptive effect in mice via a mechanism that is adrenergic systems dependent

    Institute of Scientific and Technical Information of China (English)

    Jamylle Nunes de Souza Ferro; Juliane Pereira da Silva; Lucia Maria Conserva; Emiliano Barreto


    Previous studies on the genus Clusia have shown anti-inflammatory and antiproliferative effects of the leaf extracts,but its antinociceptive activity has never been characterized.In the present study,the antinociceptive activity of the hexane extract of the leaves of Clusia nemorosa G.Mey,called HECn,was examined.Antinociceptive activity was evaluated using acetic acid-induced writhing,formalin,and hot-plate tests.All experiments were carried out on male Swiss mice.The extract (1-400 mg·kg-1),given by intraperitoneal route (i.p.) 1 h prior to testing,produced a dose-dependent inhibition on the number of abdominal writhings,with an ID50 of 62 mg·kg-1.In addition,HECn was able to prevent the visceral pain induced by acetic acid in mice for at least 2 h.In the formalin test,HECn had no effect in the first phase,but produced an analgesic effect on the second phase with the inhibition of licking time.The HECn did not show a significant analgesic effect in the hot plate test.Pretreatment with yohimbine attenuated the antinociceptive effect induced by HECn in the writhing test.However,naloxone,atropine,or haloperidol did not affect antinociception induced by HECn in the writhing test.Together,these results indicate that the extract from the leaves of Clusia nemorosa produces antinociception in models of chemical pain through mechanisms that suggest participation of the adrenergic systems pathway.

  10. Norepinephrine depresses the immunity and disease-resistance ability via α1- and β1-adrenergic receptors of Macrobrachium rosenbergii. (United States)

    Chang, Chin-Chyuan; Hung, Ming-Di; Cheng, Winton


    In this study, we determined the effects of norepinephrine (NE) on immunity and the pathway of its function in the freshwater giant prawn, Macrobrachium rosenbergii. The total hemocyte count (THC), differential hemocyte count (DHC), phenoloxidase activity, respiratory bursts, superoxide dismutase (SOD) activity, phagocytic activity, and clearance efficiency in response to the pathogen, Lactococcus garvieae, were measured when the freshwater giant prawn, M. rosenbergii (16.2±2.1 g) was individually injected with saline or NE at 0.5, 5.0, and 50.0 pmol prawn(-1). Results showed that semi-granular cells, respiratory bursts and phagocytic activity at 2 h, PO activity and clearance efficiency from 2 to 4 h, THC at 8 h, and SOD activity from 4 to 8 h significantly decreased, but hyaline cells at 2 h, and respiratory bursts at 8 h had significantly increased after injection of NE at 50.0 pmol prawn(-1). In prawns that had received 5.0 pmol NE prawn(-1), the PO activity had decreased at 2 h, SOD activity at 8 h, and the clearance efficiency at 2 h. PO activity had decreased at 2 h after prawns had received 0.5 pmol NE prawn(-1). All of the immune parameters had returned to control values by 16 h after receiving NE. However, no significant differences were observed in the granular cells during the experimental period. An injection of NE also significantly increased the mortality of prawns challenged with L. garvieae, which appeared to be dose dependent. In another experiment, NE co-injected with prazosin, metoprolol, or propranolol significantly decreased the mortality of challenged prawns, especially when co-injected with prazosin and metoprolol. These results suggest that stress-inducing NE suppresses the immune system, which in turn promotes the susceptibility of M. rosenbergii to L. garvieae via both α1- and β1-adrenergic receptors.

  11. Combining opioid and adrenergic mechanisms for chronic pain. (United States)

    Smith, Howard S; Raffa, Robert B; Pergolizzi, Joseph V; Taylor, Robert; Tallarida, Ronald J


    Chronic pain is a highly prevalent medical problem in the United States. Although opioids and serotonin-norepinephrine reuptake inhibitors (SNRIs) have demonstrated efficacy for relief of chronic pain, each has risks of adverse events in patients. Because of the risk of opioid abuse and addiction, combinations reducing opioid requirements are particularly valuable. Opioid and SNRI agents relieve pain by different pathways; concurrent use of each agent separately offers many potential benefits: complementary and possibly synergistic analgesic efficacy, separate titrations of opioid and SNRI effects, and the reduction of opioid requirements. However, few clinical studies have investigated the ideal ratios for combinations of opioids and SNRIs. A number of factors affect whether specific combinations have additive, synergistic, less than additive efficacy, or increase adverse events in patients, including general pharmacokinetic considerations, the potential for pharmacodynamic drug interactions, dose, and timing. Because there is little clinical evidence guiding combination therapy with separate opioid and SNRI agents, using single-molecule agents provides safe and effective therapy and should be the first option presented to patients. The use of empiric combinations of separate opioid and SNRI combinations needs to be considered in light of clinical cautions, including the lack of published evidence to guide dose conversion from any opioid to tramadol or to tapentadol, and vice versa; the need to avoid combinations with known drug interactions; and the need to titrate the dose when adding an SNRI to an opioid, and vice versa.

  12. Norepinephrine-Induced Adrenergic Activation Strikingly Increased the Atrial Fibrillation Duration through β1- and α1-Adrenergic Receptor-Mediated Signaling in Mice.

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    Kenji Suita

    Full Text Available Atrial fibrillation (AF is the most common arrhythmias among old people. It causes serious long-term health problems affecting the quality of life. It has been suggested that the autonomic nervous system is involved in the onset and maintenance of AF in human. However, investigation of its pathogenesis and potential treatment has been hampered by the lack of suitable AF models in experimental animals.Our aim was to establish a long-lasting AF model in mice. We also investigated the role of adrenergic receptor (AR subtypes, which may be involved in the onset and duration of AF.Trans-esophageal atrial burst pacing in mice could induce AF, as previously shown, but with only a short duration (29.0 ± 8.1 sec. We found that adrenergic activation by intraperitoneal norepinephrine (NE injection strikingly increased the AF duration. It increased the duration to more than 10 minutes, i.e., by more than 20-fold (656.2 ± 104.8 sec; P<0.001. In this model, a prior injection of a specific β1-AR blocker metoprolol and an α1-AR blocker prazosin both significantly attenuated NE-induced elongation of AF. To further explore the mechanisms underlying these receptors' effects on AF, we assessed the SR Ca(2+ leak, a major trigger of AF, and consequent spontaneous SR Ca(2+ release (SCR in atrial myocytes. Consistent with the results of our in-vivo experiments, both metoprolol and prazosin significantly inhibited the NE-induced SR Ca(2+ leak and SCR. These findings suggest that both β1-AR and α1-AR may play important roles in the development of AF.We have established a long-lasting AF model in mice induced by adrenergic activation, which will be valuable in future AF study using experimental animals, such as transgenic mice. We also revealed the important role of β1- and α1-AR-mediated signaling in the development of AF through in-vivo and in-vitro experiments.

  13. Developmental and diurnal dynamics of Pax4 expression in the mammalian pineal gland: nocturnal down-regulation is mediated by adrenergic-cyclic adenosine 3',5'-monophosphate signaling. (United States)

    Rath, Martin F; Bailey, Michael J; Kim, Jong-So; Ho, Anthony K; Gaildrat, Pascaline; Coon, Steven L; Møller, Morten; Klein, David C


    Pax4 is a homeobox gene that is known to be involved in embryonic development of the endocrine pancreas. In this tissue, Pax4 counters the effects of the related protein, Pax6. Pax6 is essential for development of the pineal gland. In this study we report that Pax4 is strongly expressed in the pineal gland and retina of the rat. Pineal Pax4 transcripts are low in the fetus and increase postnatally; Pax6 exhibits an inverse pattern of expression, being more strongly expressed in the fetus. In the adult the abundance of Pax4 mRNA exhibits a diurnal rhythm in the pineal gland with maximal levels occurring late during the light period. Sympathetic denervation of the pineal gland by superior cervical ganglionectomy prevents the nocturnal decrease in pineal Pax4 mRNA. At night the pineal gland is adrenergically stimulated by release of norepinephrine from the sympathetic innervation; here, we found that treatment with adrenergic agonists suppresses pineal Pax4 expression in vivo and in vitro. This suppression appears to be mediated by cAMP, a second messenger of norepinephrine in the pineal gland, based on the observation that treatment with a cAMP mimic reduces pineal Pax4 mRNA levels. These findings suggest that the nocturnal decrease in pineal Pax4 mRNA is controlled by the sympathetic neural pathway that controls pineal function acting via an adrenergic-cAMP mechanism. The daily changes in Pax4 expression may influence gene expression in the pineal gland.

  14. Signaling pathways in failing human heart muscle cells. (United States)

    Drexler, H; Hasenfuss, G; Holubarsch, C


    Experimental studies have delineated important signaling pathways in cardiomyocytes and their alterations in heart failure; however, there is now evidence that these observations are not necessarily applicable to human cardiac muscle cells. For example, angiotensin II (A II) does not exert positive inotropic effects in human ventricular muscle cells, in contrast to observation in rats. Thus, it is important to elucidate cardiac signaling pathways in humans in order to appreciate the functional role of neurohumoral or mechanical stimulation in human myocardium in health and disease. In the present article, we review signal pathways in the failing human heart based on studies in human cardiac tissues and in vivo physiological studies related to A II, nitric oxide, and β-adrenergic stimulation. (Trends Cardiovasc Med 1997; 7:151-160). © 1997, Elsevier Science Inc.

  15. Facts and fictions about polymorphism. (United States)

    Cruz-Cabeza, Aurora J; Reutzel-Edens, Susan M; Bernstein, Joel


    We present new facts about polymorphism based on (i) crystallographic data from the Cambridge Structural Database (CSD, a database built over 50 years of community effort), (ii) 229 solid form screens conducted at Hoffmann-La Roche and Eli Lilly and Company over the course of 8+ and 15+ years respectively and (iii) a dataset of 446 polymorphic crystals with energies and properties computed with modern DFT-d methods. We found that molecular flexibility or size has no correlation with the ability of a compound to be polymorphic. Chiral molecules, however, were found to be less prone to polymorphism than their achiral counterparts and compounds able to hydrogen bond exhibit only a slightly higher propensity to polymorphism than those which do not. Whilst the energy difference between polymorphs is usually less than 1 kcal mol(-1), conformational polymorphs are capable of differing by larger values (up to 2.5 kcal mol(-1) in our dataset). As overall statistics, we found that one in three compounds in the CSD are polymorphic whilst at least one in two compounds from the Roche and Lilly set display polymorphism with a higher estimate of up to three in four when compounds are screened intensively. Whilst the statistics provide some guidance of expectations, each compound constitutes a new challenge and prediction and realization of targeted polymorphism still remains a holy grail of materials sciences.

  16. β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway

    Directory of Open Access Journals (Sweden)

    Zhang Dong


    Full Text Available Abstract Background Smoking and stress, pancreatic cancer (PanCa risk factors, stimulate nitrosamine 4-(methylnitrosamino-1-(3-pyridyl-1-butanone (NNK and catecholamines production respectively. NNK and catecholamine bind the β-adrenoceptors and induce PanCa cell proliferation; and we have previously suggested that β-adrenergic antagonists may suppress proliferation and invasion and stimulate apoptosis in PanCa. To clarify the mechanism of apoptosis induced by β2-adrenergic antagonist, we hypothesize that blockage of the β2-adrenoceptor could induce G1/S phase arrest and apoptosis and Ras may be a key player in PanCa cells. Results The β1 and β2-adrenoceptor proteins were detected on the cell surface of PanCa cells from pancreatic carcinoma specimen samples by immunohistochemistry. The β2-adrenergic antagonist ICI118,551 significantly induced G1/S phase arrest and apoptosis compared with the β1-adrenergic antagonist metoprolol, which was determined by the flow cytometry assay. β2-adrenergic antagonist therapy significantly suppressed the expression of extracellular signal-regulated kinase, Akt, Bcl-2, cyclin D1, and cyclin E and induced the activation of caspase-3, caspase-9 and Bax by Western blotting. Additionally, the β2-adrenergic antagonist reduced the activation of NFκB in vitro cultured PanCa cells. Conclusions The blockage of β2-adrenoceptor markedly induced PanCa cells to arrest at G1/S phase and consequently resulted in cell death, which is possibly due to that the blockage of β2-adrenoceptor inhibited NFκB, extracellular signal-regulated kinase, and Akt pathways. Therefore, their upstream molecule Ras may be a key factor in the β2-adrenoceptor antagonist induced G1/S phase arrest and apoptosis in PanCa cells. The new pathway discovered in this study may provide an effective therapeutic strategy for PanCa.

  17. Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

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    Choi, Yoon Jung [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Lee, Jue Yeon [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Lee, Seung Jin [Department of Industrial Pharmacy, College of Pharmacy, Ewha Womans University, Seoul (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Chung, Chong-Pyoung [Department of Periodontology, School of Dentistry, Seoul National University, Seoul (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Park, Yoon Jeong, E-mail: [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of)


    Highlights: Black-Right-Pointing-Pointer Doxazocin directly up-regulated bone metabolism at a low dose. Black-Right-Pointing-Pointer Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. Black-Right-Pointing-Pointer This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor {gamma}, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and

  18. Effect Of α2-Adrenergic Agonists And Antagonists On Cytokine Release From Human Lung Macrophages Cultured In Vitro (United States)

    Piazza, O.; Staiano, R.I.; De Robertis, E.; Conti, G.; Di Crescenzo, V.; Loffredo, S.; Marone, G.; Marinosci, G. Zito; Cataldi, M. M.


    The most trusted hypothesis to explain how α2-adrenergic agonists may preserve pulmonary functions in critically ill patients is that they directly act on macrophages by interfering with an autocrine/paracrine adrenergic system that controls cytokine release through locally synthetized noradrenaline and α1- and α2-adrenoreceptors. We tested this hypothesis in primary cultures of resident macrophages from human lung (HLMs). HLMs were isolated by centrifugation on percoll gradients from macroscopically healthy human lung tissue obtained from four different patients at the time of lung resection for cancer. HLMs from these patients showed a significant expression of α2A, α2B and α2C adrenoreceptors both at the mRNA and at the protein level. To evaluate whether α2 adrenoreceptors controlled cytokine release from HMLs, we measured IL-6, IL-8 and TNF-α concentrations in the culture medium in basal conditions and after preincubation with several α2-adrenergic agonists or antagonists. Neither the pretreatment with the α2-adrenergic agonists clonidine, medetomidine or dexdemetomidine or with the α2-adrenergic antagonist yohimbine caused significant changes in the response of any of these cytokines to LPS. These results show that, different from what reported in rodents, clonidine and dexdemetomidine do not directly suppress cytokine release from human pulmonary macrophages. This suggests that alternative mechanisms such as effects on immune cells activation or the modulation of autonomic neurotransmission could be responsible for the beneficial effects of these drugs on lung function in critical patients. PMID:27896229

  19. β-Adrenergic receptor agonist increases voltage-gated Na(+) currents in medial prefrontal cortex pyramidal neurons. (United States)

    Szulczyk, Bartlomiej


    The prefrontal cortex does not function properly in neuropsychiatric diseases and during chronic stress. The aim of this study was to test the effects of isoproterenol, a β-adrenergic receptor agonist, on the voltage-dependent fast-inactivating Na(+) currents in medial prefrontal cortex (mPFC) pyramidal neurons obtained from young rats. The recordings were performed in the cell-attached configuration. Isoproterenol (2μM) did not change the peak Na(+) current amplitude but shifted the IV curve of the Na(+) currents toward hyperpolarization. Pretreatment of the cells with the β-adrenergic antagonists propranolol and metoprolol abolished the effect of isoproterenol on the Na(+) currents, suggesting the involvement of β1-adrenergic receptors. The effect of β-adrenergic receptor stimulation on the sodium currents was dependent on kinase A and kinase C; the effect was diminished in the presence of the kinase A antagonist H-89 and the kinase C antagonist chelerythrine and abolished when the antagonists were coapplied. Moreover, isoproterenol depolarized the membrane potential recorded using the perforated-patch method, and this depolarization was abolished by cesium ions. Thus, in mPFC pyramidal neurons, stimulation of β-adrenergic receptors up-regulates the fast-inactivating voltage-gated Na(+) currents evoked by suprathreshold depolarizations.

  20. Electrical Stimulation Decreases Coupling Efficiency Between Beta-Adrenergic Receptors and Cyclic AMP Production in Cultured Muscle Cells (United States)

    Young, R. B.; Bridge, K. Y.


    Electrical stimulation of skeletal muscle cells in culture is an effective way to simulate the effects of muscle contraction and its effects on gene expression in muscle cells. Expression of the beta-adrenergic receptor and its coupling to cyclic AMP synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this project was to determine if electrical stimulation altered the beta-adrenergic response in muscle cells. Chicken skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. At the end of this two-day stimulation period, beta-adrenergic receptor population was measured by the binding of tritium-labeled CGP-12177 to muscle cells, and coupling to cAMP synthesis was measured by Radioimmunoassay (RIA) after treating the cells for 10 min with the potent (beta)AR agonist, isoproterenol. The number of beta adrenergic receptors and the basal levels of intracellular cyclic AMP were not affected by electrical stimulation. However, the ability of these cells to synthesize cyclic AMP was reduced by approximately 50%. Thus, an enhanced level of contraction reduces the coupling efficiency of beta-adrenergic receptors for cyclic AMP production.

  1. Prostaglandin (PG) E3 synthesis elicted by adrenergic stimuli in guinea-pig trachea (GPT) is mediated primarily by B2 adrenergic receptors

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    Nadel, G.L.; Malik, K.U.; Lew, D.B. (Univ. of Tennessee, Memphis (United States))


    The purpose of this study was to examine arachidonic acid (AA) metabolism and to characterize the type of adrenergic receptor (AR) involved in the production of the major metabolite of this fatty acid. ({sup 14}C)AA was incubated with GPT-rings and the radiolabelled products were extracted and separated by TLC method. The medium was also assayed for radiolabelled immunoreactive PG's (iPG's) and leukotrienes (LT) B4 and C4 by RIA or Enzyme immunoassay (EIA) after exposure to various AR agonists. ({sup 14}C)AA was incorporated into GPT-rings and metabolized mainly into iPGE2 and smaller amounts into PGF2{alpha}. Trace amounts of PGD2 and 6-keto-PGF1{alpha} but not LTB4 or LTC4 were detected by RIA and/or EIA. Incubation of GPT rings for 15 minutes with isoproterenol and salbutamol resulted in a significant increase of PGE2 synthesis (optimum conc: 10{sup {minus}7}, 10{sup {minus}7}M respectively). In contrast, dobutamine, norepinephrine, phenylnephrine and xylazine (up to 10{sup {minus}6}M) did not significantly increase PGE2 production. Isoproterenol-induced iPGE2 production was inhibited by a selective {beta}2 antagonist, butoxamine (70%: 10{sup {minus}7}M, 91%: 10{sup {minus}6}M) and somewhat reduced by {beta}1 antagonists practolol and metoprolol (30-64%:10{sup {minus}6}M). These data suggest that isoproterenol induced iPGE2 synthesis is primarily mediated via activation of {beta}2 adrenergic receptor.

  2. Determinants Present in the Receptor Carboxy Tail Are Responsible for Differences in Subtype-Specific Coupling of β-Adrenergic Receptors to Phosphoinositide 3-Kinase

    Directory of Open Access Journals (Sweden)

    Julie Simard


    Full Text Available An agonist-occupied β2-adrenergic receptor (β2-AR recruits G protein receptor kinase-2 (GRK2 which is recruited to the membrane. Thus, the physical proximity of activated β2-AR and PI-3K allows the activation of the latter. In contrast, it has been observed that the β1-AR is unable to activate the PI-3K/Akt pathway. We hypothesized that the difference might be due to molecular determinants present in the carboxy termini of the two β-AR subtypes. Using transiently transfected HEK 293 cells expressing either β1- or β2-AR, we also observed that in presence of an agonist, β2-AR, but not β1-AR, is able to activate the PI-3K/Akt pathway. Switching the seventh transmembrane domain and the carboxy tail between the two receptors reverses this phenotype; that is, β1×β2-AR can activate the PI-3K/Akt pathway whereas β2×β1-AR cannot. Pretreatment with pertussis toxin abolished the activation of PI-3K by β2- or β1×β2-AR stimulation. Ligand-mediated internalization of the β2-AR induced by a 15-minute stimulation with agonist was abolished in the presence of a dominant negative of PI-3K or following pertussis toxin pretreatment. These results indicate that the subtype-specific differences in the coupling to PI-3K/Akt pathway are due to molecular determinants present in the carboxy tail of the receptor and further that β2-AR activates PI-3K via a pertussis toxin-sensitive mechanism.

  3. No association between MspI allele of the ADRA2A polymorphism and ADHD: meta-analysis of family-based studies. (United States)

    Shiffrin, Nina D; Gruber, June; Glatt, Stephen J; Faraone, Stephen V


    There is evidence for a genetic contribution to attention-deficit hyperactivity disorder (ADHD), although no candidate genes have attained genome-wide significance to date. Given that the noradrenergic system has been implicated in ADHD, the gene for the α2-adrenergic receptor (ADRA2A) has been hypothesized to contribute to the pathogenesis of ADHD. The present investigation reports results from a meta-analysis of family-based studies that did not find a significant association between the MspI polymorphism of the ADRA2A gene and ADHD.

  4. Investigation of the Polymorphs and Hydrolysis of Uranium Trioxide

    Energy Technology Data Exchange (ETDEWEB)

    Sweet, Lucas E.; Blake, Thomas A.; Henager, Charles H.; Hu, Shenyang Y.; Johnson, Timothy J.; Meier, David E.; Peper, Shane M.; Schwantes, Jon M.


    This work focuses on progress in gaining a better understanding of the polymorphic nature of the UO3-water system, one of several important materials associated with the nuclear fuel cycle. The UO3-water system is complex and has not been fully characterized, even though these species are common throughout the fuel cycle. Powder x-ray diffraction, Raman and fluorescence characterization was performed on polymorphic forms of UO3 and UO3 hydrolysis products for the purpose of developing some predictive capability of estimating process history and utility, e.g. for polymorphic phases of unknown origin. Specifically, we have investigated three industrially relevant production pathways of UO3 and discovered a previously unknown low temperature route to β-UO3. Pure phases of UO3, hydrolysis products and starting materials were used to establish optical spectroscopic signatures for these compounds.

  5. Cyclic Adenosine Monophosphate Accumulation and beta-Adrenergic Binding in Unweighted and Denervated Rat Soleus Muscle (United States)

    Kirby, Christopher R.; Woodman, Christopher R.; Woolridge, Dale; Tischler, Marc E.


    Unweighting, but not denervation, of muscle reportedly "spares" insulin receptors, increasing insulin sensitivity. Unweighting also increases beta-adrenergic responses of carbohydrate metabolism. These differential characteristics were studied further by comparing cyclic adenosine monophosphate (cAMP) accumulation and beta-adrenergic binding in normal and 3-day unweighted or denervated soleus muscle. Submaximal amounts of isoproterenol, a p-agonist, increased cAMP accumulation in vitro and in vivo (by intramuscular (IM) injection) to a greater degree (P less than .05) in unweighted muscles. Forskolin or maximal isoproterenol had similar in vitro effects in all muscles, suggesting increased beta-adrenergic sensitivity following unweighting. Increased sensitivity was confirmed by a greater receptor density (B(sub max)) for iodo-125(-)-pindolol in particulate preparations of unweighted (420 x 10(exp -18) mol/mg muscle) than of control or denervated muscles (285 x 10(exp-18) mol/mg muscle). The three dissociation constant (Kd) values were similar (20.3 to 25.8 pmol/L). Total binding capacity (11.4 fmol/muscle) did not change during 3 days of unweighting, but diminished by 30% with denervation. This result illustrates the "sparing" and loss of receptors, respectively, in these two atrophy models. In diabetic animals, IM injection of insulin diminished CAMP accumulation in the presence of theophylline in unweighted muscle (-66% +/- 2%) more than in controls (-42% +'- 6%, P less than .001). These results show that insulin affects CAMP formation in muscle, and support a greater in vivo insulin response following unweighting atrophy. These various data support a role for lysosomal proteolysis in denervation, but not in unweighting, atrophy.

  6. Alpha adrenergic receptors in dog coronary arteries as detected with autoradiography

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    Muntz, K.; Calianos, T.; Buja, L.M.


    The authors used previously established methods to determine the presence of alpha adrenergic receptors in different sizes of dog coronary arteries using autoradiography of /sup 3/H-prazosin (PRAZ) and /sup 125/I-BE 2254 (HEAT) to label alpha/sub 1/ adrenergic receptors and /sup 3/H-rauwolscine (RAUW) to label alpha/sub 2/ adrenergic receptors. Frozen sections of the left main coronary artery (LMA), the left anterior descending artery (LAD) and myocardium were incubated in 3 concentrations of PRAZ (0.1, 0.5 and 1.0 nM) (n=5 dogs), 3 concentrations of RAUW (1, 3 and 5 nM) (n=5) and one concentration of HEAT (50 pM) (n=3). All incubations were done in the absence of (total binding) or presence of (nonspecific binding) 10/sup -5/ M phentolamine or yohimbine. The sections were processed for autoradiography and silver grains quantitated using an image analyzer. Analysis of variance determined that there was a significant difference between total and nonspecific binding in the LMA incubated with PRAZ (p < 0.016), but no significant difference between total and nonspecific binding in the LAD (p < 0.19) or in the arterioles (p < 0.68). In the experiments with HEAT, similar results were obtained. With RAUW, there was significant labeling of arterioles (p < 0.004), but not over the LAD (p < 0.11) or the LMA (p < 0.49). The results suggest that the number of coronary alpha/sub 1/ receptors decreases as vessel size decreases, while the number of alpha/sub 2/ receptors increases as vessel size decreases.

  7. MiRNA-1/133a clusters regulate adrenergic control of cardiac repolarization.

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    Johannes Besser

    Full Text Available The electrical properties of the heart are primarily determined by the activity of ion channels and the activity of these molecules is permanently modulated and adjusted to the physiological needs by adrenergic signaling. miRNAs are known to control the expression of many proteins and to fulfill distinct functions in the mammalian heart, though the in vivo effects of miRNAs on the electrical activity of the heart are poorly characterized. The miRNAs miR-1 and miR-133a are the most abundant miRNAs of the heart and are expressed from two miR-1/133a genomic clusters. Genetic modulation of miR-1/133a cluster expression without concomitant severe disturbance of general cardiomyocyte physiology revealed that these miRNA clusters govern cardiac muscle repolarization. Reduction of miR-1/133a dosage induced a longQT phenotype in mice especially at low heart rates. Longer action potentials in cardiomyocytes are caused by modulation of the impact of β-adrenergic signaling on the activity of the depolarizing L-type calcium channel. Pharmacological intervention to attenuate β-adrenergic signaling or L-type calcium channel activity in vivo abrogated the longQT phenotype that is caused by modulation of miR-1/133a activity. Thus, we identify the miR-1/133a miRNA clusters to be important to prevent a longQT-phenotype in the mammalian heart.

  8. Beta-adrenergic stimulation of skeletal muscle HSL can be overridden by AMPK signaling. (United States)

    Watt, Matthew J; Steinberg, Gregory R; Chan, Stanley; Garnham, Andrew; Kemp, Bruce E; Febbraio, Mark A


    Hormone-sensitive lipase (HSL), an important regulatory enzyme for triacylglycerol hydrolysis within skeletal muscle, is controlled by beta-adrenergic signaling as well as intrinsic factors related to contraction and energy turnover. In the current study, we tested the capacity of 5'AMP-activated protein kinase (AMPK) to suppress beta-adrenergic stimulation of HSL activity. Eight male subjects completed 60 min of cycle exercise at 70% VO2 peak on two occasions: either with normal (CON) or low (LG) pre-exercise muscle glycogen content, which is known to enhance exercise-induced AMPK activity. Muscle samples were obtained before and immediately after exercise. Pre-exercise glycogen averaged 375 +/- 35 and 163 +/- 27 mmol x kg(-1) dm for CON and LG, respectively. AMPK alpha-2 was not different between trials at rest and was increased (3.7-fold, PHSL activity did not differ between trials at rest and increased (0 min: 1.67 +/- 0.13; 60 min: 2.60 +/- 0.26 mmol x min(-1) x kg(-1) dm) in CON. The exercise-induced increase in HSL activity was attenuated by AMPK alpha-2 activation in LG. The attenuated HSL activity during LG occurred despite higher plasma epinephrine levels (60 min: CON, 1.96 +/- 0.29 vs LG, 4.25 +/- 0.60 nM, PHSL activity in LG, IMTG was decreased by exercise (0 min: 27.1 +/- 2.0; 60 min: 22.5 +/- 2.0 mmol x kg(-1) dm, PHSL activity, we performed experiments in muscle cell culture. The epineprine-induced increase in HSL activity was totally attenuated (PHSL activity that can override beta-adrenergic stimulation. However, the increased IMTG degradation in LG suggests factors other than HSL activity are important for IMTG degradation.

  9. A compartmentalized mathematical model of the β1-adrenergic signaling system in mouse ventricular myocytes.

    Directory of Open Access Journals (Sweden)

    Vladimir E Bondarenko

    Full Text Available The β1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca(2+]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of β1-adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the β1-adrenergic signaling system for mouse ventricular myocytes is developed, which includes major subcellular functional compartments (caveolae, extracaveolae, and cytosol. The model describes biochemical reactions that occur during stimulation of β1-adrenoceptors, changes in ionic currents, and modifications of Ca(2+ handling system. Simulations describe the dynamics of major signaling molecules, such as cyclic AMP and protein kinase A, in different subcellular compartments; the effects of inhibition of phosphodiesterases on cAMP production; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca(2+ handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of [Ca(2+]i transients; changes in intracellular and transmembrane Ca(2+ fluxes; and [Na(+]i fluxes and dynamics. The model elucidates complex interactions of ionic currents upon activation of β1-adrenoceptors at different stimulation frequencies, which ultimately lead to a relatively modest increase in action potential duration and significant increase in [Ca(2+]i transients. In particular, the model includes two subpopulations of the L-type Ca(2+ channels, in caveolae and extracaveolae compartments, and their effects on the action potential and [Ca(2+]i transients are investigated. The presented model can be used by researchers for the interpretation of experimental data and for the developments of

  10. The role of basolateral amygdala adrenergic receptors in hippocampus dependent spatial memory in rat

    Directory of Open Access Journals (Sweden)

    Vafaei A.L.


    Full Text Available Background and the purpose of the study: There are extensive evidences indicating that the noradrenergic system of the basolateral nucleus of the amygdala (BLA is involved in memory processes. The present study investigated the role of the BLA adrenergic receptors (ARs in hippocampus dependent spatial memory in place avoidance task in male rat. Material and Methods: Long Evans rats (n=150 were trained to avoid footshock in a 60° segment while foraging for scattered food on a circular (80-cm diameter arena. The rats were injected bilaterally in the BLA specific ARS (Adrenergic receptors agonist norepinephrine (NE, 0.5 and 1 µg/µl and specific β-ARs antagonist propranolol (PRO, 0.5 and 1 µg/µl before acquisition, after training or before retrieval of the place avoidance task. Control rats received vehicle at the same volume. The learning in a single 30-min session was assessed 24h later by a 30-min extinction trial in which the time to first entrance and the number of entrances to the shocked area measured the avoidance memory. Results: Acquisition and consolidation were enhanced and impaired significantly by NE and PRO when the drugs were injected 10 min before or immediately after training, respectively. In contrast, neither NE nor PRO influenced animal performances when injected before retention testing. Conclusion: Findings of this study indicates that adrenergic system of the BLA plays an important role in regulation of memory storage and show further evidences for the opinion that the BLA plays an important role in integrating hormonal and neurotransmitter influences on memory storage.

  11. Bacterial Adrenergic Sensors Regulate Virulence of Enteric Pathogens in the Gut

    Directory of Open Access Journals (Sweden)

    Cristiano G. Moreira


    Full Text Available Enteric pathogens such as enterohemorrhagic Escherichia coli (EHEC and Citrobacter rodentium, which is largely used as a surrogate EHEC model for murine infections, are exposed to several host neurotransmitters in the gut. An important chemical exchange within the gut involves the neurotransmitters epinephrine and/or norepinephrine, extensively reported to increase virulence gene expression in EHEC, acting through two bacterial adrenergic sensors: QseC and QseE. However, EHEC is unable to establish itself and cause its hallmark lesions, attaching and effacing (AE lesions, on murine enterocytes. To address the role of these neurotransmitters during enteric infection, we employed C. rodentium. Both EHEC and C. rodentium harbor the locus of enterocyte effacement (LEE that is necessary for AE lesion formation. Here we show that expression of the LEE, as well as that of other virulence genes in C. rodentium, is also activated by epinephrine and/or norepinephrine. Both QseC and QseE are required for LEE gene activation in C. rodentium, and the qseC and qseE mutants are attenuated for murine infection. C. rodentium has a decreased ability to colonize dopamine β-hydroxylase knockout (Dbh−/− mice, which do not produce epinephrine and norepinephrine. Both adrenergic sensors are required for C. rodentium to sense these neurotransmitters and activate the LEE genes during infection. These data indicate that epinephrine and norepinephrine are sensed by bacterial adrenergic receptors during enteric infection to promote activation of their virulence repertoire. This is the first report of the role of these neurotransmitters during mammalian gastrointestinal (GI infection by a noninvasive pathogen.

  12. 164Ile allele in the beta2-Adrenergic receptor gene is associated with risk of elevated blood pressure in women. The Copenhagen City Heart Study

    DEFF Research Database (Denmark)

    Sethi, Amar A; Tybjaerg-Hansen, Anne; Jensen, Gorm B;


    Since beta2-adrenergic receptors are important regulators of blood pressure, genetic variation in this receptor could explain risk of elevated blood pressure in selected individuals. We tested the hypothesis that Gly16Arg, Gln27Glu, and Thr164Ile in the beta2-adrenergic receptor gene associated w...

  13. Effects of local alpha2-adrenergic receptor blockade on adipose tissue lipolysis during prolonged systemic adrenaline infusion in normal man

    DEFF Research Database (Denmark)

    Simonsen, Lene; Enevoldsen, Lotte H; Stallknecht, Bente


    During prolonged adrenaline infusion, lipolysis peaks within 30 min and thereafter tends to decline, and we hypothesized that the stimulation of local adipose tissue alpha2-adrenergic receptors accounts for this decline. The lipolytic effect of a prolonged intravenous adrenaline infusion combined....... Regional adipose tissue blood flow was measured by the (133)Xe clearance technique. Regional glycerol output (lipolytic rate) was calculated from these measurements and simultaneous measurements of arterial glycerol concentrations. Adrenaline infusion increased lipolysis in all three depots (data...... circulating adrenaline concentrations, and the decrease in lipolysis in subcutaneous adipose tissue under prolonged adrenaline stimulation is thus not attributed to alpha2-adrenergic receptor inhibition of lipolysis. However, in the preperitoneal adipose tissue depot, alpha2-adrenergic receptor tone plays...

  14. A comparison of adrenergic receptors of rat ascites hepatoma AH130 cells with those of normal rat hepatocytes. (United States)

    Sanae, F; Miyamoto, K; Koshiura, R


    The pharmacological specificity of adrenergic receptors in the plasma membrane of rat ascites hepatoma AH130 cells was compared with that in normal rat hepatocytes. The number of [125I]iodocyanopindolol-binding sites was much greater in AH130 cells than in the hepatocytes. We characterized the alpha-adrenergic receptor subtypes using the alpha 1-selective ligand [3H]prazosin and the alpha 2-selective ligand [3H]clonidine. AH130 cells had fewer prazosin-binding sites than the hepatocytes and about 8 times as many clonidine-binding sites of high affinity. The results showed that the adrenergic receptors in AH130 cells have pharmacological properties that are very different from those of the receptors in normal rat hepatocytes.

  15. Changes in number of alpha-adrenergic receptor subtypes in hepatocytes from rats fed 3'-methyl-4-dimethylaminoazobenzene. (United States)

    Miyamoto, K; Sanae, F; Kohei, K; Nomura, M; Koshiura, R


    Changes in numbers of alpha 1- and alpha 2-adrenergic receptors in the plasma membranes of hepatocytes from female Donryu rats given feed containing 0.06% of the carcinogen 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), were examined. alpha 1-Adrenergic receptors, measured in terms of [3H]prazosin binding, decreased to half of the control 2 weeks after the start of this diet, then gradually decreased for the next 22 weeks. alpha 2-Adrenergic receptors, measured in terms of [3H]clonidine binding, transiently increased 3-fold over the control at 2 weeks. These changes in the early period of the 3'-MeDAB diet intake may be related to hepatocarcinogenesis.

  16. β1- and β2-adrenergic stimulation-induced electrogenic transport by human endolymphatic sac epithelium and its clinical implications (United States)

    Kim, Bo Gyung; Kim, Jin Young; Jung, JinSei; Moon, In Seok; Yoon, Joo-Heon; Choi, Jae Young; Kim, Sung Huhn


    The endolymphatic sac (ES) is a cystic structure of the inner ear connected to the cochlea and vestibule, which plays a role in regulating ion homeostasis in inner ear fluid. Disruption of ion homeostasis can cause inner ear disorders with hearing loss and dizziness, such as Meniere’s disease. Herein, we found, for the first time, functional evidence for the involvement of β1- and β2-adrenergic receptors in apical electrogenic ion transport by human ES epithelium by using electrophysiological/pharmacological and molecular biological methods, which were dependent on K+ and Cl− ion transport. The apical electrogenic transport was absent or very weak in ES epithelia of patients with Meniere’s disease. These results suggested that adrenergic stimulation via β1- and β2-adrenergic receptors in the human ES was involved in regulation of inner ear fluid ion homeostasis and impairment of this response could be a pathological mechanism of Meniere’s disease. PMID:28165045

  17. Label-free integrative pharmacology on-target of drugs at the β2-adrenergic receptor (United States)

    Ferrie, Ann M.; Sun, Haiyan; Fang, Ye


    We describe a label-free integrative pharmacology on-target (iPOT) method to assess the pharmacology of drugs at the β2-adrenergic receptor. This method combines dynamic mass redistribution (DMR) assays using an array of probe molecule-hijacked cells with similarity analysis. The whole cell DMR assays track cell system-based, ligand-directed, and kinetics-dependent biased activities of the drugs, and translates their on-target pharmacology into numerical descriptors which are subject to similarity analysis. We demonstrate that the approach establishes an effective link between the label-free pharmacology and in vivo therapeutic indications of drugs.

  18. Recent advances in the molecular pharmacology of the alpha 1-adrenergic receptors. (United States)

    Guarino, R D; Perez, D M; Piascik, M T


    This review is intended to discuss recent developments in the molecular pharmacology of the alpha 1-adrenergic receptor (alpha 1-AR) subtypes. After a brief historical development, we will focus on the more contemporary issues having to do with this receptor family. Emphasis will be put on recent data regarding the cloning, nomenclature, signalling mechanisms, and genomic organization of the alpha 1-AR subtypes. We will also highlight recent mutational studies that identify key amino acid residues involved in ligand binding, as well as the role of the alpha 1-AR subtypes in regulating physiologic processes.

  19. Cholesterol increases kinetic, energetic, and mechanical stability of the human β2-adrenergic receptor

    DEFF Research Database (Denmark)

    Zocher, Michael; Zhang, Cheng; Rasmussen, Søren Gøgsig Faarup;


    the kinetic, energetic, and mechanical stability of almost every structural segment at sufficient magnitude to alter the structure and functional relationship of β(2)AR. One exception was the structural core segment of β(2)AR, which establishes multiple ligand binding sites, and its properties were...... to quantify the mechanical strength and flexibility, conformational variability, and kinetic and energetic stability of structural segments stabilizing the human β(2)-adrenergic receptor (β(2)AR) in the absence and presence of the cholesterol analog cholesteryl hemisuccinate (CHS). CHS considerably increased...

  20. Alpha-adrenergic regulation of growth hormone release after electroconvulsive therapy in man. (United States)

    Vigas, M; Wiedermann, V; Németh, S; Jurcovicová, J; Zigo, L


    When electroshcok therapy was administered to male psychiatric patients without anticonvulsive premedication, serum growth hormone (GH) increased; the increase was not prevented by an infusion of 20% glucose (5 ml per min) 20 min prior to electroshock. Therefore, the GH rise is not caused by muscle exercise during convulsions. Infusing 30 mg of phentolamine 40 min prior to electroshcok inhibited the GH response. Phentolamine's effect shows that the stress-induced GH release that follows electroconvulsive therapy is mediated by alpha-adrenergic neurons.

  1. GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function

    DEFF Research Database (Denmark)

    Rosenbaum, Daniel M; Cherezov, Vadim; Hanson, Michael A


    crystallization, we engineered a beta2AR fusion protein in which T4 lysozyme (T4L) replaces most of the third intracellular loop of the GPCR ("beta2AR-T4L") and showed that this protein retains near-native pharmacologic properties. Analysis of adrenergic receptor ligand-binding mutants within the context...... of the reported high-resolution structure of beta2AR-T4L provides insights into inverse-agonist binding and the structural changes required to accommodate catecholamine agonists. Amino acids known to regulate receptor function are linked through packing interactions and a network of hydrogen bonds, suggesting...

  2. Antidiuretic effect of ritodrine with and without beta-adrenergic blockade. (United States)

    Gerritse, R; Pinas, I M; Reuwer, P J; Haspels, A A; Charbon, G A; Beijer, H J


    Dose-related effects of ritodrine and ritodrine combined with metoprolol on urinary excretion rate were studied in anesthetized dogs. Urine production was abruptly reduced after a total dose of 4 of ritodrine. This effect could not be antagonized by metoprolol, although the ritodrine-induced decrease of mean arterial pressure and renal arterial blood flow was significantly inhibited. The possible role of fluid retention during tocolytic treatment, even with beta-adrenergic blockade, in the etiology of pulmonary edema is discussed with a review on recent literature.

  3. Exercise training modulates functional sympatholysis and α-adrenergic vasoconstrictor responsiveness in hypertensive and normotensive individuals

    DEFF Research Database (Denmark)

    Mortensen, Stefan; Nyberg, Michael; Gliemann, Lasse;


    were measured before and after 8 weeks of aerobic training (3-4 times per week) in eight hypertensive (47 ± 2 years) and eight normotensive untrained individuals (46 ± 1 years) during arterial tyramine infusion, arterial ATP infusion and/or one-legged knee extensions. Before training, exercise......Essential hypertension is linked to an increased sympathetic vasoconstrictor activity and reduced tissue perfusion. We investigated the role of exercise training on functional sympatholysis and postjunctional α-adrenergic responsiveness in individuals with essential hypertension. Leg haemodynamics...... hyperaemia and leg vascular conductance (LVC) were lower in the hypertensive individuals (P

  4. Stimulation of postsynapse adrenergic α2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder. (United States)

    Kawaura, Kazuaki; Karasawa, Jun-ichi; Chaki, Shigeyuki; Hikichi, Hirohiko


    A 5-trial inhibitory avoidance test using spontaneously hypertensive rat (SHR) pups has been used as an animal model of attention deficit hyperactivity disorder (ADHD). However, the roles of noradrenergic systems, which are involved in the pathophysiology of ADHD, have not been investigated in this model. In the present study, the effects of adrenergic α2 receptor stimulation, which has been an effective treatment for ADHD, on attention/cognition performance were investigated in this model. Moreover, neuronal mechanisms mediated through adrenergic α2 receptors were investigated. We evaluated the effects of both clonidine, a non-selective adrenergic α2 receptor agonist, and guanfacine, a selective adrenergic α2A receptor agonist, using a 5-trial inhibitory avoidance test with SHR pups. Juvenile SHR exhibited a shorter transfer latency, compared with juvenile Wistar Kyoto (WKY) rats. Both clonidine and guanfacine significantly prolonged the transfer latency of juvenile SHR. The effects of clonidine and guanfacine were significantly blocked by pretreatment with an adrenergic α2A receptor antagonist. In contrast, the effect of clonidine was not attenuated by pretreatment with an adrenergic α2B receptor antagonist, or an adrenergic α2C receptor antagonist, while it was attenuated by a non-selective adrenergic α2 receptor antagonist. Furthermore, the effects of neither clonidine nor guanfacine were blocked by pretreatment with a selective noradrenergic neurotoxin. These results suggest that the stimulation of the adrenergic α2A receptor improves the attention/cognition performance of juvenile SHR in the 5-trial inhibitory avoidance test and that postsynaptic, rather than presynaptic, adrenergic α2A receptor is involved in this effect.

  5. ADRA2A Germline Gene Polymorphism is Associated to the Severity, but not to the Risk, of Breast Cancer. (United States)

    Kaabi, Batoul; Belaaloui, Ghania; Benbrahim, Wassila; Hamizi, Kamel; Sadelaoud, Mourad; Toumi, Wided; Bounecer, Hocine


    Breast cancer (BC) prognosis and risk were associated to obesity, metabolic syndrome and type 2 diabetes mellitus. Two Single Nucleotide Polymorphisms (SNPs) of the adrenergic receptor-2a gene (ADRA2A): rs1800544 and rs553668, have been associated to these metabolic disorders. We investigated these SNPs in BC risk and prognosis. A total of 102 BC patients and 102 healthy controls were included. The rs1800544 and rs553668 were determined by real-time PCR. Genotypes and haplotypes frequencies between patients and controls, and for different clinico-pathologic parameters were compared. We found a significant association of rs1800544 GG genotype with young age at diagnosis, premenopausal status, higher tumor size, metastasis in lymph nodes, advanced TNM stages and higher Nottingham Prognosis Indicator (NPI) (p 0.05). ADRA2A polymorphism is associated with indicators BC poor prognosis but not with BC susceptibility. This is the first report suggesting that ADRA2A germline gene polymorphism could represent a predictor factor for BC outcome. Further investigation of other ADRA2A polymorphisms in BC risk or prognosis are needed and may lead to a genotype-based therapy.

  6. Doxazosin stimulates galectin-3 expression and collagen synthesis in HL-1 cardiomyocytes independent of protein kinase C pathway

    Directory of Open Access Journals (Sweden)

    Xiaoqian Qian


    Full Text Available Doxazosin, a drug commonly prescribed for hypertension and prostate disease, increases heart failure risk. However, the underlying mechanism remains unclear. Galectin-3 is an important mediator that plays a pathogenic role in cardiac hypertrophy and heart failure. In the present study, we investigated whether doxazosin could stimulate galectin-3 expression and collagen synthesis in cultured HL-1 cardiomyocytes. We found that doxazosin dose-dependently induced galectin-3 protein expression, with a statistically significant increase in expression with a dose as low as 0.01 μM. Doxazosin upregulated collagen I and α-smooth muscle actin (α-SMA protein levels and also induced apoptotic protein caspase-3 in HL-1 cardiomyocytes. Although we previously reported that activation of protein kinase C (PKC stimulates galectin-3 expression, blocking the PKC pathway with the PKC inhibitor chelerythrine did not prevent doxazosin-induced galectin-3 and collagen expression. Consistently, doxazosin treatment did not alter total and phosphorylated PKC. These results suggest that doxazosin-stimulated galectin-3 is independent of PKC pathway. To determine if the α1-adrenergic pathway is involved, we pretreated the cells with the irreversible α-adrenergic receptor blocker phenoxybenzamine and found that doxazosin-stimulated galectin-3 and collagen expression was similar to controls, suggesting that doxazosin acts independently of α1-adrenergic receptor blockade. Collectively, we show a novel effect of doxazosin on cardiomycytes by stimulating heart fibrosis factor galectin-3 expression. The mechanism of action of doxazosin is not mediated through either activation of the PKC pathway or antagonism of α1-adrenergic receptors.

  7. Identification of possible genetic polymorphisms involved in cancer cachexia: a systematic review

    Indian Academy of Sciences (India)

    Benjamin H. L. Tan; James A. Ross; Stein Kaasa; Frank Skorpen; Kenneth C. H. Fearon; European Palliative Care Research Collaborative


    Cancer cachexia is a polygenic and complex syndrome. Genetic variations in regulation of the inflammatory response, muscle and fat metabolic pathways, and pathways in appetite regulation are likely to contribute to the susceptibility or resistance to developing cancer cachexia. A systematic search of Medline and EmBase databases, covering 1986–2008 was performed for potential candidate genes/genetic polymorphisms relating to cancer cachexia. Related genes were then identified using pathway functional analysis software. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Genes with variants which had functional or clinical associations with cachexia and replicated in at least one study were entered into pathway analysis software to reveal possible network associations between genes. A total of 184 polymorphisms with functional or clinical relevance to cancer cachexia were identified in 92 candidate genes. Of these, 42 polymorphisms (in 33 genes) were replicated in more than one study with 13 polymorphisms found to influence two or more hallmarks of cachexia (i.e. inflammation, loss of fat mass and/or lean mass and reduced survival). Thirty-three genes were found to be significantly interconnected in two major networks with four genes (ADIPOQ, IL6, NFKB1 and TLR4) interlinking both networks. Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides an initial framework to select genes/polymorphisms for further study in cancer cachexia, and to develop their potential as susceptibility biomarkers of developing cachexia.

  8. Alpha2-Adrenergic Receptors and Breast Tumor Stroma: A Novel Pathway Driving Breast Cancer Growth and Metastasis (United States)


    increased metastasis to the lungs in conjunction with elevated tumor SHG-emitting collagen. DEX did not alter metastasis or tumor SHG in immunodeficient ...undergoing diagnosis and treatment of breast cancer often experience severe and chronic psychological stress. The sympathetic nervous system (SNS) is...anesthesia administered for IVIS imaging may interact with DEX. For example, anesthesia (ketamine combined with xylazine, an α2-AR agonist) may reduce

  9. Polymorphisms in the inflammatory pathway genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG are associated with susceptibility of inflammatory bowel disease in a Danish cohort

    DEFF Research Database (Denmark)

    Bank, Steffen; Skytt Andersen, Paal; Burisch, Johan


    BACKGROUND: The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage. METHODS: Using a candid...

  10. Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats. (United States)

    Frank, J A; Wang, Y; Osorio, O; Matthay, M A


    To determine whether beta-adrenergic agonist therapy increases alveolar liquid clearance during the resolution phase of hydrostatic pulmonary edema, we studied alveolar and lung liquid clearance in two animal models of hydrostatic pulmonary edema. Hydrostatic pulmonary edema was induced in sheep by acutely elevating left atrial pressure to 25 cmH(2)O and instilling 6 ml/kg body wt isotonic 5% albumin (prepared from bovine albumin) in normal saline into the distal air spaces of each lung. After 1 h, sheep were treated with a nebulized beta-agonist (salmeterol) or nebulized saline (controls), and left atrial pressure was then returned to normal. beta-Agonist therapy resulted in a 60% increase in alveolar liquid clearance over 3 h (P Ringer lactate). beta-Agonist therapy resulted in a significant decrease in excess lung water (P < 0.01) and significant improvement in arterial blood gases by 2 h (P < 0.03). These preclinical experimental studies support the need for controlled clinical trials to determine whether beta-adrenergic agonist therapy would be of value in accelerating the resolution of hydrostatic pulmonary edema in patients.

  11. Cocaine increases dopaminergic neuron and motor activity via midbrain α1 adrenergic signaling. (United States)

    Goertz, Richard Brandon; Wanat, Matthew J; Gomez, Jorge A; Brown, Zeliene J; Phillips, Paul E M; Paladini, Carlos A


    Cocaine reinforcement is mediated by increased extracellular dopamine levels in the forebrain. This neurochemical effect was thought to require inhibition of dopamine reuptake, but cocaine is still reinforcing even in the absence of the dopamine transporter. Here, we demonstrate that the rapid elevation in dopamine levels and motor activity elicited by cocaine involves α1 receptor activation within the ventral midbrain. Activation of α1 receptors increases dopaminergic neuron burst firing by decreasing the calcium-activated potassium channel current (SK), as well as elevates dopaminergic neuron pacemaker firing through modulation of both SK and the hyperpolarization-activated cation currents (Ih). Furthermore, we found that cocaine increases both the pacemaker and burst-firing frequency of rat ventral-midbrain dopaminergic neurons through an α1 adrenergic receptor-dependent mechanism within the ventral tegmental area and substantia nigra pars compacta. These results demonstrate the mechanism underlying the critical role of α1 adrenergic receptors in the regulation of dopamine neurotransmission and behavior by cocaine.

  12. Effect of adrenergic receptor ligands on metaiodobenzylguanidine uptake and storage in neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Babich, J.W. [Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts (United States)]|[Department of Radiology, Harvard Medical School, Boston, Massachusetts (United States); Graham, W. [Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts (United States); Fischman, A.J. [Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts (United States)]|[Department of Radiology, Harvard Medical School, Boston, Massachusetts (United States)


    The effects of adrenergic receptor ligands on uptake and storage of the radiopharmaceutical [{sup 125}I]metaiodobenzylguanidine (MIBG) were studied in the human neuroblastoma cell line SK-N-SH. For uptake studies, cells were with varying concentrations of {alpha}-agonist (clonidine, methoxamine, and xylazine), {alpha}-antagonist (phentolamine, tolazoline, phenoxybenzamine, yohimbine, and prazosin), {beta}-antagonist (propranolol, atenolol), {beta}-agonist (isoprenaline and salbutamol), mixed {alpha}/{beta} antagonist (labetalol), or the neuronal blocking agent guanethidine, prior to the addition of [{sup 125}I]MIBG (0.1 {mu}M). The incubation was continued for 2 h and specific cell-associated radioactivity was measured. For the storage studies, cells were incubated with [{sup 125}I]MIBG for 2 h, followed by replacement with fresh medium with or without drug (MIBG, clonidine, or yohimbine). Cell-associated radioactivity was measured at various times over the next 20 h. Propanolol reduced [{sup 125}I]MIBG uptake by approximately 30% (P<0.01) at all concentrations tested, most likely due to nonspecific membrane changes. In conclusion, the results of this study establish that selected adrenergic ligands can significantly influence the pattern of uptake and storage of MIBG in cultured neuroblastoma cells, most likely through inhibition of uptake or through noncompetitive inhibition. The potential inplications of these findings justify further study. (orig./VHE). With 4 figs., 1 tab.

  13. Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier.

    Directory of Open Access Journals (Sweden)

    Akihiko Urayama

    Full Text Available The impermeability of the adult blood-brain barrier (BBB to lysosomal enzymes impedes the ability to treat the central nervous system manifestations of lysosomal storage diseases. Here, we found that simultaneous stimulation of the alpha1 and alpha2 adrenoreceptor restores in adult mice the high rate of transport for the lysosomal enzyme P-GUS that is seen in neonates but lost with development. Beta adrenergics, other monoamines, and acetylcholine did not restore this transport. A high dose (500 microg/mouse of clonidine, a strong alpha2 and weak alpha1 agonist, was able to act as monotherapy in the stimulation of P-GUS transport. Neither use of alpha1 plus alpha2 agonists nor the high dose clonidine disrupted the BBB to albumin. In situ brain perfusion and immunohistochemistry studies indicated that adrengerics act on transporters already at the luminal surface of brain endothelial cells. These results show that adrenergic stimulation, including monotherapy with clonidine, could be key for CNS enzyme replacement therapy.

  14. Long-acting β2-adrenergic receptor agonist in pediatric asthma

    Directory of Open Access Journals (Sweden)

    Shigemi Yoshihara


    Full Text Available Long-acting β2-adrenergic receptor agonists (LABA, a class of agents for the long-term management of childhood bronchial asthma, are recommended for use in combination with steroid inhalation for the treatment of the morning dip in severe childhood asthma. In the present review, salmeterol (SM, a LABA inhalant with a long-acting bronchodilator effect, was compared with the recently introduced tulobuterol patch (TBP in terms of safety and efficacy, based on their respective clinical effects on childhood asthma. From a clinical perspective, both drugs had a preventive effect by suppressing the morning dip and exercise-induced asthma when used concomitantly with an inhaled corticosteroid, and both agents were associated with a lower incidence of adverse effects on the cardiovascular system than oral β2-adrenergic receptor agonists. Based on these findings, both SM and TBP are concluded to be highly efficacious and safe bronchodilator agents that are appropriate for the long-term management of childhood asthma.

  15. Effect of beta-adrenergic stimulants on cytotoxicity of mitomycin C in HeLa cells. (United States)

    Miyamoto, K; Sanae, F; Iwasaki, M; Koshiura, R


    Effects of several autonomic agents on the cytotoxicity of mitomycin C in HeLa cells were studied. When beta-adrenergic stimulants such as isoproterenol, epinephrine, terbutaline and turobuterol were added at concentrations over 10(-14) M 15 to 60 min before mitomycin C, the colony-forming ability of HeLa cells was significantly inhibited more than by mitomycin C alone. The action of isoproterenol and epinephrine on the colony-forming ability of the cells was abolished by propranolol. The intracellular cyclic AMP level of HeLa cells reached the peak of about two-fold the basal level at 30 min after the addition of 10(-8) M isoproterenol. In combination with mitomycin C, the high level of intracellular cyclic AMP induced by isoproterenol was maintained for a significantly longer period in comparison with that by isoproterenol alone, while mitomycin C alone caused essentially no change in the cyclic AMP level. The pretreatment with dibutyryl cyclic AMP also enhanced the effect of mitomycin C. From these findings, it is strongly suggested that the synergistic effect of beta-adrenergic stimulants on the cytotoxicity of mitomycin C is mediated via stimulation of the beta-adrenoceptors of HeLa cells which elevates the intracellular cyclic AMP for a long time in combination with mitomycin C.

  16. The role of adrenergic agonists on glycogenolysis in rat hepatocyte cultures and possible involvement of NO. (United States)

    Hodis, J; Kutinová-Canová, N; Potmesil, P; Kameníková, L; Kmonícková, E; Zídek, Z; Farghali, H


    Certain liver metabolic diseases point to the presence of disturbances in glycogen deposition. Epinephrine raises the cAMP level that activates protein kinase A leading to the activation of phosphorylase and glycogen breakdown. In the present report, we sought to investigate whether NO is produced during adrenoceptor agonist-induced glycogenolysis in rat hepatocytes in cultures. Isolated glycogen rich rat hepatocytes in cultures were used. NO production (NO(2)(-)) was assessed under the effect of adrenergic agonists and adrenergic agonist/antagonist pairs, dibutyryl cyclic AMP sodium-potassium salt (db-cAMP), NO synthase (NOS) inhibitors N(omega)-nitro-L-arginine methyl ester (L-NAME), aminoguanidine (AG) and the NO donor S-nitroso-N-acetyl penicillamine (SNAP). The inducible NO synthase (iNOS) mRNA was examined by the reverse transcription-polymerase chain reaction (RT-PCR). Glycogenolysis was quantified by glucose levels released into medium. The amount of glucose and NO(2)(-) released by hepatocytes was increased as a result of epinephrine, phenylephrine or db-cAMP treatments. The increase in glucose and NO(2)(-) released by epinephrine or phenylephrine was blocked or reduced by prazosin pretreatment and by NOS inhibitors aminoguanidine and L-NAME. iNOS gene expression was up-regulated by epinephrine. It can be concluded that glycogenolysis occurs through -adrenoceptor stimulation and a signaling cascade may involve NO production.

  17. Determination of beta-adrenergic receptor blocking pharmaceuticals in united states wastewater effluent

    Energy Technology Data Exchange (ETDEWEB)

    Huggett, D.B.; Khan, I.A.; Foran, C.M.; Schlenk, D


    This is the first report of beta-adrenergic receptor antagonist pharmaceuticals in United States wastewater effluent. - Beta adrenergic receptor antagonists ({beta}-Blockers) are frequently prescribed medications in the United States and have been identified in European municipal wastewater effluent, however no studies to date have investigated these compounds in United States wastewater effluent. Municipal wastewater effluent was collected from treatment facilities in Mississippi, Texas, and New York to investigate the occurrence of metoprolol, nadolol, and propranolol. Propranolol was identified in all wastewater samples analyzed (n=34) at concentrations {<=}1.9 {mu}g/l. Metoprolol and nadolol were identified in {>=}71% of the samples with concentrations of metoprolol {<=}1.2 {mu}g/l and nadolol {<=}0.36 {mu}g/l. Time course studies at both Mississippi plants and the Texas plant indicate that concentrations of propranolol, metoprolol, and nadolol remain relatively constant at each sampling period. This study indicates that {beta}-Blockers are present in United States wastewater effluent in the ng/l to {mu}g/l range.

  18. Alpha-1 adrenergic receptors gate rapid orientation-specific reduction in visual discrimination. (United States)

    Treviño, Mario; Frey, Sebastian; Köhr, Georg


    Prolonged imbalance in sensory experience leads to dramatic readjustments in cortical representation. Neuromodulatory systems play a critical role in habilitating experience-induced plasticity and regulate memory processes in vivo. Here, we show that a brief period of intense patterned visual stimulation combined with systemic activation of alpha-1 adrenergic neuromodulator receptors (α(1)-ARs) leads to a rapid, reversible, and NMDAR-dependent depression of AMPAR-mediated transmission from ascending inputs to layer II/III pyramidal cells in the visual cortex of young and adult mice. The magnitude of this form of α(1)-AR long-term depression (LTD), measured ex vivo with miniature EPSC recordings, is graded by the number of orientations used during visual experience. Moreover, behavioral tests of visual function following the induction of α(1)-AR LTD reveal that discrimination accuracy of sinusoidal drifting gratings is selectively reduced at high spatial frequencies in a reversible, orientation-specific, and NMDAR-dependent manner. Thus, α(1)-ARs enable rapid cortical synaptic depression which correlates with an orientation-specific decrease in visual discrimination. These findings contribute to our understanding of how adrenergic receptors interact with neuronal networks in response to changes in active sensory experience to produce adaptive behavior.

  19. α1B-Adrenoceptors mediate adrenergically-induced renal vasoconstrictions in rats with renal impairment

    Institute of Scientific and Technical Information of China (English)

    Md Abdul Hye KHAN; Munavvar Abdul SATTAR; Nor Azizan ABDULLAH; Edward James JOHNS


    Aim: This study examined whether α1B-adrenoceptors are involved in mediating adrenergically-induced renal vasoconstrictor responses in rats with pathophysi-ological and normal physiological states. Methods: Male Wistar Kyoto and spon-taneously hypertensive rats were induced with acute renal failure or experimental early diabetic nephropathy by cisplatin or streptozotocin, respectively. Cisplatin-induced renal failure was confirmed by impaired renal function and pronounced tubular damage. Experimental early diabetic nephropathy was confirmed by hyperglycemia, changes in physiological parameters, and renal function. The hemodynamic study was conducted on anesthetized rats after 7 d of cisplatin (renal failure) and 4 weeks of streptozotocin (experimental early diabetic nephropathy). Results: In the rats with renal failure and experimental early dia-betic nephropathy, there were marked reductions in their baseline renal blood flow (P0.05) in the renal failure and experimental early diabetic nephropathy rats, respectively, as compared to their non-renal failure and non-diabetic nephropathy controls. In the rats with renal impairment, chloroethylclonidine caused either accentuation or attenuation (all P0.05). Conclusion: This study demonstrated the presence of functional α1B-adrenoceptors that mediated the adrenergically-induced renal vaso-constrictions in rats with renal impairment, but not in rats with normal renal function.

  20. Beta-adrenergic Blockade at Memory Encoding, but Not Retrieval, Decreases the Subjective Sense of Recollection. (United States)

    Rimmele, Ulrike; Lackovic, Sandra F; Tobe, Russell H; Leventhal, Bennett L; Phelps, Elizabeth A


    Humans remember emotional events not only better but also exhibit a qualitatively distinct recollective experience-that is, emotion intensifies the subjective vividness of the memory, the sense of reliving the event, and confidence in the accuracy of the memory [Phelps, E. A., & Sharot, T. How (and why) emotion enhances the subjective sense of recollection. Current Directions in Psychological Science, 17, 147-152, 2008]. Although it has been demonstrated that activation of the beta-adrenergic system, linked to increases in stress hormone levels and physiological arousal, mediates enhanced emotional memory accuracy, the mechanism underlying the increased subjective sense of recollection is unknown. Behavioral evidence suggests that increased arousal associated with emotional events, either at encoding or retrieval, underlies their increased subjective sense of recollection. Using a double-blind, placebo-controlled, within-subject design, we showed that reducing arousal at encoding through oral intake of 80-mg of the beta-adrenergic receptor antagonist propranolol decreases the subjective sense of recollection for both negative and neutral stimuli 24 hr later. In contrast, administration of propranolol before memory retrieval did not alter the subjective sense of recollection. These results suggest that the neurohormonal changes underlying increased arousal at the time of memory formation, rather than the time of memory retrieval, modulate the subjective sense of recollection.

  1. β-Adrenergic Control of Hippocampal Function: Subserving the Choreography of Synaptic Information Storage and Memory. (United States)

    Hagena, Hardy; Hansen, Niels; Manahan-Vaughan, Denise


    Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are "earmarked" for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength.The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3 > CA1). Moreover, NA released from the locus coeruleus that acts on β-AR leads to hippocampal LTD and an enhancement of LTD-related memory processing. We propose that NA acting on hippocampal β-AR, that is graded according to the novelty or saliency of the experience, determines the content and persistency of synaptic information storage in the hippocampal subfields and therefore of spatial memories.

  2. Astrocytic β2-adrenergic receptors mediate hippocampal long-term memory consolidation

    KAUST Repository

    Gao, Virginia


    Emotionally relevant experiences form strong and long-lasting memories by critically engaging the stress hormone/neurotransmitter noradrenaline, which mediates and modulates the consolidation of these memories. Noradrenaline acts through adrenergic receptors (ARs), of which β2- Adrenergic receptors (βARs) are of particular importance. The differential anatomical and cellular distribution of βAR subtypes in the brain suggests that they play distinct roles in memory processing, although much about their specific contributions and mechanisms of action remains to be understood. Here we show that astrocytic rather than neuronal β2ARs in the hippocampus play a key role in the consolidation of a fear-based contextual memory. These hippocampal β2ARs, but not β1ARs, are coupled to the training-dependent release of lactate from astrocytes, which is necessary for long- Term memory formation and for underlying molecular changes. This key metabolic role of astrocytic β2ARs may represent a novel target mechanism for stress-related psychopathologies and neurodegeneration.

  3. β-Adrenergic-mediated vasodilation in young men and women: cyclooxygenase restrains nitric oxide synthase. (United States)

    Limberg, Jacqueline K; Johansson, Rebecca E; Peltonen, Garrett L; Harrell, John W; Kellawan, J Mikhail; Eldridge, Marlowe W; Sebranek, Joshua J; Schrage, William G


    We tested the hypothesis that women exhibit greater vasodilator responses to β-adrenoceptor stimulation compared with men. We further hypothesized women exhibit a greater contribution of nitric oxide synthase and cyclooxygenase to β-adrenergic-mediated vasodilation compared with men. Forearm blood flow (Doppler ultrasound) was measured in young men (n = 29, 26 ± 1 yr) and women (n = 33, 25 ± 1 yr) during intra-arterial infusion of isoproterenol (β-adrenergic agonist). In subset of subjects, isoproterenol responses were examined before and after local inhibition of nitric oxide synthase [N(G)-monomethyl-l-arginine (l-NMMA); 6 male/10 female] and/or cyclooxygenase (ketorolac; 5 male/5 female). Vascular conductance (blood flow ÷ mean arterial pressure) was calculated to assess vasodilation. Vascular conductance increased with isoproterenol infusion (P 0.99) or women (P = 0.21). In contrast, ketorolac infusion markedly increased isoproterenol-mediated responses in both men (P vasodilation is not different between men and women and sex differences in the independent contribution of nitric oxide synthase and cyclooxygenase to β-mediated vasodilation are not present. However, these data are the first to demonstrate β-adrenoceptor activation of cyclooxygenase suppresses nitric oxide synthase signaling in human forearm microcirculation and may have important implications for neurovascular control in both health and disease.

  4. Beta-adrenergic receptor sensitivity, autonomic balance and serotonergic activity in practitioners of Transcendental Meditation

    Energy Technology Data Exchange (ETDEWEB)

    Hill, D.A.


    The aim of this thesis was to investigate the acute autonomic effects of the Transcendental Meditation Program (TM) and resolve the conflict arising from discrepant neurochemical and psychophysiological data. Three experimental investigations were performed. The first examined beta{sub 2}-adrenergic receptors (AR's) on peripheral blood lymphocytes, via (I{sup 125})iodocyanopindolol binding, in 10 male mediating and 10 age matched non-meditating control subjects, to test the hypothesis that the long-term practice of TM and the TM Sidhi Program (TMSP) reduces end organ sensitivity to adrenergic agonists. The second investigated respiratory sinus arrhythmia (an indirect measure of cardiac Parasympathetic Nervous System tone), and skin resistance (a measure of Sympathetic Nervous System tone) during periods of spontaneous respiratory apneusis, a phenomenon occurring during TM that is known to mark the subjective experience of transcending. The third was within subject investigation of the acute effects of the TMSP on 5-hydroxytryptamine (5-HT) activity. Platelet 5-HT was assayed by high pressure liquid chromatography with electrochemical detection, plasma prolactin (PL) and lutenizing hormone (LH) by radioimmunoassay, tryptophan by spectrofluorimetry, and alpha-1-acid glycoprotein (AGP, a modulator of 5-HT uptake) by radial immunodiffusion assay.

  5. β-Adrenergic Control of Hippocampal Function: Subserving the Choreography of Synaptic Information Storage and Memory (United States)

    Hagena, Hardy; Hansen, Niels; Manahan-Vaughan, Denise


    Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are “earmarked” for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength. The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3 > CA1). Moreover, NA released from the locus coeruleus that acts on β-AR leads to hippocampal LTD and an enhancement of LTD-related memory processing. We propose that NA acting on hippocampal β-AR, that is graded according to the novelty or saliency of the experience, determines the content and persistency of synaptic information storage in the hippocampal subfields and therefore of spatial memories. PMID:26804338

  6. Avaliação da influência do polimorfismo do códon 16 do receptor beta-2 adrenérgico na incidência de hipotensão arterial e uso de efedrina em grávidas submetidas à anestesia subaracnoidea Evaluación de la influencia del polimorfismo del codón 16 del receptor beta-2 adrenérgico en la incidencia de hipotensión arterial y uso de efedrina en embarazadas sometidas a la anestesia subaracnoidea Evaluation of the influence of the codon 16 polymorphism of the beta-2 adrenergic receptor gene on the incidence of arterial hypotension and ephedrine use in pregnant patients submitted to subarachnoid anesthesia

    Directory of Open Access Journals (Sweden)

    Edno Magalhães


    recientes han venido demostrando su importancia clínica. El objetivo de este trabajo, fue evaluar la influencia del polimorfismo Arg16Gli en la incidencia de hipotensión arterial y el uso de efedrina en parturientas sometidas al bloqueo subaracnoideo para cesárea. MÉTODO: Parturientas sanas (ASA I y II fueron sometidas a la anestesia raquídea para la realización de cesárea electiva (n = 50. Efedrina fue administrada en los casos de hipotensión arterial. La incidencia de hipotensión arterial y la dosis requerida de efedrina para la corrección de la presión arterial fueron comparadas entre los diferentes genotipos encontrados. RESULTADOS: El genotipo que más prevaleció fue el Arg16Gli (60%, n = 30 seguido por el Gli16Gli (26%, n = 13 y Arg16Arg (14%, n = 7. No se observaron diferencias entre las características básicas de los genotipos. Con relación al genotipo Arg16Arg, el genotipo Gli16Gli presentó un aumento de la razón de riesgo de hipotensión arterial (hazard ratio de 3,95 veces (IC 95% 0,86-18,11; p = 0,076, mientras que el genotipo Arg16Gli presentó un aumento de 4,83 veces (IC 95% 1,13-20,50; p = 0,033. Las parturientas con genotipo Arg16Arg, necesitaron como promedio 6,4 ± 8,5 mg de efedrina para la corrección de la hipotensión arterial, mientras que las del genotipo Arg16Gli necesitaron 19,5 ± 15,9 mg (p = 0,0445; IC 95% 0.3325-25.78 y las del tipo Gli16Gli 19,2 ± 14,3 (p = 0,0445, IC 95% 0.3476-25.26. CONCLUSIONES: Los resultados mostraron que la variante genética Arg16Arg presenta una menor incidencia de hipotensión arterial y que menores dosis de efedrina fueron necesarias para el reestablecimiento de la normotensión arterial en las pacientes con ese perfil genético. Concluimos que el genotipo Arg16Arg le da una mayor estabilidad de presión a las parturientas sometidas a la anestesia raquídea para cesárea.BACKGROUND AND OBJECTIVES: The beta-2 adrenergic receptor gene has several polymorphisms. Recent studies have demonstrated the

  7. Thymidylate synthase (TS tandem repeat promoter polymorphism and susceptibility to colorectal cancer of romanian subjects

    Directory of Open Access Journals (Sweden)

    Mihai TOMA


    Full Text Available The risk of colorectal cancer (CRC is influence by polymorphisms located in the genes encoding enzymes of the folate pathway. The aim of this study was to evaluate if 2R/3R TS (rs34743033 polymorphism is involved in predisposition for colorectal in Romanian subjects. In the present case-control study, 75 sporadic CRC subjects and 60 healthy controls were genotyped by PCR method. The frequency of 3R/3R genotype was 40% in control group and 42.7% in cancer group. We found that there was no statistically significant association between the risk for CRC and 2R/3R TS polymorphism in Romanian subjects.

  8. Molecular pathways

    DEFF Research Database (Denmark)

    Cox, Thomas R; Erler, Janine Terra


    that 45% of deaths in the developed world are linked to fibrotic disease. Fibrosis and cancer are known to be inextricably linked; however, we are only just beginning to understand the common and overlapping molecular pathways between the two. Here, we discuss what is known about the intersection...... of fibrosis and cancer, with a focus on cancer metastasis, and highlight some of the exciting new potential clinical targets that are emerging from analysis of the molecular pathways associated with these two devastating diseases. Clin Cancer Res; 20(14); 3637-43. ©2014 AACR....

  9. Genetic variation in the beta2-adrenergic receptor but not catecholamine-O-methyltransferase predisposes to chronic pain: results from the 1958 British Birth Cohort Study. (United States)

    Hocking, Lynne J; Smith, Blair H; Jones, Gareth T; Reid, David M; Strachan, David P; Macfarlane, Gary J


    More than 1 in 10 adults in the general population experience chronic widespread body pain (CWP), which lies at one end of a continuous spectrum of pain ranging in both severity and duration. Neuroendocrine factors can modify the effect of known psychological and psychosocial risk factors for progression along the spectrum of pain and development of CWP, and genetic variants that affect neuroendocrine and neural processing potentially affect susceptibility to chronic pain development. We have examined variants across genes encoding the beta2-adrenergic receptor (ADRB2) and catecholamine-O-methyltransferase (COMT) - key neuroendocrine signalling factors - in a large population-based sample to determine whether these may be involved in pain progression and CWP development. A nested association study was conducted using individuals from the 1958 British Birth Cohort Study who had been assessed for pain status. Genotypes were available for nine single nucleotide polymorphisms (SNPs) across ADRB2 and 11 SNPs across COMT. ADRB2 SNPs rs12654778 and rs1042713 were associated either with CWP alone (p=0.02 for both) or with position along pain spectrum (pain status; p=0.04). Common functional ADRB2 haplotype combinations were also associated with pain status (p(model)=0.002) and, further, with both extent and duration of pain (p(model)=0.003 and p(model)=0.002, respectively). There were no associations of either CWP or pain status with COMT genotypes or haplotypes. These results are the first to suggest that functional ADRB2 variants are involved in regulating pain status at a population level. A role for COMT in chronic pain development was not identified, though could not be excluded.

  10. Identification of alpha 2-adrenergic receptor sites in human retinoblastoma (Y-79) and neuroblastoma (SH-SY5Y) cells

    Energy Technology Data Exchange (ETDEWEB)

    Kazmi, S.M.; Mishra, R.K.


    The existence of specific alpha 2-adrenergic receptor sites has been shown in human retinoblastoma (Y-79) and neuroblastoma (SH-SH5Y) cells using direct radioligand binding. (/sup 3/H)Rauwolscine, a selective alpha 2-adrenergic receptor antagonist, exhibited high affinity, saturable binding to both Y-79 and SH-SY5Y cell membranes. The binding of alpha 1 specific antagonist, (/sup 3/H)Prazocine, was not detectable in either cell type. Competition studies with antagonists yielded pharmacological characteristics typical of alpha 2-adrenergic receptors: rauwolscine greater than yohimbine greater than phentolamine greater than prazocine. Based on the affinity constants of prazocine and oxymetazoline, it appears that Y-79 cells contain alpha 2A receptor, whereas SH-SY5Y cells probably represent a mixture of alpha 2A and alpha 2B receptors. alpha 2-agonists clonidine and (-)epinephrine inhibition curves yielded high and low affinity states of the receptor in SH-SY5Y cells. Gpp(NH)p and sodium ions reduced the proportion of high affinity sites of alpha 2 receptors. These two neuronal cell lines of human origin would prove useful in elucidating the action and regulation of human alpha 2-adrenergic receptors and their interaction with other receptor systems.

  11. The insula modulates arousal-induced reluctance to try novel tastes through adrenergic transmission in the rat (United States)

    Rojas, Sebastián; Diaz-Galarce, Raúl; Jerez-Baraona, Juan Manuel; Quintana-Donoso, Daisy; Moraga-Amaro, Rodrigo; Stehberg, Jimmy


    Reluctance to try novel tastes (neophobia) can be exacerbated in arousing situations, such as when children are under social stress or in rodents, when the new taste is presented in a high arousal context (HA) compared to a low arousal context (LA). The present study aimed at determining whether adrenergic transmission at the Insula regulates the reluctance to try novel tastes induced by arousing contexts. To this end, a combination of systemic and intra-insular manipulations of adrenergic activity was performed before the novel taste (saccharin 0.1%) was presented either in LA or HA contexts in rats. Our results show that systemic adrenergic activity modulates reluctance to try novel tastes. Moreover, intra-insular microinjections of propranolol or norepinephrine (NE) were found to modulate the effects of arousing contexts on reluctance to try novel tastes. Finally, intra-insular propranolol blocked epinephrine-induced increased reluctance, while intra-insular NE blocked oral propranolol-induced decreases in reluctance and increased the reluctance to try novel tastes presented in low arousing contexts. In conclusion, our results suggest that the insula is a critical site for regulating the effects of arousal in the reluctance to try novel tastes via the adrenergic system. PMID:26175672

  12. Subthreshold α2-Adrenergic Activation Counteracts Glucagon-Like Peptide-1 Potentiation of Glucose-Stimulated Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Minglin Pan


    Full Text Available The pancreatic β cell harbors α2-adrenergic and glucagon-like peptide-1 (GLP-1 receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the α2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS-1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold α2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX- sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold α2-adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release.

  13. How Can 1+1=3? beta(2)-Adrenergic and Glucocorticoid Receptor Agonist Synergism in Obstructive Airway Diseases

    NARCIS (Netherlands)

    Schmidt, Martina; Michel, Martin C.


    For a long time it was believed that beta(2)-adrenergic receptor agonists used in the treatment of obstructive airway diseases worked primarily on airway smooth muscle cells, causing relaxation, whereas glucocorticoids primarily improved airway function via their anti-inflammatory action, indicating

  14. Heterocyclic acetamide and benzamide derivatives as potent and selective beta3-adrenergic receptor agonists with improved rodent pharmacokinetic profiles. (United States)

    Goble, Stephen D; Wang, Liping; Howell, K Lulu; Bansal, Alka; Berger, Richard; Brockunier, Linda; DiSalvo, Jerry; Feighner, Scott; Harper, Bart; He, Jiafang; Hurley, Amanda; Hreniuk, Donna; Parmee, Emma; Robbins, Michael; Salituro, Gino; Sanfiz, Anthony; Streckfuss, Eric; Watkins, Eloisa; Weber, Ann E; Struthers, Mary; Edmondson, Scott D


    A series of amide derived beta(3)-adrenergic receptor (AR) agonists is described. The discovery and optimization of several series of compounds derived from 1, is used to lay the SAR foundation for second generation beta(3)-AR agonists for the treatment of overactive bladder.

  15. Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4

    DEFF Research Database (Denmark)

    Richter, Wito; Day, Peter; Agrawal, Rani


    Beta1- and beta2-adrenergic receptors (betaARs) are highly homologous, yet they play clearly distinct roles in cardiac physiology and pathology. Myocyte contraction, for instance, is readily stimulated by beta1AR but not beta2AR signaling, and chronic stimulation of the two receptors has opposing...

  16. Participation of beta-adrenergic activity in modulation of GLUT4 expression during fasting and refeeding in rats (United States)

    Through in vitro studies, several factors have been reported as modulators of GLUT4 gene expression. However, the role(s) of each potential GLUT4 modulator is not completely understood in the in vivo setting. The present study has investigated the hypothesis that beta-adrenergic stimulation particip...

  17. Circadian-related heteromerization of adrenergic and dopamine D₄ receptors modulates melatonin synthesis and release in the pineal gland.

    Directory of Open Access Journals (Sweden)

    Sergio González

    Full Text Available The role of the pineal gland is to translate the rhythmic cycles of night and day encoded by the retina into hormonal signals that are transmitted to the rest of the neuronal system in the form of serotonin and melatonin synthesis and release. Here we describe that the production of both melatonin and serotonin by the pineal gland is regulated by a circadian-related heteromerization of adrenergic and dopamine D₄ receptors. Through α(₁B-D₄ and β₁-D₄ receptor heteromers dopamine inhibits adrenergic receptor signaling and blocks the synthesis of melatonin induced by adrenergic receptor ligands. This inhibition was not observed at hours of the day when D₄ was not expressed. These data provide a new perspective on dopamine function and constitute the first example of a circadian-controlled receptor heteromer. The unanticipated heteromerization between adrenergic and dopamine D₄ receptors provides a feedback mechanism for the neuronal hormone system in the form of dopamine to control circadian inputs.

  18. The Insula modulates arousal-induced reluctance to try novel tastes through adrenergic transmission in the rat

    Directory of Open Access Journals (Sweden)

    Sebastián Andrés Rojas


    Full Text Available Reluctance to try novel tastes (neophobia can be exacerbated in arousing situations, such as when children are under social stress or in rodents, when the new taste is presented in a high arousal context (HA compared to a low arousal context (LA. The present study aimed at determining whether adrenergic transmission at the Insula regulates the reluctance to try novel tastes induced by arousing contexts. To this end, a combination of systemic and intra-insular manipulations of adrenergic activity was performed before the novel taste (saccharin 0.1% was presented either in LA or HA contexts in rats. Our results show that systemic adrenergic activity modulates reluctance to try novel tastes. Moreover, intra-insular microinjections of propranolol or norepinephrine were found to modulate the effects of arousing contexts on reluctance to try novel tastes. Finally, intra-insular propranolol blocked epinephrine-induced increased reluctance, while intra-insular norepinephrine blocked oral propranolol-induced decreases in reluctance and increased the reluctance to try novel tastes presented in low arousing contexts. In conclusion, our results suggest that the insula is a critical site for regulating the effects of arousal in the reluctance to try novel tastes via the adrenergic system.

  19. Angiogenin gene polymorphism

    Institute of Scientific and Technical Information of China (English)

    Hongli Wang; Dongsheng Fan; Yingshuang Zhang


    Angiogenin is associated with the pathogenesis of diabetic peripheral neuropathy. Here, we se-quenced the coding region of the angiogenin gene in genomic DNA from 207 patients with type 2 diabetes mel itus (129 diabetic peripheral neuropathy patients and 78 diabetic non-neuropathy pa-tients) and 268 healthy controls. Al subjects were from the Han population of northern China. No mutations were found. We then compared the genotype and allele frequencies of the angiogenin synonymous single nucleotide polymorphism rs11701 between the diabetic peripheral neuropathy patients and controls, and between the diabetic neuropathy and non-neuropathy patients, using a case-control design. We detected no statistical y significant genetic associations. Angiogenin may not be associated with genetic susceptibility to diabetic peripheral neuropathy in the Han population of northern China.

  20. SUMO4基因多态性与NF-κB、糖尿病及冠心病的关系%Role of SUMO4 gene polymorphism in NF-κB signalling pathway and its research advances in genetic susceptibility to DM and CAD

    Institute of Scientific and Technical Information of China (English)

    蒲连美; 南楠; 杨泽; 金泽宁; 刘铭


    Diabetes mellitus ( DM ) and coronary artery disease ( CAD ) are both complex chronic diseases which are caused by interactions of multiple genes with environmental factors.Nuclear factor kappa- B ( NF-κB ) is a family of critical transcription factors modulating the expression of diverse genes involved in the pathogenesis of several inflammatory diseases,including DM and CAD. IκBα is one of the most important inhibitory proteins for NF-κB.SUMO4 conjugates IκBα and stabilizes it from degradation.As a result NF-κB is kept inactive in the cytosol by forming a complex with IκBα and SUMO4.Moreover dissociated NF-κB binds to SUMO4 promoter and activates its transcription.S(o) SUMO4 can function as a negative feedback regulator for the NF-κB signaling pathway.Studies confirmed that SUMO4 M55V substitution results in significant higher levels of NF-κB activity and is associated with susceptibility to DM and CAD.This review focuses on the role of SUMO4 gene polymorphism in NF-κB signalling pathway and its research advances in genetic susceptibility to DM and CAD.%糖尿病( diabetes mellitus,DM)和冠心病(coronary artery disease,CAD)均为多基因介导、基因和环境相互作用的慢性复杂疾病.核因子κB(nuclear factor kappa B,NF- κB)是一类转录因子家族,在细胞内信号传导系统中起关键作用,参与包括DM和CAD在内的多种炎症性疾病的发生发展.研究证实小泛素样修饰蛋白4( small ubiquitin- like modi - fier 4,SUMO4)使NF- κB的抑制剂IκBα免于降解,负性调节NF- κB的转录活性,另外游离的NF- κB能够与SUMO4基因启动子结合并激活SUMO4基因的转录.而SUMO4基因多态性导致NF-κB活性显著增加,并与DM和CAD的易感性相关.此文主要就SUMO4基因多态性对NF-κB转录活性的影响及其在DM和CAD遗传易感性的关联研究进展作一概述.

  1. Common genetic variations in cell cycle and DNA repair pathways associated with pediatric brain tumor susceptibility

    DEFF Research Database (Denmark)

    Adel Fahmideh, Maral; Lavebratt, Catharina; Schüz, Joachim


    Knowledge on the role of genetic polymorphisms in the etiology of pediatric brain tumors (PBTs) is limited. Therefore, we investigated the association between single nucleotide polymorphisms (SNPs), identified by candidate gene-association studies on adult brain tumors, and PBT risk.The study...... cycle and DNA repair pathways variations associated with susceptibility to adult brain tumors also seem to be associated with PBT risk, suggesting pediatric and adult brain tumors might share similar etiological pathways....

  2. Intracellular β2-adrenergic receptor signaling specificity in mouse skeletal muscle in response to single-dose β2-agonist clenbuterol treatment and acute exercise. (United States)

    Sato, Shogo; Shirato, Ken; Mitsuhashi, Ryosuke; Inoue, Daisuke; Kizaki, Takako; Ohno, Hideki; Tachiyashiki, Kaoru; Imaizumi, Kazuhiko


    The aim of this study was to clarify the intracellular β2-adrenergic receptor signaling specificity in mouse slow-twitch soleus and fast-twitch tibialis anterior (TA) muscles, resulting from single-dose β2-agonist clenbuterol treatment and acute exercise. At 1, 4, and 24 h after single-dose treatment with clenbuterol or after acute running exercise, the soleus and TA muscles were isolated and subjected to analysis. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) increased after single-dose clenbuterol treatment and acute exercise in the soleus muscle but not in the TA muscle. Although there was no change in the phosphorylation of Akt after acute exercise in either muscle, phosphorylation of Akt in the soleus muscle increased after single-dose clenbuterol treatment, whereas that in the TA muscle remained unchanged. These results suggest that p38 MAPK and Akt pathways play a functional role in the adaptation to clenbuterol treatment and exercise, particularly in slow-twitch muscles.

  3. Colorectal Cancer & Molecular Mutations and Polymorphism

    Directory of Open Access Journals (Sweden)

    Aga Syed Sameer


    Full Text Available Colorectal cancer (CRC is one of the major causes of mortality and morbidity, and is the third most common cancer in men and the second most common cancer in women worldwide. The incidence of CRC shows considerable variation among racially or ethnically defined populations in multiracial/ethnic countries. The tumorigenesis of CRC is either because of the chromosomal instability (CIN or microsatellite instability (MIN or involving various proto-oncogenes, tumor suppressor genes and also epigenetic changes in the DNA. In this review I have focused on the mutations and polymorphisms of various important genes of the CIN and MIN pathways which have been implicated in the development of CRC.

  4. β-arrestin and β-adrenergic Receptor%β-arrestin与β-肾上腺素受体

    Institute of Scientific and Technical Information of China (English)

    杨承志; 李子健


    The Nobel Prize in Chemistry 2012 was awarded jointly to Robert J. Lefkowitz and Brian K. Kobilka "for studies of G-protein-coupled receptors". Robert J. Lefkowitz discovered β-arrestinl more than 20 years ago, when he studied the mechanism of β-AR (p-adrenergic receptor) desensitization, and proved that it involves in the desensitization, internalization and degradation of β-AR in his subsequent researches. More recently, new evidence has revealed the "biased agonism" of β-arrestin dependent signal pathway of β-AR, which is independent of G protein. Excitingly, this biased signaling was suggested to confer cardioprotection. In addition, β-AR blockers were discovered and widely used in the pharmacotherapy of cardiovascular diseases among many other β-AR targeted cardiovascular drugs, which was a breakthrough in the 20th century. However, most of these drugs take effect only by regulating the β-AR itself and block all of the signal pathways and functions, including both the pathological signaling and effect induced by the increased stimulation of β-AR and the normal physiological ones, which leads to some severe adverse reactions. Therefore, it will be a great progress in the treatment of cardiovascular diseases to develop the drug that can both selectively block the harmful signaling and effect and activate the beneficial physiological signaling (such as the β-arrestin signaling) of β-AR. The research and development of ligand drug for β-AR will focus on its highly selective downstream signal pathways. This article is to review the discovery of the β-arrestin and its interaction with β-AR, to offer a reference for the pharmacotherapy of cardiovascular diseases.%2012年度诺贝尔化学奖授予了美国科学家罗伯特·莱夫科维茨(Robert J.Lefkowitz)和布莱恩·克比尔卡(Brian K.Kobilka),以表彰他们在G蛋白偶联受体研究中的贡献.从Robert J.Lefkowitz最初研究β-肾上腺素受体(β-adrenergic receptor,β-AR

  5. Beta adrenergic overstimulation impaired vascular contractility via actin-cytoskeleton disorganization in rabbit cerebral artery.

    Directory of Open Access Journals (Sweden)

    Hyoung Kyu Kim

    Full Text Available BACKGROUND AND PURPOSE: Beta adrenergic overstimulation may increase the vascular damage and stroke. However, the underlying mechanisms of beta adrenergic overstimulation in cerebrovascular dysfunctions are not well known. We investigated the possible cerebrovascular dysfunction response to isoproterenol induced beta-adrenergic overstimulation (ISO in rabbit cerebral arteries (CAs. METHODS: ISO was induced in six weeks aged male New Zealand white rabbit (0.8-1.0 kg by 7-days isoproterenol injection (300 μg/kg/day. We investigated the alteration of protein expression in ISO treated CAs using 2DE proteomics and western blot analysis. Systemic properties of 2DE proteomics result were analyzed using bioinformatics software. ROS generation and following DNA damage were assessed to evaluate deteriorative effect of ISO on CAs. Intracellular Ca(2+ level change and vascular contractile response to vasoactive drug, angiotensin II (Ang II, were assessed to evaluate functional alteration of ISO treated CAs. Ang II-induced ROS generation was assessed to evaluated involvement of ROS generation in CA contractility. RESULTS: Proteomic analysis revealed remarkably decreased expression of cytoskeleton organizing proteins (e.g. actin related protein 1A and 2, α-actin, capping protein Z beta, and vimentin and anti-oxidative stress proteins (e.g. heat shock protein 9A and stress-induced-phosphoprotein 1 in ISO-CAs. As a cause of dysregulation of actin-cytoskeleton organization, we found decreased level of RhoA and ROCK1, which are major regulators of actin-cytoskeleton organization. As functional consequences of proteomic alteration, we found the decreased transient Ca(2+ efflux and constriction response to angiotensin II and high K(+ in ISO-CAs. ISO also increased basal ROS generation and induced oxidative damage in CA; however, it decreased the Ang II-induced ROS generation rate. These results indicate that ISO disrupted actin cytoskeleton proteome network

  6. Binding of (3H)dihydroergocryptine to an alpha-adrenergic site in the stalk median eminence of the steer

    Energy Technology Data Exchange (ETDEWEB)

    Chen, H.T.; Roberts, J.M.; Weiner, R.I.


    Dihydroergocryptine (DHE), a potent dopamine agonist and alpha-adrenergic antagonist, has been used as a radioligand to characterize both dopamine and alpha-adrenergic receptors. In the present study, the binding of (3H)DHE to particulate fractions of the steer stalk median eminence was characterized using a filtration assay. Specific binding was defined by the presence of 10 microM phentolamine or by an iterative nonlinear hyperbolic curve-fitting program. Scatchard analysis of equilibrium isotherms of specific binding defined a single high affinity (Kd . 1.78 +/- 0.22 nM), saturable (maximum binding, 481 +/- 39 fmol/mg protein), stereoselective binding site. The Kd, calculated from the ratio of the rate constants k2 and k1, was 2.8 +/- 0.14 nM. The rank order of potency of agonists to compete for (3H)DHE binding (l-epinephrine greater than l-norepinephrine greater than dopamine greater than l-isoproterenol) was consistent with interactions at an alpha-adrenergic site. The rank order of potency of alpha-antagonists (phentolamine greater than yohimbine greater than prazosin) suggested that this was an alpha 2-adrenergic receptor. The affinity of dopamine agonists for the (3H)DHE-binding site was 10-fold lower relative to their potency at known dopamine receptors, while the affinity of dopaminergic antagonists was 100-fold lower. Furthermore, Scatchard analysis of specific (3H)DHE binding in the presence of a concentration of spiperone which should saturate dopamine receptors, only decreased the number of binding sites by 9%. These data demonstrate the presence of large numbers of alpha-adrenergic receptors in the stalk median eminence of the steer. Only a small number of dopaminergic binding sites for (3H)DHE appeared to be present.

  7. Effects of β2-Adrenergic Antagonist on Cytosolic Ca2+ in Ventricular Myocytes from Infarcted Rat Heart

    Institute of Scientific and Technical Information of China (English)

    Yang Hui; Wu Wei; Zeng Chong; Deng Chunyu; Fang Chang; Chen Shanming


    Objectives To investigate the effects of β2-adrenergic antagonist on cytosolic Ca2 +([Ca2+]i) in ventricular myocytes from infarcted rat heart. Methods A ligature was placed around left anterior descending coronary artery of rat hearts. Rats in the control group were sham-operated.Cardiomyocytes were dissociated at two, four, eight weeks after myocardial infarction (MI) and [Ca2+]i was measured via fura-2 fluorescence. The response of cardiomyocytes to isoproterenol in presence or absenceof beta1-adrenergic antagonist atenolol, beta2-adrenergic antagonist ICI118, 551 or non-selective β1,2- adrenergic antagonists propranolol was examined.Results The followings were found that ICI11 8, 551 had no significant effects on the rise of [Ca2+]i induced by isoproterenol in normal ventricular myocytes (P >0.05), ICI118, 551 only significantly attenuated the rise of [Ca2+]i induced by isoproterenol at four weeks and eight weeks after MI (24.5% ±5.7% vs 57.8% ±13.2%, P< 0.01; 12.2%±7.9% vs 44.6%±11.3%, P<0.01). Atenolol had suppressive effects only in the control group and the post-MI group of two weeks (P<0.05), and propranolol had suppressive effects in the control and all the three post-MI groups (P<0.01).Conclusions Beta2-adrenergic antagonist ICI118,551 may exert negative effects on Ca2+ overload initiated by sympathetic stimulation after MI.

  8. Beta-adrenergic stimulation reverses the I Kr-I Ks dominant pattern during cardiac action potential. (United States)

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T; Chen-Izu, Ye


    β-Adrenergic stimulation differentially modulates different K(+) channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of I Ks, I Kr, and I K1 currents in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K(+) current to the total repolarization reserve. In this study, we used an innovative AP-clamp sequential dissection technique to directly record the dynamic I Ks, I Kr, and I K1 currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of I Ks, I Kr, and I K1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca(2+) homeostasis. We found that isoproterenol treatment significantly enhanced I Ks, moderately increased I K1, but slightly decreased I Kr in a dose-dependent manner. The dominance pattern of the K(+) currents was I Kr > I K1 > I Ks at the control condition, but reversed to I Kr < I K1 < I Ks following β-adrenergic stimulation. We systematically determined the changes in the relative contribution of I Ks, I Kr, and I K1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K(+) currents in a dose-dependent manner. This knowledge is important for designing antiarrhythmic drug strategies to treat hearts exposed to various sympathetic tones.

  9. The use of alpha-1 adrenergic blockers in children with distal ureterolithiasis: a systematic review and meta-analysis (United States)

    Glina, F.P.; Castro, P.M.V.; Monteiro, G.G.R.; Guerra, G.C. Del; Glina, S.; Mazzurana, M.; Bernardo, W.M.


    ABSTRACT Introduction: Urinary lithiasis is the main urologic cause of emergency treatment in adult patient. In the past years, the incidence in children population has increased. However, literature about the use of alpha-1 adrenergic blockers in pediatric population with distal ureterolithiasis is still scarce. The drug acts by decreasing ureter contractions, especially in the distal portion, facilitating calculus expulsion. Objective: This review has the objective to evaluate the use of alpha-1 adrenergic blockers as medical expulsive treatment in children with distal ureterolithiasis. Evidence Acquisition: An electronic literature search was performed using the MEDLINE, COCHRANE, and LILACS databases. We further searched manually the references of the primary studies. Searches were concluded on October 4th, 2014. Articles were selected, independently and in pairs, by the respective titles and summaries. Any divergence was resolved by consensus. Evidence Synthesis: Alpha-1 adrenergic antagonists increased the probability of calculus expulsion by 27% (NNT=4). Calculi smaller than 5mm, increased by 33% (NNT=3). Larger than 5mm, increased by 34% (NNT=3). Conclusion: Alpha-1 adrenergic blocker use is related with a greater incidence of expulsion of ureteral calculi, smaller or greater than 5mm, and fewer episodes of pain when compared to ibuprofen. However it is necessary larger samples to enhance the power analysis of the expulsion of ureteral calculi larger than 5mm and the episodes of pain. Patient Summary: This review analyzed the outcome of alpha adrenergic antagonist in children with ureteral calculi. We conclude that it is the best medicine for use, since it helps the expulsion of the stone. PMID:26717117

  10. The use of alpha-1 adrenergic blockers in children with distal ureterolithiasis: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    F.P. Glina


    Full Text Available Introduction: Urinary lithiasis is the main urologic cause of emergency treatment in adult patient. In the past years, the incidence in children population has increased. However, literature about the use of alpha-1 adrenergic blockers in pediatric population with distal ureterolithiasis is still scarce. The drug acts by decreasing ureter contractions, especially in the distal portion, facilitating calculus expulsion. Objective: This review has the objective to evaluate the use of alpha-1 adrenergic blockers as medical expulsive treatment in children with distal ureterolithiasis. Evidence Acquisition: An electronic literature search was performed using the MEDLINE, COCHRANE, and LILACS databases. We further searched manually the references of the primary studies. Searches were concluded on October 4th, 2014. Articles were selected, independently and in pairs, by the respective titles and summaries. Any divergence was resolved by consensus. Evidence Synthesis: Alpha-1 adrenergic antagonists increased the probability of calculus expulsion by 27% (NNT=4. Calculi smaller than 5mm, increased by 33% (NNT=3. Larger than 5mm, increased by 34% (NNT=3. Conclusion: Alpha-1 adrenergic blocker use is related with a greater incidence of expulsion of ureteral calculi, smaller or greater than 5mm, and fewer episodes of pain when compared to ibuprofen. However it is necessary larger samples to enhance the power analysis of the expulsion of ureteral calculi larger than 5mm and the episodes of pain. Patient Summary: This review analyzed the outcome of alpha adrenergic antagonist in children with ureteral calculi. We conclude that it is the best medicine for use, since it helps the expulsion of the stone.

  11. Stress-induced decrease of uterine blood flow in sheep is mediated by alpha 1-adrenergic receptors. (United States)

    Dreiling, Michelle; Bischoff, Sabine; Schiffner, Rene; Rupprecht, Sven; Kiehntopf, Michael; Schubert, Harald; Witte, Otto W; Nathanielsz, Peter W; Schwab, Matthias; Rakers, Florian


    Prenatal maternal stress can be transferred to the fetus via a catecholamine-dependent decrease of uterine blood flow (UBF). However, it is unclear which group of adrenergic receptors mediates this mechanism of maternal-fetal stress transfer. We hypothesized that in sheep, alpha 1-adrenergic receptors may play a key role in catecholamine mediated UBF decrease, as these receptors are mainly involved in peripheral vasoconstriction and are present in significant number in the uterine vasculature. After chronic instrumentation at 125 ± 1 days of gestation (dGA; term 150 dGA), nine pregnant sheep were exposed at 130 ± 1 dGA to acute isolation stress for one hour without visual, tactile, or auditory contact with their flockmates. UBF, blood pressure (BP), heart rate (HR), stress hormones, and blood gases were determined before and during this isolation challenge. Twenty-four hours later, experiments were repeated during alpha 1-adrenergic receptor blockage induced by a continuous intravenous infusion of urapidil. In both experiments, ewes reacted to isolation with an increase in serum norepinephrine, cortisol, BP, and HR as typical signs of activation of sympatho-adrenal and the hypothalamic-pituitary-adrenal axis. Stress-induced UBF decrease was prevented by alpha 1-adrenergic receptor blockage. We conclude that UBF decrease induced by maternal stress in sheep is mediated by alpha 1-adrenergic receptors. Future studies investigating prevention strategies of impact of prenatal maternal stress on fetal health should consider selective blockage of alpha 1-receptors to interrupt maternal-fetal stress transfer mediated by utero-placental malperfusion.


    Directory of Open Access Journals (Sweden)

    Lucian Hritcu


    Full Text Available : 3 consecutive days propranolol hydrochloride administration (5 mg/kg b.w., subcutaneous injections under acute and chronic stress conditions causes changes of peripheral erythrocyte distribution in rats. The effects of acute stress and its combination with ȕ-adrenergic receptor blockade on erythrocyte dynamic were more pregnant beside the effects of chronic stress and its combination with ȕ-adrenergic receptor blockade, respectively. ȕ-adrenergic mechanisms were shown to be involved in regulation of erythrocyte dynamic in acute and chronic stress response.

  13. Comparative hydrodynamics of bacterial polymorphism

    CERN Document Server

    Spagnolie, Saverio E


    Most bacteria swim through fluids by rotating helical flagella which can take one of twelve distinct polymorphic shapes. The most common helical waveform is the "normal" form, used during forward swimming runs. To shed light on the prevalence of the normal form in locomotion, we gather all available experimental measurements of the various polymorphic forms and compute their intrinsic hydrodynamic efficiencies. The normal helical form is found to be the most hydrodynamically efficient of the twelve polymorphic forms by a significant margin - a conclusion valid for both the peritrichous and polar flagellar families, and robust to a change in the effective flagellum diameter or length. The hydrodynamic optimality of the normal polymorph suggests that, although energetic costs of locomotion are small for bacteria, fluid mechanical forces may have played a significant role in the evolution of the flagellum.

  14. Expressions of cardiac sympathetic norepinephrine transporter and β1-adrenergic receptor decreased in aged rats

    Institute of Scientific and Technical Information of China (English)

    He LI; Xiao-qing MA; Fan YE; Jing ZHANG; Xin ZHOU; Zhi-hong WANG; Yu-ming LI; Guo-yuan ZHANG


    Evidence suggests that the deterioration of communication between the sympathetic nervous system and cardiovas-cular system always accompanies the aging of human and animals. Cardiac sympathetic norepinephrine (NE) transporter (NET) on presynaptic membrane is a predominant component to eliminate released NE in the synaptic cleff and maintains the sensitivity of the β-adrenergic receptor (β-AR). In the present study, we investigated NET and β1-AR mRNA levels and sympathetic nerve density in cardiac sympathetic ganglion and leff ventricular myocardium in 2- and 16-month-old rats with Northern blot analysis and immunohistochemistry. The expression levels of NET mRNA, NET protein and β1-AR mRNA in the ganglia or myocardia of 16-month-old rats were markedly reduced by 67%, 26%, and 43%, respectively, in comparison with those in 2-month-old rats. Our results also show that aging induces a strong decrease of the catecholaminergic nerve fiber density.

  15. a-Adrenergic vasoconstrictor responsiveness is preserved in the heated human leg

    DEFF Research Database (Denmark)

    Keller, David M; Sander, Mikael; Stallknecht, Bente Merete;


    This study tested the hypothesis that passive leg heating attenuates a-adrenergic vasoconstriction within that limb. Femoral blood flow (FBF, femoral artery ultrasound Doppler) and femoral vascular conductance (FVC, FBF/mean arterial blood pressure), as well as calf muscle blood flow (Calf......BF, ¹³³xenon) and calf vascular conductance (CalfVC) were measured during intra-arterial infusion of an a1-adrenoreceptor agonist, phenylephrine (PE, 0.025 to 0.8 µg kg¿1 min¿1) and an a2-adrenoreceptor agonist, BHT-933 (1.0 to 10 µg kg¿1 min¿1) during normothermia and passive leg heating (water-perfused pant...... leg). Passive leg heating (~46¿C water temperature) increased FVC from 4.5 ± 0.5 to 11.9 ± 1.3 ml min¿1 mmHg¿1 (P

  16. Synthesis of the sup 11 C-labelled. beta. -adrenergic receptor ligands atenolol, metoprolol and propanolol

    Energy Technology Data Exchange (ETDEWEB)

    Antoni, G.; Ulin, J.; Laangstroem, B. (Uppsala Univ. (Sweden). Dept. of Organic Chemistry)


    The {sup 11}C-labelled {beta}-adrenergic receptor ligands atenolol 1, metoprolol 2 and propranolol 3 have been synthesized by an N-alkylation reaction using (2-{sup 11}C)isopropyl iodide. The labelled isopropyl iodide was prepared in a one-pot reactor system from ({sup 11}C)carbon dioxide and obtained in 40% radiochemical yield within 14 min reaction time. The total reaction times for compounds 1-3, counted from the start of the isopropyl iodide synthesis and including purification were 45-55 min. The products were obtained in 5-15% radiochemical yields and with radiochemical purities higher than 98%. The specific activity ranged from 0.4 to 4 GBq/{mu}mol. In a typical experiment starting with 4 GBq around 75 MBq of product was obtained. (author).

  17. Postcountershock myocardial damage after pretreatment with adrenergic and calcium channel antagonists in halothane-anesthetized dogs

    Energy Technology Data Exchange (ETDEWEB)

    Gaba, D.M.; Metz, S.; Maze, M.


    Transthoracic electric countershock can cause necrotic myocardial lesions in humans as well as experimental animals. The authors investigated the effect on postcountershock myocardial damage of pretreatment with prazosin, an alpha-1 antagonist; L-metoprolol, a beta-1 antagonist, and verapamil, a calcium channel-blocking agent. Twenty dogs were anesthetized with halothane and given two transthoracic countershocks of 295 delivered joules each after drug or vehicle treatment. Myocardial injury was quantitated 24 h following countershock by measuring the uptake of technetium-99m pyrophosphate in the myocardium. Elevated technetium-99m pyrophosphate uptake occurred in visible lesions in most dogs regardless of drug treatment. For each of four parameters of myocardial damage there was no statistically significant difference between control animals and those treated with prazosin, metoprolol, or verapamil. These data suggest that adrenergic or calcium channel-mediated mechanisms are not involved in the pathogenesis of postcountershock myocardial damage.

  18. beta2 adrenergic agonists in acute lung injury? The heart of the matter. (United States)

    Lee, Jae W


    Despite extensive research into its pathophysiology, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) remains a devastating syndrome with mortality approaching 40%. Pharmacologic therapies that reduce the severity of lung injury in vivo and in vitro have not yet been translated to effective clinical treatment options, and innovative therapies are needed. Recently, the use of beta2 adrenergic agonists as potential therapy has gained considerable interest due to their ability to increase the resolution of pulmonary edema. However, the results of clinical trials of beta agonist therapy for ALI/ARDS have been conflicting in terms of benefit. In the previous issue of Critical Care, Briot and colleagues present evidence that may help clarify the inconsistent results. The authors demonstrate that, in oleic acid lung injury in dogs, the inotropic effect of beta agonists may recruit damaged pulmonary capillaries, leading to increased lung endothelial permeability.

  19. PET measures of pre- and post-synaptic cardiac beta adrenergic function

    Energy Technology Data Exchange (ETDEWEB)

    Link, Jeanne M.; Stratton, John R.; Levy, Wayne; Poole, Jeanne E.; Shoner, Steven C.; Stuetzle, Werner; Caldwell, James H. E-mail:


    Positron Emission Tomography was used to measure global and regional cardiac {beta}-adrenergic function in 19 normal subjects and 9 congestive heart failure patients. [{sup 11}C]-meta-hydroxyephedrine was used to image norepinephrine transporter function as an indicator of pre-synaptic function and [{sup 11}C]-CGP12177 was used to measure cell surface {beta}-receptor density as an indicator of post-synaptic function. Pre-synaptic, but not post-synaptic, function was significantly different between normals and CHF patients. Pre-synaptic function was well matched to post-synaptic function in the normal hearts but significantly different and poorly matched in the CHF patients studied. This imaging technique can help us understand regional sympathetic function in cardiac disease.

  20. Heterogeneous responses of human limbs to infused adrenergic agonists: a gravitational effect? (United States)

    Pawelczyk, James A.; Levine, Benjamin D.


    Unlike quadrupeds, the legs of humans are regularly exposed to elevated pressures relative to the arms. We hypothesized that this "dependent hypertension" would be associated with altered adrenergic responsiveness. Isoproterenol (0.75-24 ng x 100 ml limb volume-1 x min-1) and phenylephrine (0.025-0.8 microg x 100 ml limb volume-1 x min-1) were infused incrementally in the brachial and femoral arteries of 12 normal volunteers; changes in limb blood flow were quantified by using strain-gauge plethysmography. Compared with the forearm, baseline calf vascular resistance was greater (38.8 +/- 2.5 vs. 26.9 +/- 2.0 mmHg x 100 ml x min x ml-1; P filtration in the legs during standing.

  1. [Beta-3 adrenergic receptor--structure and role in obesity and metabolic disorders]. (United States)

    Wiejak, J; Wyroba, E


    Structure and essential motifs of beta 3-adrenergic receptor (known previously as atypical beta-AR), which plays a central role in regulation of lipid metabolism have been described. Obesity results from an imbalance between caloric intake and energy expenditure. The consequence of catecholamine activation of beta 3-AR is increased mobilization of fatty acids from triglyceride stores (lipolysis) in brown and white adipose tissue as well as increased fatty acid beta-oxidation and heat-production via UCP-1 (thermogenesis) in brown adipose tissue. A pharmacokinetic effects of beta 3-agonists and putative involvement of Trp/Arg mutation in beta 3-AR gene in obesity and another metabolic disorders have been discussed.

  2. Conversion of agonist site to metal-ion chelator site in the beta(2)-adrenergic receptor

    DEFF Research Database (Denmark)

    Elling, C E; Thirstrup, K; Holst, Birgitte


    in the mutant receptors not by normal catecholamine ligands but instead either by free zinc ions or by zinc or copper ions in complex with small hydrophobic metal-ion chelators. Chelation of the metal ions by small hydrophobic chelators such as phenanthroline or bipyridine protected the cells from the toxic......Previously metal-ion sites have been used as structural and functional probes in seven transmembrane receptors (7TM), but as yet all the engineered sites have been inactivating. Based on presumed agonist interaction points in transmembrane III (TM-III) and -VII of the beta(2)-adrenergic receptor......, in this paper we construct an activating metal-ion site between the amine-binding Asp-113 in TM-III-or a His residue introduced at this position-and a Cys residue substituted for Asn-312 in TM-VII. No increase in constitutive activity was observed in the mutant receptors. Signal transduction was activated...

  3. Trafficking of α1B-adrenergic receptor mediated by inverse agonist in living cells

    Institute of Scientific and Technical Information of China (English)

    MingXU; Ying-huaGUAN; NingXU; Zhang-yiLIANG; Shu-yiWang; YaoSONG; Chi-deHAN; Xin-shengZHAO; You-yiZHANG


    AIM The project is aimed at understanding the action of inverse agonist at single molecule level and capturing the real time picture of molecular behavior of α1B-adrenergic receptor (AR) mediated by inverse agonist in living cells by single molecule detection (SMD). METHODS The location and distribution of α1B-AR was detected by laser confocal and whole cell 3H-prazosin binding assay. Dynamic imaging of BODIPY-FL-labeled prazosin (Praz), specific antagonist of (1-AR, was observed in α1B-AR stably expressed human embryonic kidney 293 (HEK293) living cells. The detection of real-time dynamic behaviors of AR was achieved by using fluorescence-labeled AR and its ligand combined with SMD techniques. RESULTS α1B-AR was predominantly distributed on the cell surface and 8.2% of the total receptors were located in cytosol.

  4. Presence and location of adrenergic nerve endings in the dental pulps of mouse molars. (United States)

    Avery, J K; Cox, C F; Chiego, D J


    In all, 30 adult (45-day-old) Swiss Webster mice were used for light and electron microscopic examination of the presence, number, and location of adrenergic endings in the first molar teeth. Prior to sacrifice, 10 animals received i.p. injections at 8, 6, 4, and 2 hours of 0.5 cc of 20 mg/kg solution of 5-hydroxydopamine (5-OH-DA) as a label for adrenergic endings. The animals were then anesthetized, perfused with Karnovsky's fixative, and the teeth were postfixed in Osmic acid, decalcified, embedded in methacrylate, and serial-sectioned. The sections were surveyed by light microscopy, and the number and location of nerve endings containing the reduced 5-OH-DA were recorded. Ten control mice were injected with the vehicle solution and prepared in the same manner. A third series of mice were given a single injection of 5-OH-DA, sacrificed, and prepared for ultrastructural study. The molar pulps were divided into four areas to facilitate examination: pulp horns, coronal pulp, bifurcation area, and root pulp. These four areas were further divided into three zones: odontogenic, vascular-related, and nonvascular-associated. The location and number of endings were evaluated, and an average of approximately 70 endings containing the 5-OH-DA were found in each tooth using light microscopy. These represented 35.5 +/- 5.2 in the pulp horns; 26.1 +/- 2.4 in the central coronal; 5.4 +/- 0.7 in the bifurcation, and 5.6 +/- 0.9 in the root pulp per tooth. Vascular related endings were found in greatest number, the odontogenic zone next, and free endings lease. Verification of location of 5-OH-DA by ultrastructural analysis revealed the false transmitter in vesiculated endings in the four areas and zones of the pulp.

  5. Increased circulating β2-adrenergic receptor autoantibodies are associated with smoking-related emphysema (United States)

    Hu, Jia-yi; Liu, Bei-bei; Du, Yi-peng; Zhang, Yuan; Zhang, Yi-wei; Zhang, You-yi; Xu, Ming; He, Bei


    Smoking is a dominant risk factor for chronic obstructive pulmonary disease (COPD) and emphysema, but not every smoker develops emphysema. Immune responses in smokers vary. Some autoantibodies have been shown to contribute to the development of emphysema in smokers. β2-adrenergic receptors (β2-ARs) are important targets in COPD therapy. β2-adrenergic receptor autoantibodies (β2-AAbs), which may directly affect β2-ARs, were shown to be increased in rats with passive-smoking-induced emphysema in our current preliminary studies. Using cigarette-smoke exposure (CS-exposure) and active-immune (via injections of β2-AR second extracellular loop peptides) rat models, we found that CS-exposed rats showed higher serum β2-AAb levels than control rats before alveolar airspaces became enlarged. Active-immune rats showed increased serum β2-AAb levels, and exhibited alveolar airspace destruction. CS-exposed-active-immune treated rats showed more extensive alveolar airspace destruction than rats undergoing CS-exposure alone. In our current clinical studies, we showed that plasma β2-AAb levels were positively correlated with the RV/TLC (residual volume/total lung capacity) ratio (r = 0.455, p < 0.001) and RV%pred (residual volume/residual volume predicted percentage, r = 0.454, p < 0.001) in 50 smokers; smokers with higher plasma β2-AAb levels exhibited worse alveolar airspace destruction. We suggest that increased circulating β2-AAbs are associated with smoking-related emphysema. PMID:28262783

  6. -Adrenergic receptors on rat ventricular myocytes: characteristics and linkage to cAMP metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Buxton, I.L.O.; Brunton, L.L.


    When incubated with purified cardiomyocytes from adult rat ventricle, the 1-antagonist (TH)prazosin binds to a single class of sites with high affinity. Competition for (TH)prazosin binding by the 2-selective antagonist yohimbine and the nonselective -antagonist phentolamine demonstrates that these receptors are of the 1-subtype. In addition, incubation of myocyte membranes with (TH)yohimbine results in no measurable specific binding. Agonist competition for (TH)prazosin binding to membranes prepared from purified myocytes demonstrates the presence of two components of binding: 28% of 1-receptors interact with norepinephrine with high affinity (K/sub D/ = 36 nM), whereas the majority of receptors (72%) have a low affinity for agonist (K/sub D/ = 2.2 M). After addition of 10 M GTP, norepinephrine competes for (TH)prazosin binding to a single class of sites with lower affinity (K/sub D/ = 2.2 M). Incubation of intact myocytes for 2 min with 1 M norepinephrine leads to significantly less cyclic AMP (cAMP) accumulation than stimulation with either norepinephrine plus prazosin or isoproterenol. Likewise, incubation of intact myocytes with 10 W M norepinephrine leads to significantly less activation of cAMP-dependent protein kinase than when myocytes are stimulated by both norepinephrine and the 1-adrenergic antagonist, prazosin or the US -adrenergic agonist, isoproterenol. They conclude that the cardiomyocyte 1 receptor is coupled to a guanine nucleotide-binding protein, that 1-receptors are functionally linked to decreased intracellular cAMP content, and that this change in cellular cAMP is expressed as described activation of cAMP-dependent protein kinase.

  7. Comparison of alpha-2 adrenergic receptors and their regulation in rodent and porcine species

    Energy Technology Data Exchange (ETDEWEB)

    Feller, D.J.; Bylund, D.B.


    The alpha-2 adrenergic antagonist (/sup 3/H)yohimbine (YOH) and the alpha-2 agonist (/sup 3/H)p-aminoclonidine (PAC) saturably label high-affinity binding sites in the submandibular gland from 3-week-old rats and 5-week-old pigs and in the lung from neonatal rats and 5-week-old pigs. (/sup 3/H)YOH had KD values of 5.5, 1.8, 0.45 and 0.22 nM in the rat gland and lung and porcine gland and lung, respectively. KD values of 2.4, 5.3 and 1.3 nM were found for (/sup 3/H)PAC in rodent and pig submandibular gland and pig lung, respectively. Both /sup 3/H-ligands labeled approximately the same density of sites within each tissue except in the rat lung in which (/sup 3/H)PAC binding was too low to reliably estimate. In all cases the pharmacologic profile was indicative of an alpha-2 adrenergic receptor site. However, the Ki of yohimbine vs. (/sup 3/H)PAC was 30- to 140-fold higher for the rodent relative to the porcine species. GTP decreased the affinity of (-)-epinephrine and PAC at (/sup 3/H)YOH-labeled sites in the pig gland and lung, but did not shift the affinity of epinephrine in the rat gland. These results suggest the possibility of subtype or species differences for the alpha-2 receptor. The Ki values of the antagonists YOH and phentolamine were different at (/sup 3/H)PAC and (/sup 3/H)YOH sites. GTP caused a dose-dependent reduction in (/sup 3/H)PAC binding in the porcine submandibular gland and lung. At 10 microM GTP, this loss was due to a decrease in /sup 3/H-agonist affinity, but not density.

  8. Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists.

    Directory of Open Access Journals (Sweden)

    Gunnar Kleinau

    Full Text Available Trace amine-associated receptors (TAAR are rhodopsin-like G-protein-coupled receptors (GPCR. TAAR are involved in modulation of neuronal, cardiac and vascular functions and they are potentially linked with neurological disorders like schizophrenia and Parkinson's disease. Subtype TAAR1, the best characterized TAAR so far, is promiscuous for a wide set of ligands and is activated by trace amines tyramine (TYR, phenylethylamine (PEA, octopamine (OA, but also by thyronamines, dopamine, and psycho-active drugs. Unfortunately, effects of trace amines on signaling of the two homologous β-adrenergic receptors 1 (ADRB1 and 2 (ADRB2 have not been clarified yet in detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular reasons for TAAR1 ligand promiscuity and for observed differences in signaling effects on particular aminergic receptors we compared TAAR, tyramine (TAR octopamine (OAR, ADRB1/2 and dopamine receptors at the structural level. We found especially for TAAR1 that the remarkable ligand promiscuity is likely based on high amino acid similarity in the ligand-binding region compared with further aminergic receptors. On the other hand few TAAR specific properties in the ligand-binding site might determine differences in ligand-induced effects compared to ADRB1/2. Taken together, this study points to molecular details of TAAR1-ligand promiscuity and identified specific trace amines as allosteric or orthosteric ligands of particular β-adrenergic receptor subtypes.

  9. Effects of adrenalectomy on the alpha-adrenergic regulation of cytosolic free calcium in hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Freudenrich, C.C.; Borle, A.B.


    We have previously published that bilateral adrenalectomy in the rat reduces the Ca2+-mediated alpha-adrenergic activation of hepatic glycogenolysis, while it increases the cellular calcium content of hepatocytes. In the experiments presented here, the concentration of cytosolic free calcium (Ca2+i) at rest and in response to epinephrine was measured in aequorin-loaded hepatocytes isolated from sham and adrenalectomized male rats. We found that in adrenalectomized rats the resting Ca2+i was elevated, the rise in Ca2+i evoked by epinephrine was reduced, and the rise in /sup 45/Ca efflux that follows such stimulation was depressed. Furthermore, the slope of the relationship between Ca2+i and calcium efflux was decreased 60% in adrenalectomized. Adrenalectomy did not change Ca2+ release from intracellular calcium pools in response to IP3 in saponin-permeabilized hepatocytes. The EC50 for inositol 1,4,5-triphosphate and the maximal Ca2+ released were similar in both sham and adrenalectomized animals. Finally, the liver calmodulin content determined by radioimmunoassay was not significantly different between sham and adrenalectomized rats. These results suggest that 1) adrenalectomy reduces calcium efflux from the hepatocyte, probably by an effect on the plasma membrane (Ca2+-Mg2+)-ATPase-dependent Ca2+ pump and thus alters cellular calcium homeostasis; 2) adrenalectomy decreases the rise in Ca2+i in response to epinephrine; 3) this decreased rise in Ca2+i is not due to defects in the intracellular Ca2+ storage and mobilization processes; and 4) the effects of adrenalectomy on cellular calcium metabolism and on alpha-adrenergic activation of glycogenolysis are not caused by a reduction in soluble calmodulin.

  10. Histone H3 phosphorylation in the rat pineal gland: adrenergic regulation and diurnal variation. (United States)

    Chik, C L; Arnason, T G; Dukewich, W G; Price, D M; Ranger, A; Ho, A K


    In this study, we investigated phosphorylation of Ser10 in histone H3 by norepinephrine (NE) in the rat pineal gland. In whole-animal studies, we demonstrated a marked increase in histone H3 phosphorylation in the rat pineal gland during the first half of the dark period. Exposure to light during this period caused a rapid decline in histone H3 phosphorylation with an estimated t1/2 of less than 15 min, indicating a high level of dephosphorylation activity. Corresponding studies in cultured pineal cells revealed that treatment with NE produced an increase in histone H3 phosphorylation that peaked between 2 and 3 h and declined rapidly by 4 h. The NE-induced histone H3 phosphorylation was blocked by cotreatment with propranolol or KT5720, a protein kinase A inhibitor, but not by prazosin or other kinase inhibitors. Moreover, only treatment with dibutyryl cAMP but not other kinase activators mimicked the effect of NE on histone H3 phosphorylation. The NE-stimulated H3 phosphorylation was markedly increased by cotreatment with a serine/threonine phosphatase inhibitor, tautomycin or okadaic acid, supporting a high level of ongoing histone H3 dephosphorylation activity. Together, our results indicate that histone H3 phosphorylation is a naturally occurring event at night in the rat pineal gland that is driven almost exclusively by a NE-->beta-adrenergic-->cAMP/protein kinase A signaling mechanism. This transient histone H3 phosphorylation probably reflects the nocturnal activation of multiple adrenergic-regulated genes in the rat pineal gland.

  11. Diaphragm arterioles are less responsive to alpha1- adrenergic constriction than gastrocnemius arterioles. (United States)

    Aaker, Aaron; Laughlin, M H


    The sympathetic nervous system has greater influence on vascular resistance in low-oxidative, fast-twitch skeletal muscle than in high-oxidative skeletal muscle (17). The purpose of this study was to test the hypothesis that arterioles isolated from low-oxidative, fast-twitch skeletal muscle [the white portion of gastrocnemius (WG)] possess greater responsiveness to adrenergic constriction than arterioles isolated from high-oxidative skeletal muscle [red portion of the gastrocnemius muscle (RG) and diaphragm (Dia)]. Second-order arterioles (2As) were isolated from WG, RG, and Dia of rats and reactivity examined in vitro. Results reveal that Dia 2As constrict less to norepinephrine (NE) (10(-9) to 10 (-4) M) than 2As from RG and WG, which exhibited similar NE-induced constrictions. This difference was not endothelium dependent, because responses of denuded 2As were similar to those of intact arterioles. The blunted NE-induced constrictor response of Dia 2As appears to be the result of differences in alpha1-receptor effects because 1) arterioles from Dia also responded less to selective alpha1-receptor stimulation with phenylephrine than RG and WG arterioles; 2) arterioles from Dia, RG, and WG dilated similarly to isoproterenol (10(-9) to 10(-4) M) and did not respond to selective alpha2-receptor stimulation with UK-14304; and 3) endothelin-1 produced similar constriction in 2As from Dia, RG, and WG. We conclude that differences in oxidative capacity and/or fiber type composition of muscle tissue do not explain different NE responsiveness of Dia 2As compared with 2As from gastrocnemius muscle. Differences in alpha1-adrenergic constrictor responsiveness among arterioles in skeletal muscle may contribute to nonuniform muscle blood flow responses observed during exercise and serve to maintain blood flow to Dia during exercise-induced increases in sympathetic nerve activity.

  12. Adrenergic responsiveness is reduced, while baseline cardiac function is preserved in old adult conscious monkeys (United States)

    Sato, N.; Kiuchi, K.; Shen, Y. T.; Vatner, S. F.; Vatner, D. E.


    To examine the physiological deficit to adrenergic stimulation with aging, five younger adult (3 +/- 1 yr old) and nine older adult (17 +/- 1 yr old) healthy monkeys were studied after instrumentation with a left ventricular (LV) pressure gauge, aortic and left atrial catheters, and aortic flow probes to measure cardiac output directly. There were no significant changes in baseline hemodynamics in conscious older monkeys. For example, an index of contractility, the first derivative of LV pressure (LV dP/dt) was similar (3,191 +/- 240, young vs. 3,225 +/- 71 mmHg/s, old) as well as in isovolumic relaxation, tau (24.3 +/- 1.7 ms, young vs. 23.0 +/- 1.0 ms, old) was similar. However, inotropic, lusitropic, and chronotropic responses to isoproterenol (Iso; 0.1 micrograms/kg), norepinephrine (NE; 0.4 micrograms/kg), and forskolin (For; 75 nmol/kg) were significantly (P monkeys. For example. Iso increased LV dP/dt by by 146 +/- 14% in younger monkeys and by only 70 +/- 5% in older monkeys. Iso also reduced tau more in younger monkeys (-28 +/- 7%) compared with older monkeys (-13 +/- 3%). Furthermore, peripheral vascular responsiveness to Iso, NE, For, and phenylephrine (PE; 5 micrograms/kg) was significantly (P monkeys. For example, phenylephrine (5 micrograms/kg) increased total peripheral resistence by 69 +/- 4% in younger monkeys and by only 45 +/- 3% in older monkeys. Thus in older monkeys without associated cardiovascular disease, baseline hemodynamics are preserved, but adrenergic receptor responsiveness is reduced systemically, not just in the heart.

  13. Involvement of β3-adrenergic receptors in the control of food intake in rats

    Directory of Open Access Journals (Sweden)

    S.A. Kanzler


    Full Text Available This study examined the food intake changes evoked by intracerebroventricular (icv injection of a selective agonist (BRL37344, 2 and 20 nmol or antagonist (SR59230A, 10 and 50 nmol of β3-adrenergic receptors in 24-h fasted rats (adult male Wistar rats, 200-350 g, N = 6/treatment. The animals were also pretreated with saline icv (SAL or SR59230A (50 nmol followed by BRL37344 (20 nmol or SAL in order to determine the selectivity of the effects evoked by BRL37344 on food intake or the selectivity of the effects evoked by SR59230A on risk assessment (RA behavior. The highest dose of BRL37344 (N = 7 decreased food intake 1 h after the treatment (6.4 ± 0.5 g in SAL-treated vs 4.2 ± 0.8 g in drug-treated rats. While both doses of SR59230A failed to affect food intake (5.1 ± 1.1 g for 10 nmol and 6.0 ± 1.8 g for 50 nmol, this treatment reduced the RA frequency (number/30 min (4 ± 2 for SAL-treated vs 1 ± 1 for 10 nmol and 0.5 ± 1 for 50 nmol SR59230A-treated rats, an ethological parameter related to anxiety. While pretreatment with SR59230A (7.0 ± 0.5 g abolished the hypophagia induced by BRL37344 (3.6 ± 0.9 g, BRL37344 suppressed the reduction in RA frequency caused by SR59230A. These results show that the hypophagia caused by BRL37344 is selectively mediated by β3-adrenergic receptors within the central nervous system. Moreover, they suggest the involvement of these receptors in the control of anxiety.

  14. Alpha/sub 2/-adrenergic receptors on a platelet precursor cell line, HEL

    Energy Technology Data Exchange (ETDEWEB)

    McKernan, R.M.; Motulsky, H.J.; Rozansky, D.; Insel, P.A.


    The authors have identified ..cap alpha../sub 2/-adrenergic receptors on human erythroleukemia HEL cells, a suspension-growing, bone-marrow-derived cell line related to human platelets. Intact HEL cells were studied using radioligand binding and cAMP accumulation assays. The authors identified saturable specific binding of the ..cap alpha../sub 2/-antagonist (/sup 3/H)yohimbine (yoh) in cells incubated at 37/sup 0/C for 1 hr (B/sub max/ 5900 +/- 2100 sites/cell, K/sub d/ 3.6 +/- 0.9 nM, n = 7). Competition for (/sup 3/H)yoh binding sites with antagonists confirmed that these sites were similar to human ..cap alpha../sub 2/-adrenoceptors from platelets and other resources, as typified by their high affinity for WY-26392, yohimbine and idazoxan, and very low affinity for prazosin. Studies at 37/sup 0/C revealed a low affinity of these sites for catecholamines (K/sub i/ for (-)-epinephrine, 21; (-)-norepinephrine, 45, (+)-epinephrine, 80 When experiments were conducted at 4 /sup 0/C, (-)-epinephrine was able to compete for only 50-60% of the sites specifically labelled by (/sup 3/H)yoh at 37/sup 0/, but (-)-epinephrine had an approximately 10-fold greater affinity for these sites (K/sub i/ at 4 /sup 0/C = 2.4 In addition, epinephrine inhibited cAMP accumulation stimulated by forskolin and PGE/sub 1/ in HEL cells; this response was inhibited by pertussis toxin. The authors conclude that HEL cells possess ..cap alpha../sub 2/-adrenergic receptors linked to G/sub i/ and thus should serve as a useful model to explore metabolism and regulation of these receptors in human cells.

  15. Mapping genetic variants associated with beta-adrenergic responses in inbred mice.

    Directory of Open Access Journals (Sweden)

    Micha Hersch

    Full Text Available β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS addressing the values and susceptibility of cardiovascular-related traits to a selective β(1-blocker, Atenolol (ate, and a β-agonist, Isoproterenol (iso. The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA, a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8. An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6. Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD. Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied.

  16. The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder. (United States)

    Taylor, Fletcher; Raskind, Murray A


    Heightened noradrenergic reactivity may be a contributing factor in the pathophysiology of posttraumatic stress disorder (PTSD). Prazosin is an alpha1-adrenoceptor antagonist commonly used as an antihypertensive agent. Because alpha1-adrenergic activity has been associated with fear and startle responses, a drug that blocks central alpha1-adrenergic activity may be useful in the treatment of PTSD symptoms. An outpatient who had been exposed to civilian trauma and had subsequent chronic refractory PTSD was thus prescribed prazosin. The marked reduction in PTSD symptoms, particularly sleep and nightmares, prompted the following open-label feasibility trial. Five outpatients with non-combat-related PTSD were consecutively identified and received prazosin in a 6-week open-label trial. In each case, the prazosin doses were slowly increased until optimal benefit was achieved. Change was assessed with the Clinician-Administered PTSD Scale for DSM-IV, One Week Symptom Version (CAPS-SX), the Clinical Global Impression of Change Scale (CGIC), and the Clinical Impression of Change-Nightmares (CIC-Nightmares) score. All five patients experienced moderate to marked improvement on the CGIC. The CAPS-SX PTSD nightmare and sleep PTSD categories showed at least a four-point reduction of those symptoms. All patients reported at least moderate improvement on the CIC-Nightmare score. Optimal doses of prazosin ranged from 1 to 4 mg/day. The drug was reasonably tolerated, and there were no drug discontinuations. These preliminary findings provide a rationale for blind placebo-controlled efficacy trials of the alpha 1 antagonist prazosin for PTSD.

  17. Recipient IL28B polymorphism is an important independent predictor of posttransplant diabetes mellitus in liver transplant patients with chronic hepatitis C

    NARCIS (Netherlands)

    B.J. Veldt (Bart); A. Duarte-Rojo (Andres); A.J. Thompson (Amber); K. Watt (Kym); J.K. Heimbach (Julie); H. Tillmann (Hans); D.D. Goldstein (D.); J.G. McHutchison (John); M.R. Charlton


    textabstractIL28B polymorphisms are strongly associated with response to treatment for HCV infection. IL28B acts on interferon-stimulated genes via the JAK-STAT pathway, which has been implicated in development of insulin resistance. We investigated whether IL28B polymorphisms are associated with po

  18. Polymorphism of lead oxoborate

    Energy Technology Data Exchange (ETDEWEB)

    Tyulyupa, A.G. [Middle School, Sablinskoe, Stavropol region, 356322 (Russian Federation); Voronov, V.V. [A.M. Prokhorov General Physics Institute RAS, 38 Vavilov Street, Moscow 119991 (Russian Federation); Fedorov, P.P., E-mail: [A.M. Prokhorov General Physics Institute RAS, 38 Vavilov Street, Moscow 119991 (Russian Federation)


    Highlights: • Pb{sub 4}B{sub 2}O{sub 7} melt undergoes statistical undercooling. • Orthorhombic nonlinear optical crystal Pb{sub 4}O(BO{sub 3}){sub 2} is the metastable γ-polymorph. • Temperature of metastable melting of γ-Pb{sub 4}O(BO{sub 3}){sub 2} is equal to 530 °C. - Abstract: The study of lead borate melt crystallization by differential thermal analysis (DTA) and X-ray diffraction analysis has shown that, for Pb{sub 4}O(BO{sub 3}){sub 2} (or 4PbO·B{sub 2}O{sub 3}) stoichiometric compound, its well-known orthorhombic modification (non-centrosymmetric Aba2 space symmetry group (SSG), a = 15.472(1), b = 10.802(1), c = 9.9486(6) Å unit cell parameters) is metastable. It forms from the undercooled melt and has a melting point of 530 ± 5 °C.

  19. Polymorphism of tedisamil dihydrochloride. (United States)

    Henck, J O; Finner, E; Burger, A


    The results of studies on tedisamil dihydrochloride in the solid state demonstrate that the compound occurs in three polymorphic forms. The three modifications have been characterized by thermomicroscopy, differential scanning calorimetry (DSC), vibrational spectroscopy, solid-state nuclear magnetic resonance (NMR), and X-ray powder diffractometry (XRPD). The thermodynamic relationships are illustrated in a semischematic energy/temperature diagram that gives information about the relative stability and physical properties of the three modifications between 0 K and the melting temperatures. The three modifications are enantiotropically related. Modification II, the material obtained during manufacturing, is the thermodynamically stable crystal form at 20 degrees C. The thermodynamic transition point of mod II with I (instant melting point: 248-250 degrees C) is between 100 and approximately 140 degrees C (DeltaH(t,II/I) = 4.4+/-0.8 kJ/mol (95% CI)). A phase transition of mod II (probably into mod III) was detected thermomicroscopically at about -180 degrees C. The thermodynamic transition point of mod III with I was determined to be at -9 to -6 degrees C. Because mods I and III are thermodynamically and kinetically unstable at ambient conditions, these crystal forms are of analytical interest.

  20. Designing pathways

    DEFF Research Database (Denmark)

    Scheuer, John Damm


    The theoretical background in this chapter is organizational studies and especially theories about design and design processes in organizations. The concept of design is defined as a particular kind of work aimed at making arrangements in order to change existing situations into desired ones....... The illustrative case example is the introduction of clinical pathways in a psychiatric department. The contribution to a general core of design research is the development of the concept of design work and a critical discussion of the role of technological rules in design work....

  1. Tyrosine Kinase Domain Gene Polymorphism of Epidermal Growth Factor Receptor in Gastric Cancer in Northern Iran

    Directory of Open Access Journals (Sweden)

    Jeivad F


    Full Text Available Background: Gastric cancer is one of the most common diseases of digestive system with a low 5-year survival rate and metastasis is the main cause of death. Multi-factors, such as changes in molecular pathways and deregulation of cells are involved in the disease development. Epidermal growth factor receptor pathway (EGFR which is associated with cell proliferation and survival can influence cancer development. EGFR function is governed by its genetic polymorphism; thus, we aimed to study the tyrosine kinase domain gene mutations of the receptor in patients with gastric cancer.Methods : In this experimental study, 123 subjects (83 patients with gastric cancer and 40 normal subjects were investigated in north of Iran for EGFR gene polymorphisms during 1 year. Genomic DNA was extracted by DNA extraction kit according to the manufacture's protocol. Polymerase chain reaction single-stranded conformation polymorphism (PCR-SSCP and silver staining were performed for investigating EGFR gene polymorphisms. Results : The participants included 72 men and 44 women. Gene polymorphism in exon 18 was present in 10% of the study population but SSCP pattern in exon 19 did not show different migrate bands neither in patients nor in normal subjects.Conclusion: It seems that screening for tyrosine kinas gene polymorphism of epidermal growth factor receptor in patients with gastric cancer and use of tyrosine kinas inhibitors could be useful in the prevention of disease progress and improvement of treatment process for a better quality of life in these patients.

  2. Are Toll-like receptor gene polymorphisms associated with prostate cancer?

    Directory of Open Access Journals (Sweden)

    Kutikhin AG


    Full Text Available Anton G Kutikhin, Arseniy E YuzhalinDepartment of Epidemiology, Kemerovo State Medical Academy, Kemerovo, Russian FederationAbstract: The suggestion that there is a connection between chronic intraprostatic inflammation and prostate cancer was declared some years ago. As Toll-like receptors (TLRs are the key players in the processes of chronic intraprostatic inflammation, there is a hypothesis that TLR gene polymorphisms may be associated with prostate cancer risk. Although a number of comprehensive studies have been conducted on large samples in various countries, reliable connections between these single nucleotide polymorphisms and prostate cancer risk, stage, grade, aggressiveness, ability to metastasize, and mortality have not been detected. Results have also varied slightly in different populations. The data obtained regarding the absence of connection between the polymorphisms of the genes encoding interleukin-1 receptor-associated kinases (IRAK1 and IRAK4 and prostate cancer risk might indicate a lack of association between inherited variation in the TLR signaling pathway and prostate cancer risk. It is possible to consider that polymorphisms of genes encoding TLRs and proteins of the TLR pathway also do not play a major role in the etiology and pathogenesis of prostate cancer. Feasibly, it would be better to focus research on associations between TLR single nucleotide polymorphisms and cancer risk in other infection-related cancer types.Keywords: TLRs, single nucleotide polymorphisms, genetic variation, inflammation, innate immunity

  3. Thyrotoxic Periodic Paralysis and Polymorphisms of the , , and Genes in Men with Graves Disease

    Directory of Open Access Journals (Sweden)

    Suyeon Park


    Full Text Available BackgroundThyrotoxic periodic paralysis (TPP is a rare complication of thyrotoxicosis characterized by acute attacks of muscle weakness and hypokalemia. Recently, variation in several genes was suggested to be associated with TPP. This study evaluated the genetic predisposition to TPP in terms of the β2-adrenergic receptor (ADRB2, androgen receptor (AR, and γ-aminobutyric acid receptor α3 subunit (GABRA3 genes.MethodsThis study enrolled 48 men with Graves disease (GD and TPP, and 48 GD patients without TPP. We compared the frequencies of candidate polymorphisms between the two groups.ResultsThe frequency of the Gly16/Gly16 genotype in ADRB2 was not significantly associated with TPP (P=0.32. More CAG repeats (≥26 in the AR gene were not correlated with TPP (odds ratio [OR], 2.46; 95% confidence interval [CI], 0.81 to 8.09; P=0.08. The allele frequency of the TT genotype in the GABRA3 gene was not associated with TPP (OR, 1.83; 95% CI, 0.54 to 6.74; P=0.41.ConclusionThe polymorphisms in the ADRB2, AR, and GABRA3 genes could not explain the genetic susceptibility to TPP in Korean men with GD.

  4. Neurotransmitter receptor-mediated signaling pathways as modulators of carcinogenesis. (United States)

    Schuller, Hildegard M


    The autonomic nervous system with its two antagonistic branches, the sympathicus and the parasympathicus, regulates the activities of all body functions that are not under voluntary control. While the autonomic regulation of organ functions has been extensively studied, little attention has been given to the potential role of neurohumoral transmission at the cellular level in the development of cancer. Studies conducted by our laboratory first showed that binding of the parasympathetic neurotransmitter, acetylcholine, as well as nicotine or its nitrosated cancer-causing derivative, NNK, to nicotinic acetylcholine receptors comprised of alpha7 subunits activated a mitogenic signal transduction pathway in normal and neoplastic pulmonary neuroendocrine cells. On the other hand, beta-adrenergic receptors (Beta-ARs), which transmit signals initiated by binding of the catecholamine neurotransmitters of the sympathicus, were identified by our laboratory as important regulators of cell proliferation in cell lines derived from human adenocarcinomas of the lungs, pancreas, and breast. The tobacco-specific carcinogen NNK bound with high affinity to Beta1- and Beta2-ARs, thus activating cAMP, protein kinase A, and the transcription factor CREB. Collectively, neurotransmitter receptors of the nicotinic and Beta-adrenergic families appear to regulate cellular functions essential for the development and survival of the most common human cancers.

  5. Time sequence of changes in the responsiveness of glycogen breakdown to adrenergic agonists in perfused liver of rats with insulin-induced hypoglycemia

    Directory of Open Access Journals (Sweden)

    Vardanega-Peicher M.


    Full Text Available The time-course changes of the responsiveness of glycogen breakdown to a- and ß-adrenergic agonists during insulin-induced hypoglycemia (IIH were investigated. Blood glucose levels were decreased prior to the alteration in the hepatic responsiveness to adrenergic agonists. The activation of hepatic glucose production and glycogenolysis by phenylephrine (2 µM and isoproterenol (20 µM was decreased in IIH. The changes in the responsiveness of glycogen catabolism were first observed for isoproterenol and later for phenylephrine. Hepatic ß-adrenergic receptors showed a higher degree of adrenergic desensitization than did a-receptors. Liver glycogen synthase activity, glycogen content and the catabolic effect of dibutyryl cyclic AMP (the ß-receptor second messenger were not affected by IIH.

  6. [Natriuretic peptides: a new lipolytic pathway in human fat cells]. (United States)

    Sengenes, Coralie; Moro, Cédric; Galitzky, Jean; Berlan, Michel; Lafontan, Max


    Human fat cell lipolysis was considered until recently to be an exclusive cAMP/protein-kinase A (PKA)-regulated metabolic pathway under the control of catecholamines and insulin. Moreover, exercise-induced lipid mobilization in humans was considered to mainly depend on catecholamine action and interplay between fat cell beta- and alpha2-adrenergic receptors controlling adenylyl cyclase activity and cAMP production. We have recently demonstrated that natriuretic peptides stimulate lipolysis and contribute to the regulation of lipid mobilization in humans. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) stimulate lipolysis in human isolated fat cells. Activation of the adipocyte plasma membrane type A guanylyl cyclase receptor (NPR-A), increase in intracellular guanosine 3',5'-cyclic monophosphate (cyclic GMP) levels and activation of hormone-sensitive lipase mediate the action of ANP. ANP does not modulate cAMP production and PKA activity. Increment of cGMP induces the phosphorylation of hormone-sensitive lipase and perilipin A via the activation of a cGMP dependent protein kinase-I (cGK-I). Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans. Physiological relevance of the ANP-dependent pathway was demonstrated in young subjects performing physical exercise. ANP plays a role in conjunction with catecholamines in the control of exercise-induced lipid mobilization. This pathway becomes of major importance when subjects are submitted to chronic treatment with a beta-blocker. Oral beta-adrenoceptor blockade suppresses the beta-adrenergic component of catecholamine action in fat cells and potentiates exercise-induced ANP release by the heart. These findings may have several implications whenever natriuretic peptide secretion is altered such as in subjects with left ventricular dysfunction, congestive heart failure and obesity.

  7. Association between cerebrospinal fluid dopamine concentrations and catechol-O-methyltransferase gene polymorphisms in forensic autopsy cases of methamphetamine abusers. (United States)

    Matsusue, Aya; Ishikawa, Takaki; Michiue, Tomomi; Waters, Brian; Hara, Kenji; Kashiwagi, Masayuki; Takayama, Mio; Ikematsu, Natsuki; Kubo, Shin-Ichi


    Methamphetamine (MA) is an illicit psychostimulant that stimulates the release of catecholamines from sympathetic nerve terminals and is widely abused worldwide. Since catechol-O-methyltransferase (COMT) metabolizes catecholamines and mediates adrenergic, noradrenergic, and dopaminergic signaling responses, we investigated the effects of the COMT polymorphisms rs4633 and rs4680 on cerebrospinal fluid (CSF) catecholamine concentrations in autopsies of subjects who died of drug intoxication. 28 MA abusers and 22 fatal psychotropic drug intoxication cases were evaluated. No correlations were identified between rs4633 or rs4680 polymorphisms and CSF concentrations of adrenaline (Adr), noradrenaline (Nad), or dopamine (DA) in fatal psychotropic cases. However, among MA abusers, DA concentrations in the CSF were significantly higher in those with the T allele (CT and TT) of rs4633 than in CC genotype carriers (p=0.004). Moreover, among MA abusers, DA concentrations were significantly higher in those with the A allele (GA and AA) of rs4680 than in GG genotype carriers (p=0.017). In subsequent haplotype analyses of MA abusers, a strong correlation was identified between two COMT haplotypes and CSF DA concentrations (p=0.002). However, the CSF concentrations of Adr and Nad were not associated with COMT genotypes or haplotypes. The present results indicate that rs4633 and rs4680 polymorphisms influence CSF DA concentrations and MA toxicity in MA abusers.

  8. 中国人群叶酸/同型半胱氨酸代谢基因多态性与非综合征型唇腭裂关联研究%Association study for gene polymorphism of folic acid/homocysteine metabolic pathway and nonsyndromic cleft lip with or without cleft palate in Chinese populations

    Institute of Scientific and Technical Information of China (English)

    王苹; 王红; 吴雅慧; 叶晓茜; 黄尚志; 石冰; 梁赓义; 曹卫华; 吴涛


    Objective:To explore the association between 18 candidate genes encoding enzymes on the folate/homocysteine metabolism pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) in Chinese populations.Methods:A total of 806 NSCL/P trios were drawn by an international consortium,which conducted a genome-wide association study using a case-parent trio design to investigate genes affecting risks to NSCL/P.The transmission disequilibrium test (TDT) was used for deviation from Mendelian expectations for 257 SNPs in 18 folate/homocysteine metabolism-related genes.The interactions between markers in these gene and environmental risk factors were also tested using conditional Logistic regressions.Results:Although four SNPs (rs6428977,rs12060264,rs7730643 and rs4920037) showed nominal significant association with NSCL/P in the TDT on 806 NSCL/P trios (P <0.05),no significant evidence of linkage and association remained in all the SNPs after Bonferroni correction.Similar tests for interactions between genes and maternal smoking,environmental tobacco smoke,alcohol consumption and multi-vitamin supplementation during pregnancy did not attain statistical significance after correction for multiple comparisons.Conclusion:Folate/homocysteine metabolism-related genes could not influence the risk of NSCL/P.%目的:探索中国人群中叶酸/同型半胱氨酸代谢通路上的基因多态性与非综合征型唇腭裂(isolated non-syndromic cleft lip with or without cleft palate,NSCL/P)的关联关系及可能存在的基因-环境交互作用.方法:在806个中国人群的核心家庭中,对叶酸/同型半胱氨酸通路上的18个基因进行了传递不平衡检验以及基因-环境交互作用分析.环境因素包括母亲孕期吸烟、被动吸烟、饮酒及服用多维生素补充剂.结果:经过质量控制的筛选,共对257个位点的单核苷酸多态性(single nucleotide polymorphisms,SNPs)进行了传递不平衡检验及交互作

  9. The role of E-cadherin - 160C/A polymorphism in breast cancer

    Directory of Open Access Journals (Sweden)

    Luo Gaojian


    Full Text Available Breast cancer is the most prevalent cancer in women worldwide. Numerous studies have suggested that the E-cadherin adhesion system is dysregulated in cancer cells. These impaired functions of E-cadherin contribute to releasing cancer cells from the primary lesion to cell dedifferentiation. Some studies have shown that polymorphism may affect E-cadherin expression, and then play a role in susceptibility to breast cancer. However, the results remained controversial. In this short review, we summarize the functions of E-cadherin and the signaling pathways it regulates, and assess the association between CDH1 polymorphisms and breast cancer susceptibility. This study suggests that genetic variation in CDH1 and -160C/A polymorphism may have an association with breast cancer risk. The assessment of CDH1 polymorphisms may be used for the identification of patients suitable for anti- CDH1 therapy.

  10. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and age at onset of schizophrenia

    DEFF Research Database (Denmark)

    Saetre, Peter; Grove, Jakob; Børglum, Anders;


    Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in metabolic pathways of importance for nucleotide synthesis and methylation of DNA, membranes, proteins and lipids. The MTHFR gene includes a common polymorphism (rs1801133 or C677T), which is associated with enzyme activity. The T......-allele of the C677T polymorphism has been associated with earlier age at onset of schizophrenia in a Scandinavian population, although no association was found in replication attempts in other populations. Extending the study to five Nordic samples consisting of 2,198 patients with schizophrenia, including...... the original Scandinavian samples, there was no significant association between MTHFR C677T polymorphism and age at onset in schizophrenia. The present results do not suggest that the investigated MTHFR polymorphism has any significant influence on age at onset of schizophrenia in the Nordic population. © 2012...

  11. Polymorphisms of the DNA repair genes XRCC1 and XRCC3 in a Brazilian population

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    Duarte Márcia Cristina


    Full Text Available In several DNA repair genes, polymorphisms may result in reduced repair capacity, which has been implicated as a risk factor for various types of cancer. The frequency of the polymorphic alleles varies among populations, suggesting an ethnic distribution of genotypes. We genotyped 300 healthy Southeastern Brazilian individuals (262 of European ancestry and 38 of African ancestry for polymorphisms of codons 194 and 399 of the XRCC1 base excision repair pathway gene and of codon 241 of the XRCC3 homologous recombination repair pathway gene. The allele frequencies were 0.07 for the Arg194Trp and 0.33 for the Arg399Gln codons of the XRCC1 gene and 0.35 for the Thr241Met codon of the XRCC3 gene. The genotypic frequencies were within Hardy-Weinberg equilibrium. These frequencies showed ethnic variability when compared with those obtained for different populations from several countries.

  12. Influence of amorphous structure on polymorphism in vanadia (United States)

    Stone, Kevin H.; Schelhas, Laura T.; Garten, Lauren M.; Shyam, Badri; Mehta, Apurva; Ndione, Paul F.; Ginley, David S.; Toney, Michael F.


    Normally we think of the glassy state as a single phase and therefore crystallization from chemically identical amorphous precursors should be identical. Here we show that the local structure of an amorphous precursor is distinct depending on the initial deposition conditions, resulting in significant differences in the final state material. Using grazing incidence total x-ray scattering, we have determined the local structure in amorphous thin films of vanadium oxide grown under different conditions using pulsed laser deposition (PLD). Here we show that the subsequent crystallization of films deposited using different initial PLD conditions result in the formation of different polymorphs of VO2. This suggests the possibility of controlling the formation of metastable polymorphs by tuning the initial amorphous structure to different formation pathways.

  13. A case of life-threatening lactic acidosis after smoke inhalation - interference between beta-adrenergic agents and ethanol? (United States)

    Taboulet, P; Clemessy, J L; Freminet, A; Baud, F J


    A 49-year-old male developed bronchospasm and severe lactic acidosis after exposition to fire smoke. The correction of lactic acidosis following beta-adrenergic agents withdrawal, and the transitory increase in lactate after salbutamol reintroduction are consistent with hypersensitivity to salbutamol. However, the plasma lactate concentration (32.6 mmol/l) that we observed 9.5 h after admission is far above those currently seen after administration of beta-adrenergic agents. We searched for causes able to potentiate the adverse effects of these drugs and we noticed that our patient had a high plasma ethanol level (2.4 g/l). Alcohol metabolism in the liver results in generation of high NADH/NAD+ ratios, thus reducing lactate liver clearance. This observation suggests that plasma lactate levels should be monitored closely in alcoholic patients treated with beta-mimetic agents.

  14. Osmotic versus adrenergic control of ion transport by ionocytes of Fundulus heteroclitus in the cold

    DEFF Research Database (Denmark)

    Tait, Janet C; Mercer, Evan W; Gerber, Lucie;


    In eurythermic vertebrates, acclimation to the cold may produce changes in physiological control systems. We hypothesize that relatively direct osmosensitive control will operate better than adrenergic receptor mediated control of ion transport in cold vs. warm conditions. Fish were acclimated...... to full strength seawater (SW) at 21°C and 5°C for four weeks, gill samples and blood were taken and opercular epithelia mounted in Ussing style chambers. Short-circuit current Isc at 21°C and 5°C (measured at acclimation temperature), was significantly inhibited by the α2-adrenergic agonist clonidine...... inhibition of Isc, was higher in warm acclimated (-95%), compared to cold acclimated fish (-75%), while hypertonic stimulations were the same, indicating equal responsiveness to hyperosmotic stimuli. Plasma osmolality was significantly elevated in cold acclimated fish and, by TEM, gill ionocytes from cold...

  15. Glucose-induced thermogenesis in patients with small cell lung carcinoma. The effect of acute beta-adrenergic inhibition

    DEFF Research Database (Denmark)

    Simonsen, L; Bülow, J; Tuxen, C


    Seven patients with histologically verified small cell lung carcinoma were given an oral glucose load of 75 g on two occasions to examine the effect of glucose on whole body and forearm thermogenesis with and without acute beta-adrenergic inhibition with propranolol. Whole body energy expenditure...... was measured by the open circuit ventilated hood system. Forearm blood flow was measured by venous occlusion strain-gauge plethysmography. The uptake of oxygen in the forearm was calculated as the product of the forearm blood flow and the difference in arteriovenous oxygen concentration. The glucose......-induced forearm oxygen uptake in the period 60-120 min following the glucose load was significantly reduced after beta-adrenergic inhibition from 103 +/- 28 mumol 100 g-1 60 min-1 to 29 +/- 29 mumol 100 g-1 60 min-1 (P blood was not increased...

  16. The relationship between some beta-adrenergic mediated responses and plasma concentrations of adrenaline and cyclic AMP in man

    DEFF Research Database (Denmark)

    Philipsen, E K; Myhre, John Gabriel; Larsen, S;


    concentrations at low adrenaline infusion rates was prevented, whereas a small increase in cyclic AMP was found at high adrenaline infusion rates, probably owing to incomplete beta-receptor blockade. Likewise, the adrenaline-induced increments in blood substrates (glucose, lactate, glycerol and beta......To test the hypothesis that increments in plasma cyclic AMP during beta-adrenergic stimulation reflect integrated second messenger function of the tissues activated by the agonist, graded adrenaline infusion resulting in plasma adrenaline concentrations within the physiological range was performed...... hydroxybutyric acid) were significantly reduced but not completely prevented by beta-blockade. We conclude that an altered relationship between beta-agonist concentrations and plasma cyclic AMP may provide evidence for the existence of differences in beta-adrenergic sensitivity in man....

  17. Association of Catechol-O-Methyltransferase (COMT) Polymorphism and Academic Achievement in a Chinese Cohort (United States)

    Yeh, Ting-Kuang; Chang, Chun-Yen; Hu, Chung-Yi; Yeh, Ting-Chi; Lin, Ming-Yeh


    Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes the degradation pathway and inactivation of dopamine. It is accepted widely as being involved in the modulation of dopaminergic physiology and prefrontal cortex (PFC) function. The COMT Val158Met polymorphism is associated with variation in COMT activity. COMT 158Met allele…

  18. Height in pre- and postmenopausal women is influenced by estrogen receptor alpha gene polymorphisms

    NARCIS (Netherlands)

    J.B.J. van Meurs (Joyce); A.P. Bergink (Arjan); M. van de Klift (Marjolein); Y. Fang (Yue); G. Leusink (Geraline); A.G. Uitterlinden (André); H.A.P. Pols (Huib); J.P.T.M. van Leeuwen (Hans); S.C.E. Schuit (Stephanie); A. Hofman (Albert)


    textabstractThe estrogen receptor alpha gene (ESR1) is known to be involved in metabolic pathways influencing growth. We have performed two population-based association studies using three common polymorphisms within this candidate gene to determine whether these are associated with variation in adu

  19. Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with β-adrenergic activity (United States)

    Careaga, Mariella B. L.; Tiba, Paula A.; Ota, Simone M.; Suchecki, Deborah


    Cognitive processes, such as learning and memory, are essential for our adaptation to environmental changes and consequently for survival. Numerous studies indicate that hormones secreted during stressful situations, such as glucocorticoids (GCs), adrenaline and noradrenaline, regulate memory functions, modulating aversive memory consolidation and retrieval, in an interactive and complementary way. Thus, the facilitatory effects of GCs on memory consolidation as well as their suppressive effects on retrieval are substantially explained by this interaction. On the other hand, low levels of GCs are also associated with negative effects on memory consolidation and retrieval and the mechanisms involved are not well understood. The present study sought to investigate the consequences of blocking the rise of GCs on fear memory retrieval in multiple tests, assessing the participation of β-adrenergic signaling on this effect. Metyrapone (GCs synthesis inhibitor; 75 mg/kg), administered 90 min before the first test of contextual or tone fear conditioning (TFC), negatively affected animals’ performances, but this effect did not persist on a subsequent test, when the conditioned response was again expressed. This result suggested that the treatment impaired fear memory retrieval during the first evaluation. The administration immediately after the first test did not affect the animals’ performances in contextual fear conditioning (CFC), suggesting that the drug did not interfere with processes triggered by memory reactivation. Moreover, metyrapone effects were independent of β-adrenergic signaling, since concurrent administration with propranolol (2 mg/kg), a β-adrenergic antagonist, did not modify the effects induced by metyrapone alone. These results demonstrate that pre-test metyrapone administration led to negative effects on fear memory retrieval and this action was independent of a β-adrenergic signaling. PMID:25784866

  20. Pre-test metyrapone impairs memory recall in fear conditioning tasks: lack of interaction with β-adrenergic activity

    Directory of Open Access Journals (Sweden)

    Mariella B.L. Careaga


    Full Text Available Cognitive processes, such as learning and memory, are essential for our adaptation to environmental changes and consequently for survival. Numerous studies indicate that hormones secreted during stressful situations, such as glucocorticoids (GCs, adrenaline and noradrenaline, regulate memory functions, modulating aversive memory consolidation and retrieval, in an interactive and complementary way. Thus, the facilitatory effects of GCs on memory consolidation as well as their suppressive effects on retrieval are substantially explained by this interaction. On the other hand, low levels of GCs are also associated with negative effects on memory consolidation and retrieval and the mechanisms involved are not well understood. The present study sought to investigate the consequences of blocking the rise of GCs on fear memory retrieval in multiple tests, assessing the participation of β-adrenergic signaling on this effect. Metyrapone (GCs synthesis inhibitor, administered 90 min before the first test of contextual or auditory fear conditioning, negatively affected animals’ performances, but this effect did not persist on a subsequent test, when the conditioned response was again expressed. This result suggested that the treatment impaired fear memory retrieval during the first evaluation. The administration immediately after the first test did not affect the animals’ performances in contextual fear conditioning, suggesting that the drug did not interfere with processes triggered by memory reactivation. Moreover, metyrapone effects were independent of β-adrenergic signaling, since concurrent administration with propranolol, a β-adrenergic antagonist, did not modify the effects induced by metyrapone alone. These results demonstrate that pre-test metyrapone administration led to negative effects on fear memory retrieval and this action was independent of a β-adrenergic signaling.

  1. Melatonin receptor-mediated protection against myocardial ischaemia/reperfusion injury: role of its anti-adrenergic actions. (United States)

    Genade, Sonia; Genis, Amanda; Ytrehus, Kirsti; Huisamen, Barbara; Lochner, Amanda


    Melatonin has potent cardioprotective properties. These actions have been attributed to its free radical scavenging and anti-oxidant actions, but may also be receptor mediated. Melatonin also exerts powerful anti-adrenergic actions based on its effects on contractility of isolated papillary muscles. The aims of this study were to determine whether melatonin also has anti-adrenergic effects on the isolated perfused rat heart, to determine the mechanism thereof and to establish whether these actions contribute to protection of the heart during ischaemia/reperfusion. The results showed that melatonin (50 microM) caused a significant reduction in both isoproterenol (10(-7) M) and forskolin (10(-6) M) induced cAMP production and that both these responses were melatonin receptor dependent, since the blocker, luzindole (5 x 10(-6) M) abolished this effect. Nitric oxide (NO), as well as guanylyl cyclase are involved, as L-NAME (50 microM), an NO synthase inhibitor and ODQ (20 microM), a guanylyl cyclase inhibitor, significantly counteracted the effects of melatonin. Protein kinase C (PKC), as indicated by the use of the inhibitor bisindolylmaleimide (50 microM), also play a role in melatonin's anti-adrenergic actions. These actions of melatonin are involved in its cardioprotection: simultaneous administration of L-NAME or ODQ with melatonin, before and after 35 min regional ischaemia, completely abolished its cardioprotection. PKC, on the other hand, had no effect on the melatonin-induced reduction in infarct size. Cardioprotection by melatonin was associated with a significant activation of PKB/Akt and attenuated activation of the pro-apoptotic kinase, p38MAPK during early reperfusion. In summary, the results show that melatonin-induced cardioprotection may be receptor dependent, and that its anti-adrenergic actions, mediated by NOS and guanylyl cyclase activation, are important contributors.

  2. Alpha1A-adrenergic receptor-directed autoimmunity induces left ventricular damage and diastolic dysfunction in rats.

    Directory of Open Access Journals (Sweden)

    Katrin Wenzel

    Full Text Available BACKGROUND: Agonistic autoantibodies to the alpha(1-adrenergic receptor occur in nearly half of patients with refractory hypertension; however, their relevance is uncertain. METHODS/PRINCIPAL FINDINGS: We immunized Lewis rats with the second extracellular-loop peptides of the human alpha(1A-adrenergic receptor and maintained them for one year. Alpha(1A-adrenergic antibodies (alpha(1A-AR-AB were monitored with a neonatal cardiomyocyte contraction assay by ELISA, and by ERK1/2 phosphorylation in human alpha(1A-adrenergic receptor transfected Chinese hamster ovary cells. The rats were followed with radiotelemetric blood pressure measurements and echocardiography. At 12 months, the left ventricles of immunized rats had greater wall thickness than control rats. The fractional shortening and dp/dt(max demonstrated preserved systolic function. A decreased E/A ratio in immunized rats indicated a diastolic dysfunction. Invasive hemodynamics revealed increased left ventricular end-diastolic pressures and decreased dp/dt(min. Mean diameter of cardiomyocytes showed hypertrophy in immunized rats. Long-term blood pressure values and heart rates were not different. Genes encoding sarcomeric proteins, collagens, extracellular matrix proteins, calcium regulating proteins, and proteins of energy metabolism in immunized rat hearts were upregulated, compared to controls. Furthermore, fibrosis was present in immunized hearts, but not in control hearts. A subset of immunized and control rats was infused with angiotensin (Ang II. The stressor raised blood pressure to a greater degree and led to more cardiac fibrosis in immunized, than in control rats. CONCLUSIONS/SIGNIFICANCE: We show that alpha(1A-AR-AB cause diastolic dysfunction independent of hypertension, and can increase the sensitivity to Ang II. We suggest that alpha(1A-AR-AB could contribute to cardiovascular endorgan damage.

  3. Protein kinase Cζ regulates phospholipase D activity in rat-1 fibroblasts expressing the α1A adrenergic receptor

    Directory of Open Access Journals (Sweden)

    Bourgoin Sylvain G


    Full Text Available Abstract Background Phenylephrine (PHE, an α1 adrenergic receptor agonist, increases phospholipase D (PLD activity, independent of classical and novel protein kinase C (PKC isoforms, in rat-1 fibroblasts expressing α1A adrenergic receptors. The aim of this study was to determine the contribution of atypical PKCζ to PLD activation in response to PHE in these cells. Results PHE stimulated a PLD activity as demonstrated by phosphatidylethanol production. PHE increased PKCζ translocation to the particulate cell fraction in parallel with a time-dependent decrease in its activity. PKCζ activity was reduced at 2 and 5 min and returned to a sub-basal level within 10–15 min. Ectopic expression of kinase-dead PKCζ, but not constitutively active PKCζ, potentiated PLD activation elicited by PHE. A cell-permeable pseudosubstrate inhibitor of PKCζ reduced basal PKCζ activity and abolished PHE-induced PLD activation. Conclusion α1A adrenergic receptor stimulation promotes the activation of a PLD activity by a mechanism dependent on PKCζ; Our data also suggest that catalytic activation of PKCζ is not required for PLD stimulation.

  4. The Effect of Prolonged Exposure to Low Frequency Electromagnetic Fields on α1 Adrenergic System of Isolated Colon in Rats

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    A Bahaodini


    Full Text Available Introduction: Prolonged exposure to electromagnetic fields (EMF influences digestive system specially its motility. The present study was performed in order to study the effects of exposure to low frequency EMF on the adrenergic system of large intestine. Methods: In this experimental study, thirty adult male rats were divided into three groups: First group (experimental included 10 male rats that were exposed to 1000µT and 50Hz for 140 days in the on solenoid. Second group (shahed included 10 rats that were kept at same condition as the first group except that the solenoid was off. Third group (control included 10 rats that were kept in a normal condition. Mechanical activity of the isolated strips of colon that were inserted to organ bath contained Kerebs solution(CaCl2 2/5, KCL 4/7, KH2Po41/2, MgSo4 1/2, NaHCO3 25, NaCl 118, glucose11, PH=7.4 (37°C and they were linked to power lab force transducer to record cumulative doses of Phenylephrin. The data was analyzed using t- test at p<0.05 as a significant level. Results: The results showed no significant difference regarding long- term exposure to low frequency Electromagnetic field on adrenergic receptor α 1 adrenergic receptor sensitivities.

  5. Locus Coeruleus Stimulation Facilitates Long-Term Depression in the Dentate Gyrus That Requires Activation of β-Adrenergic Receptors (United States)

    Hansen, Niels; Manahan-Vaughan, Denise


    Synaptic plasticity comprises a cellular mechanism through which the hippocampus most likely enables memory formation. Neuromodulation, related to arousal, is a key aspect in information storage. The activation of locus coeruleus (LC) neurons by novel experience leads to noradrenaline release in the hippocampus at the level of the dentate gyrus (DG). We explored whether synaptic plasticity in the DG is influenced by activation of the LC via electrical stimulation. Coupling of test-pulses that evoked stable basal synaptic transmission in the DG with stimulation of the LC induced β-adrenoreceptor-dependent long-term depression (LTD) at perforant path–DG synapses in adult rats. Furthermore, persistent LTD (>24 h) induced by perforant path stimulation also required activation of β-adrenergic receptors: Whereas a β-adrenergic receptor antagonist (propranolol) prevented, an agonist (isoproterenol) strengthened the persistence of LTD for over 24 h. These findings support the hypothesis that persistent LTD in the DG is modulated by β-adrenergic receptors. Furthermore, LC activation potently facilitates DG LTD. This suggests in turn that synaptic plasticity in the DG is tightly regulated by activity in the noradrenergic system. This may reflect the role of the LC in selecting salient information for subsequent synaptic processing in the hippocampus. PMID:24464942

  6. Chronic stress enhances progression of periodontitis via α1-adrenergic signaling: a potential target for periodontal disease therapy. (United States)

    Lu, Huaixiu; Xu, Minguang; Wang, Feng; Liu, Shisen; Gu, Jing; Lin, Songshan


    This study assessed the roles of chronic stress (CS) in the stimulation of the sympathetic nervous system and explored the underlying mechanisms of periodontitis. Using an animal model of periodontitis and CS, the expression of tyrosine hydroxylase (TH) and the protein levels of the α1-adrenergic receptor (α1-AR) and β2-adrenergic receptor (β2-AR) were assessed. Furthermore, human periodontal ligament fibroblasts (HPDLFs) were stimulated with lipopolysaccharide (LPS) to mimic the process of inflammation. The proliferation of the HPDLFs and the expression of α1-AR and β2-AR were assessed. The inflammatory-related cytokines interleukin (IL)-1β, IL-6 and IL-8 were detected after pretreatment with the α1/β2-AR blockers phentolamine/propranolol, both in vitro and in vivo. Results show that periodontitis under CS conditions enhanced the expression of TH, α1-AR and β2-AR. Phentolamine significantly reduced the inflammatory cytokine levels. Furthermore, we observed a marked decrease in HPDLF proliferation and the increased expression of α1-ARfollowing LPS pretreatment. Pretreatment with phentolamine dramatically ameliorated LPS-inhibited cell proliferation. In addition, the blocking of α1-ARsignaling also hindered the upregulation of the inflammatory-related cytokines IL-1β, IL-6 and IL-8. These results suggest that CS can significantly enhance the pathological progression of periodontitis by an α1-adrenergic signaling-mediated inflammatory response. We have identified a potential therapeutic target for the treatment of periodontal disease, particularly in those patients suffering from concurrent CS.

  7. Technetium-99m labeled 1-(4-fluorobenzyl)-4-(2-mercapto-2-methyl-4-azapentyl)-4- (2-mercapto-2-methylp ropylamino)-piperidine and iodine-123 metaiodobenzylguanidine for studying cardiac adrenergic function: a comparison of the uptake characteristics in vascular smooth muscle cells and neonatal cardiac myocytes, and an investigation in rats

    Energy Technology Data Exchange (ETDEWEB)

    Samnick, Samuel E-mail:; Scheuer, Claudia; Muenks, Sven; El-Gibaly, Amr M.; Menger, Michael D.; Kirsch, Carl-Martin


    -MIBG, respectively. Prazosin, urapidil, and metoprolol were as effective as treatment with other adrenergic drugs in lowering cardiac uptake of {sup 99m}Tc-FBPBAT. Uptake reduction was more pronounced in myocardium than in other adrenergic-rich organs, including the lung, spleen, kidney, and adrenals, suggesting that the {sup 99m}Tc-FBPBAT uptake in myocardium specifically reflects a high degree of {alpha}{sub 1}/{beta}{sub 1}-receptor binding to cardiac adrenergic neurons. In comparison, reduction of cardiac and pulmonary uptake of {sup 123}I-MIBG was effective after pretreatment of rats with desipramine and reserpine, confirming distinct neuronal binding sites for {sup 99m}Tc-FBPBAT and {sup 123}I-MIBG. {sup 99m}Tc-FBPBAT was excreted via urine and to a lower degree via feces. Urine analysis 6 hours p.i. revealed that more than 40% of the total excreted radioactivity was unmetabolized {sup 99m}Tc-FBPBAT. In conclusion, the uptake of {sup 99m}Tc-FBPBAT in rat myocardium specifically reflects binding to cardiac adrenergic neurons. The {sup 99m}Tc-FBPBAT uptake appears to be predominantly mediated via the {alpha}{sub 1}/{beta}{sub 1}-adrenoceptor pathway. These data indicate that {sup 99m}Tc-FBPBAT, like {sup 123}I-MIBG, may be suitable for mapping cardiac adrenergic innervation by SPET, especially for {alpha}{sub 1}/{beta}{sub 1}-adrenoceptors as target in numerous heart diseases.

  8. Characterization of a panel of six β2-adrenergic receptor antibodies by indirect immunofluorescence microscopy (United States)

    Koryakina, Yulia A; Fowler, Tristan W; Jones, Stacie M; Schnackenberg, Bradley J; Cornett, Lawrence E; Kurten, Richard C


    Background The β2-adrenergic receptor (β2AR) is a primary target for medications used to treat asthma. Due to the low abundance of β2AR, very few studies have reported its localization in tissues. However, the intracellular location of β2AR in lung tissue, especially in airway smooth muscle cells, is very likely to have a significant impact on how the airways respond to β-agonist medications. Thus, a method for visualizing β2AR in tissues would be of utility. The purpose of this study was to develop an immunofluorescent labeling technique for localizing native and recombinant β2AR in primary cell cultures. Methods A panel of six different antibodies were evaluated in indirect immunofluorescence assays for their ability to recognize human and rat β2AR expressed in HEK 293 cells. Antibodies capable of recognizing rat β2AR were identified and used to localize native β2AR in primary cultures of rat airway smooth muscle and epithelial cells. β2AR expression was confirmed by performing ligand binding assays using the β-adrenergic antagonist [3H] dihydroalprenolol ([3H]DHA). Results Among the six antibodies tested, we identified three of interest. An antibody developed against the C-terminal 15 amino acids of the human β2AR (Ab-Bethyl) specifically recognized human but not rat β2AR. An antibody developed against the C-terminal domain of the mouse β2AR (Ab-sc570) specifically recognized rat but not human β2AR. An antibody developed against 78 amino acids of the C-terminus of the human β2AR (Ab-13989) was capable of recognizing both rat and human β2ARs. In HEK 293 cells, the receptors were predominantly localized to the cell surface. By contrast, about half of the native rat β2AR that we visualized in primary cultures of rat airway epithelial and smooth muscle cells using Ab-sc570 and Ab-13989 was found inside cells rather than on their surface. Conclusion Antibodies have been identified that recognize human β2AR, rat β2AR or both rat and human β2AR

  9. Characterization of a panel of six β2-adrenergic receptor antibodies by indirect immunofluorescence microscopy

    Directory of Open Access Journals (Sweden)

    Jones Stacie M


    Full Text Available Abstract Background The β2-adrenergic receptor (β2AR is a primary target for medications used to treat asthma. Due to the low abundance of β2AR, very few studies have reported its localization in tissues. However, the intracellular location of β2AR in lung tissue, especially in airway smooth muscle cells, is very likely to have a significant impact on how the airways respond to β-agonist medications. Thus, a method for visualizing β2AR in tissues would be of utility. The purpose of this study was to develop an immunofluorescent labeling technique for localizing native and recombinant β2AR in primary cell cultures. Methods A panel of six different antibodies were evaluated in indirect immunofluorescence assays for their ability to recognize human and rat β2AR expressed in HEK 293 cells. Antibodies capable of recognizing rat β2AR were identified and used to localize native β2AR in primary cultures of rat airway smooth muscle and epithelial cells. β2AR expression was confirmed by performing ligand binding assays using the β-adrenergic antagonist [3H] dihydroalprenolol ([3H]DHA. Results Among the six antibodies tested, we identified three of interest. An antibody developed against the C-terminal 15 amino acids of the human β2AR (Ab-Bethyl specifically recognized human but not rat β2AR. An antibody developed against the C-terminal domain of the mouse β2AR (Ab-sc570 specifically recognized rat but not human β2AR. An antibody developed against 78 amino acids of the C-terminus of the human β2AR (Ab-13989 was capable of recognizing both rat and human β2ARs. In HEK 293 cells, the receptors were predominantly localized to the cell surface. By contrast, about half of the native rat β2AR that we visualized in primary cultures of rat airway epithelial and smooth muscle cells using Ab-sc570 and Ab-13989 was found inside cells rather than on their surface. Conclusion Antibodies have been identified that recognize human β2AR, rat β2AR or

  10. Cardiovascular effects of the novel histamine H2 receptor agonist amthamine: interaction with the adrenergic system. (United States)

    Coruzzi, G; Gambarelli, E; Bertaccini, G; Timmerman, H


    The cardiovascular effects of the new histamine H2 receptor agonist amthamine were studied in the anaesthetized rat, with particular reference to a possible interaction with the adrenergic system. Amthamine (0.03-3 mumol/kg i.v.) caused vasodepressor responses which were antagonized by famotidine (3 mumol/kg i.v.). At higher doses (30-100 mumol/kg i.v.), amthamine induced a modest increase in the mean arterial pressure, which was significantly enhanced by the blockade of H2 receptors and significantly reduced by the alpha 2 adrenoceptor antagonist yohimbine (1 mumol/kg i.v.). The vasopressor response to amthamine was not modified in rats pre-treated with reserpine or 6-hydroxydopamine, and was only minimally modified in adrenalectomized animals, thus suggesting a predominant interaction with postjunctional alpha 2 adrenoceptors in the vascular muscle. The H2 receptor agonist dimaprit (0.3-100 mumol/kg i.v.) caused a reduction in arterial pressure, which was antagonized by famotidine, no pressor response being unmasked. Dimaprit (0.1-30 mumol/kg i.v.) did not modify heart rate but caused a modest bradycardia at 100 mumol/kg i.v. Amthamine (1-100 mumol/kg i.v.) induced a dose-dependent tachycardia, which was only partially (approximately 20%) reduced by famotidine and was totally blocked by propranolol (0.3 mg/kg i.v.). This effect was significantly reduced in rats pre-treated with reserpine or 6-hydroxydopamine and was further reduced by cocaine, thus suggesting a tyramine-like action of amthamine. In conclusion, these data demonstrate that the H2 receptor agonist amthamine can also interact with the adrenergic system when used at doses higher than those necessary to activate H2 receptors. Whereas the increase in blood pressure induced by amthamine seems to be mainly mediated by a direct activation of postjunctional alpha 2 adrenoceptors, the increase in heart rate is predominantly due to neuronal release of catecholamines. These effects should be considered when

  11. Maltsev digraphs have a majority polymorphism

    CERN Document Server

    Kazda, Alexandr


    We prove that when a digraph $G$ has a Maltsev polymorphism, then $G$ also has a majority polymorphism. We consider the consequences of this result for the structure of Maltsev graphs and the complexity of the Constraint Satisfaction Problem.

  12. The evolution of polymorphic compatibility molecules

    NARCIS (Netherlands)

    Boer, R.J. de


    Several primitive colonial organisms distinguish self from nonself by means of polymorphic compatibility molecules bearing similarity to the major histocompatibility complex (MHC). The evolution of such polymorphisms is generally explained in terms of resistance to parasites. Ignoring parasites, I d

  13. Effect of thymidylate synthase (TYMS) gene polymorphisms with methotrexate treatment outcome in south Indian Tamil patients with rheumatoid arthritis. (United States)

    Muralidharan, Niveditha; Misra, Durga P; Jain, Vikramraj K; Negi, Vir Singh


    Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease causing joint damage and significant functional impairment. Methotrexate (MTX) remains the mainstay for the treatment of RA. MTX inhibits several enzymes of the folate and nucleotide pathways. Thymidylate synthase (TYMS) is an important enzyme in the de novo pyrimidine pathway responsible for DNA replication. The two common gene polymorphisms analyzed in TYMS are 28-bp tandem repeat polymorphism and a 6-bp insertion/deletion polymorphism. The present study was carried out to find the role of these TYMS gene polymorphisms with clinical phenotype, treatment response, and MTX adverse events in 254 patients with RA of south Indian Tamil ethnicity. TYMS gene polymorphisms were analyzed by PCR. The allele frequencies of TYMS gene polymorphisms did not differ between good and non-responders. However, the TYMS 28-bp tandem repeat 3R allele was higher in non-responders than in patients undergoing remission [64 vs 51.11%, p = 0.06, OR 0.58, 95% CI (0.34-1.00)]. The TYMS 6-bp deletion allele was higher in non-responders than good responders [78.20 vs 64.92%, p = 0.06, OR 0.51 95% CI (0.27-0.98)]. TYMS 3R allele and TYMS 6-bp deletion allele may favor non-response to MTX in south Indian Tamils. TYMS gene polymorphisms did not influence MTX adverse events.

  14. Crystal structure of the β2 adrenergic receptor-Gs protein complex

    Energy Technology Data Exchange (ETDEWEB)

    Rasmussen, Søren G.F.; DeVree, Brian T; Zou, Yaozhong; Kruse, Andrew C; Chung, Ka Young; Kobilka, Tong Sun; Thian, Foon Sun; Chae, Pil Seok; Pardon, Els; Calinski, Diane; Mathiesen, Jesper M