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Tanenao Eto – One of the best experts on this subject based on the ideXlab platform.

  • Angiotensin II stimulates cardiac Adrenomedullin production and causes accumulation of mature Adrenomedullin independently of hemodynamic stress in vivo.
    Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2005
    Co-Authors: Hisamitsu Onitsuka, Kenji Kuwasako, Kazuo Kitamura, Takuroh Imamura, Junichi Yamaga, Tanenao Eto
    Abstract:

    Adrenomedullin is a potent hypotensive peptide that may act on myocytes to inhibit hypertrophy and on fibroblasts to inhibit growth in vitro induced by mechanical stretching and angiotensin II. Adrenomedullin is processed from the inactive intermediate Adrenomedullin precursor with a glycine extension, which is subsequently converted to biologically active mature Adrenomedullin by enzymatic amidation. Total Adrenomedullin is the sum of intermediate and mature Adrenomedullin. We examined the effect of a subpressor dose of angiotensin II on the production of left ventricular Adrenomedullin and on protein levels of mature Adrenomedullin in the left ventricle in vivo. We also investigated whether the effect is mediated by the angiotensin II type 1 receptor. Concentrations of total and mature Adrenomedullin in the left ventricle and mature Adrenomedullin-to-intermediate Adrenomedullin ratio were significantly increased by angiotensin II infusion, regardless of pressure overload. Total and mature Adrenomedullin concentrations significantly correlated with the weight of the left ventricle. Furthermore, increased Adrenomedullin gene expression and protein levels were completely suppressed by a subdepressor dose of angiotensin II type 1 receptor blocker. In conclusion, angiotensin II stimulates the production of cardiac Adrenomedullin and accumulates mature Adrenomedullin in the left ventricle independently of hemodynamic stress. These processes are partially regulated through the angiotensin II type 1 receptor in vivo.

  • The calcitonin receptor-like receptor/receptor activity-modifying protein 1 heterodimer can function as a calcitonin gene-related peptide-(8-37)-sensitive Adrenomedullin receptor
    European journal of pharmacology, 2002
    Co-Authors: Yasuko Nagoshi, Kenji Kuwasako, Kaoru Ito, Tomohiko Uemura, Johji Kato, Kazuo Kitamura, Tanenao Eto
    Abstract:

    Abstract The receptor activity-modifying protprotein (RAMP)/calcitonin receptor-like (CRL) receptor heterodimer is thought to function as a receptor for either a calcitonin gene-related peptide (CGRP) (CRL receptor/RAMP1) or Adrenomedullin (CRL receptor/RAMP2 or -3), depending on the RAMP isoform present. We examined the receptor specificity of Adrenomedullin-induced increases in cAMP in human embryonic kidney (HEK)293 cells coexpressing human CRL receptor and human RAMP1 or RAMP2. In cells expressing CRL receptor/RAMP1, adrenomedulin-induced increases in cAMP were comparable to those induced by α-CGRP, and the CGRP receptor antagonist α-CGRP-(8–37), but not the Adrenomedullin receptor antagonist Adrenomedullin-(22–52), blocked the Adrenomedullin-evoked responses. Cells expressing CRL receptor/RAMP2 responded more selectively to Adrenomedullin; in this case, the effect was blocked by Adrenomedullin-(22–52) but not by α-CGRP-(8–37). Real-time quantitative polymerase chain reaction confirmed that cotransfection of CRL receptor and RAMP1 had no effect on the endogenous expression of RAMP2. Thus, CRL receptor/RAMP1 likely functions as an Adrenomedullin receptor as well as a CGRP receptor, which may explain why many of the actions of Adrenomedullin are potently antagonized by α-CGRP-(8–37).

  • the calcitonin receptor like receptor receptor activity modifying protein 1 heterodimer can function as a calcitonin gene related peptide 8 37 sensitive Adrenomedullin receptor
    European Journal of Pharmacology, 2002
    Co-Authors: Yasuko Nagoshi, Kenji Kuwasako, Kaoru Ito, Tomohiko Uemura, Johji Kato, Kazuo Kitamura, Tanenao Eto
    Abstract:

    Abstract The receptor activity-modifying protprotein (RAMP)/calcitonin receptor-like (CRL) receptor heterodimer is thought to function as a receptor for either a calcitonin gene-related peptide (CGRP) (CRL receptor/RAMP1) or Adrenomedullin (CRL receptor/RAMP2 or -3), depending on the RAMP isoform present. We examined the receptor specificity of Adrenomedullin-induced increases in cAMP in human embryonic kidney (HEK)293 cells coexpressing human CRL receptor and human RAMP1 or RAMP2. In cells expressing CRL receptor/RAMP1, adrenomedulin-induced increases in cAMP were comparable to those induced by α-CGRP, and the CGRP receptor antagonist α-CGRP-(8–37), but not the Adrenomedullin receptor antagonist Adrenomedullin-(22–52), blocked the Adrenomedullin-evoked responses. Cells expressing CRL receptor/RAMP2 responded more selectively to Adrenomedullin; in this case, the effect was blocked by Adrenomedullin-(22–52) but not by α-CGRP-(8–37). Real-time quantitative polymerase chain reaction confirmed that cotransfection of CRL receptor and RAMP1 had no effect on the endogenous expression of RAMP2. Thus, CRL receptor/RAMP1 likely functions as an Adrenomedullin receptor as well as a CGRP receptor, which may explain why many of the actions of Adrenomedullin are potently antagonized by α-CGRP-(8–37).

Kazuo Kitamura – One of the best experts on this subject based on the ideXlab platform.

  • Angiotensin II stimulates cardiac Adrenomedullin production and causes accumulation of mature Adrenomedullin independently of hemodynamic stress in vivo.
    Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2005
    Co-Authors: Hisamitsu Onitsuka, Kenji Kuwasako, Kazuo Kitamura, Takuroh Imamura, Junichi Yamaga, Tanenao Eto
    Abstract:

    Adrenomedullin is a potent hypotensive peptide that may act on myocytes to inhibit hypertrophy and on fibroblasts to inhibit growth in vitro induced by mechanical stretching and angiotensin II. Adrenomedullin is processed from the inactive intermediate Adrenomedullin precursor with a glycine extension, which is subsequently converted to biologically active mature Adrenomedullin by enzymatic amidation. Total Adrenomedullin is the sum of intermediate and mature Adrenomedullin. We examined the effect of a subpressor dose of angiotensin II on the production of left ventricular Adrenomedullin and on protein levels of mature Adrenomedullin in the left ventricle in vivo. We also investigated whether the effect is mediated by the angiotensin II type 1 receptor. Concentrations of total and mature Adrenomedullin in the left ventricle and mature Adrenomedullin-to-intermediate Adrenomedullin ratio were significantly increased by angiotensin II infusion, regardless of pressure overload. Total and mature Adrenomedullin concentrations significantly correlated with the weight of the left ventricle. Furthermore, increased Adrenomedullin gene expression and protein levels were completely suppressed by a subdepressor dose of angiotensin II type 1 receptor blocker. In conclusion, angiotensin II stimulates the production of cardiac Adrenomedullin and accumulates mature Adrenomedullin in the left ventricle independently of hemodynamic stress. These processes are partially regulated through the angiotensin II type 1 receptor in vivo.

  • The calcitonin receptor-like receptor/receptor activity-modifying protein 1 heterodimer can function as a calcitonin gene-related peptide-(8-37)-sensitive Adrenomedullin receptor
    European journal of pharmacology, 2002
    Co-Authors: Yasuko Nagoshi, Kenji Kuwasako, Kaoru Ito, Tomohiko Uemura, Johji Kato, Kazuo Kitamura, Tanenao Eto
    Abstract:

    Abstract The receptor activity-modifying protein (RAMP)/calcitonin receptor-like (CRL) receptor heterodimer is thought to function as a receptor for either a calcitonin gene-related peptide (CGRP) (CRL receptor/RAMP1) or Adrenomedullin (CRL receptor/RAMP2 or -3), depending on the RAMP isoform present. We examined the receptor specificity of Adrenomedullin-induced increases in cAMP in human embryonic kidney (HEK)293 cells coexpressing human CRL receptor and human RAMP1 or RAMP2. In cells expressing CRL receptor/RAMP1, adrenomedulin-induced increases in cAMP were comparable to those induced by α-CGRP, and the CGRP receptor antagonist α-CGRP-(8–37), but not the Adrenomedullin receptor antagonist Adrenomedullin-(22–52), blocked the Adrenomedullin-evoked responses. Cells expressing CRL receptor/RAMP2 responded more selectively to Adrenomedullin; in this case, the effect was blocked by Adrenomedullin-(22–52) but not by α-CGRP-(8–37). Real-time quantitative polymerase chain reaction confirmed that cotransfection of CRL receptor and RAMP1 had no effect on the endogenous expression of RAMP2. Thus, CRL receptor/RAMP1 likely functions as an Adrenomedullin receptor as well as a CGRP receptor, which may explain why many of the actions of Adrenomedullin are potently antagonized by α-CGRP-(8–37).

  • the calcitonin receptor like receptor receptor activity modifying protein 1 heterodimer can function as a calcitonin gene related peptide 8 37 sensitive Adrenomedullin receptor
    European Journal of Pharmacology, 2002
    Co-Authors: Yasuko Nagoshi, Kenji Kuwasako, Kaoru Ito, Tomohiko Uemura, Johji Kato, Kazuo Kitamura, Tanenao Eto
    Abstract:

    Abstract The receptor activity-modifying protein (RAMP)/calcitonin receptor-like (CRL) receptor heterodimer is thought to function as a receptor for either a calcitonin gene-related peptide (CGRP) (CRL receptor/RAMP1) or Adrenomedullin (CRL receptor/RAMP2 or -3), depending on the RAMP isoform present. We examined the receptor specificity of Adrenomedullin-induced increases in cAMP in human embryonic kidney (HEK)293 cells coexpressing human CRL receptor and human RAMP1 or RAMP2. In cells expressing CRL receptor/RAMP1, adrenomedulin-induced increases in cAMP were comparable to those induced by α-CGRP, and the CGRP receptor antagonist α-CGRP-(8–37), but not the Adrenomedullin receptor antagonist Adrenomedullin-(22–52), blocked the Adrenomedullin-evoked responses. Cells expressing CRL receptor/RAMP2 responded more selectively to Adrenomedullin; in this case, the effect was blocked by Adrenomedullin-(22–52) but not by α-CGRP-(8–37). Real-time quantitative polymerase chain reaction confirmed that cotransfection of CRL receptor and RAMP1 had no effect on the endogenous expression of RAMP2. Thus, CRL receptor/RAMP1 likely functions as an Adrenomedullin receptor as well as a CGRP receptor, which may explain why many of the actions of Adrenomedullin are potently antagonized by α-CGRP-(8–37).

Kenji Kangawa – One of the best experts on this subject based on the ideXlab platform.

  • Response of Adrenomedullin system to cytokine in cardiac fibroblasts-role of Adrenomedullin as an antifibrotic factor.
    Cardiovascular research, 2005
    Co-Authors: Toshio Nishikimi, Takeshi Horio, Kenji Kangawa, Yosuke Mori, Kazuyoshi Tadokoro, Kazumi Akimoto, Yayoi Ishikawa, Kimihiko Ishimura, Hiroaki Matsuoka
    Abstract:

    Objective : The Adrenomedullin system acts as an autocrine or paracrine factor (or both) in the development of cardiac hypertrophy and in the regulation of cardiac function. However, several aspects of the local action of Adrenomedullin remain unclear. We studied the effects of interleukin 1-beta (IL-1β) on the Adrenomedullin system in cardiac fibroblasts and also examined the pathophysiological significance of such effects. Methods : We cultured rat neonatal cardiac fibroblasts with or without IL-1β and measured (1) two molecular forms of Adrenomedullin in culture medium by specific immunoradiometric assay; (2) gene expression of Adrenomedullin, calcitonin receptor like receptor (CRLR), receptor activity modifying protein2 (RAMP2), and RAMP3, components of the Adrenomedullin receptor, by Northern blot analysis or RT-PCR analysis; (3) intracellular cAMP levels in response to exogenously administered Adrenomedullin; and (4) 3H-proline incorporation with and without a specific Adrenomedullin antisense oligoligodeoxynucleotide. Results : (1) IL-1β time-dependently increased the levels of two molecular forms of Adrenomedullin, Adrenomedullin-mature and Adrenomedullin-glycine ( P

  • Upregulation of intracardiac Adrenomedullin and its receptor system in rats with volume overload-induced cardiac hypertrophy.
    Regulatory Peptides, 2005
    Co-Authors: Fumiki Yoshihara, Toshio Nishikimi, Ichiro Okano, Jun Hino, Takeshi Horio, Takeshi Tokudome, Shin-ichi Suga, Hiroaki Matsuoka, Kenji Kangawa, Yuhei Kawano
    Abstract:

    Specific Adrenomedullin receptors have been identified as calcitonin receptor-like receptor (CRLR)/receptor activity-modifying proteins (RAMP2 and RAMP3) complexes. Although we have demonstrated that Adrenomedullin is increased in volume overload-induced cardiac hypertrophy, it remains unknown whether the Adrenomedullin receptor is altered or not. This study sought to investigate the significance of intracardiac Adrenomedullin and its receptor system in volume overload-induced cardiac hypertrophy. Left ventricular Adrenomedullin levels were higher in aortocaval shunt (ACS) rats than in controls (+58%). The left ventricular gene expressions of Adrenomedullin, CRLR, RAMP2 and RAMP3 were increased (+27%, +76%, +108% and +131%, respectively) and the left ventricular collagen gene expressions were also increased (type I: +138%, type III: +87%). The left ventricular Adrenomedullin level correlated with the gene expression of type III collagen (R=0.42). These results suggest that intracardiac Adrenomedullin and its receptor system are upregulated and may participate in the regulation of cardiac remodeling in volume overload-induced cardiac hypertrophy.

  • Adrenomedullin augments collateral development in response to acute ischemia.
    Biochemical and biophysical research communications, 2003
    Co-Authors: Minami Abe, Kenji Kangawa, Naoto Minamino, Masataka Sata, Hiroaki Nishimatsu, Daisuke Nagata, Etsu Suzuki, Yasuo Terauchi, Takashi Kadowaki, Hisayuki Matsuo
    Abstract:

    Expression of Adrenomedullin, discovered as a vasodilatory peptide, is markedly up-regulated under pathological conditions such as tissue ischemia and inflammation, which are associated with neovascularization. Here, we tested the hypothesis that overly expressed Adrenomedullin may augment collateral flow to ischemic tissues. We induced hindlimb ischemia in wild-type mice and injected a naked plasmid expressing human Adrenomedullin or an empty vector into the ischemic muscle, followed by in vivo electroporation. Adrenomedullin markedly enhanced blood flow recovery as determined by Laser Doppler imaging. The mice treated with an empty vector suffered frequent autoamputation of the ischemic toe, which was completely prevented by Adrenomedullin. Anti-CD31 immunostaining revealed that Adrenomedullin significantly increased capillary density. The angiogenic effect of Adrenomedullin was abrogated in endothelial nitric oxide synthase (eNOS)-deficient mice. These results indicate that Adrenomedullin may promote collateral growth in response to ischemia through activation of eNOS.

David M Smith – One of the best experts on this subject based on the ideXlab platform.

  • characterisation and molecular identification of Adrenomedullin binding sites in the rat spinal cord a comparison with calcitonin gene related peptide receptors
    Journal of Neurochemistry, 2002
    Co-Authors: Ali A Owji, James Gardiner, Paul D Upton, Mehdi Mahmoodi, Mohammad A Ghatei, Stephen R Bloom, David M Smith
    Abstract:

    Calcitonin gene-related peptide (CGRP) and its receptors are found in mammalian spinal cord. We show, for the first time, binding sites for the novel related peptide Adrenomedullin in rat spinal cord microsomes. 125I-Adrenomedullin binding showed high affinity (KD = 0.45 +/- 0.06 nM) and sites were abundant (Bmax = 723 +/- 71 fmol/mg of protein). CGRP, amylin, and calcitonin did not compete at these sites (Ki > 10 microM). High-affinity CGRP binding sites (KD = 0.18 +/- 0.01 nM) were much less numerous (Bmax = 17.7 +/- 2.4 fmol/mg of protein) and showed competition by unlabeled Adrenomedullin (Ki = 34.6 +/- 2.4 nM). Chemical cross-linking revealed a major band for 125I-Adrenomedullin of M(r) = 84,400 +/- 1,200 and a minor band of M(r) = 122,000 +/- 8,700. 125I-CGRP cross-linking showed bands of lower molecular weight (M(r) = 74,500 +/- 5,000 and 61,000 +/- 2,200). Enzymic deglycosylation of the Adrenomedullin binding site showed a considerable carbohydrate content. Neither Adrenomedullin nor CGRP was able to increase cyclic AMP in spinal cord. Adrenomedullin mRNA was present in spinal cord, at one-third of its level in lung, and Adrenomedullin immunoreactivity was present, at a low concentration (40 fmol/g of tissue). Thus, the presence of abundant binding sites and Adrenomedullin mRNA and immunoreactivity anticipate an as yet undefined function for this peptide in spinal cord.

  • Knockouts and transgenics confirm the importance of Adrenomedullin in the vasculature.
    Trends in pharmacological sciences, 2001
    Co-Authors: Debbie L. Hay, David M Smith
    Abstract:

    Adrenomedullin might be a much more important player in vascular function than previously thought. The Adm knockout models presented at this conference confirm the role of Adrenomedullin in control of blood pressure and also support the argument for more research on Adrenomedullin as an angiogenic factor 8xPCR display identifies tamoxifen induction of the novel angiogenic factor Adrenomedullin by a non-estrogenic mechanism in the human endometrium. Zhao, Y et al. Oncogene. 1998; 16: 409–415Crossref | PubMedSee all References8. The Adrenomedullin binding protproteins also challenge our preconceptions of effective circulating Adrenomedullin levels.Key conference outcomes Adrenomedullin receptors are combinations of a calcitonin receptor-like receptor (CRLR) with receptor activity modifying proteins (RAMPs). Two germ-line deletions of the gene encoding Adrenomedullin (Adm) were demonstrated, one deleting only Adrenomedullin and the other deleting Adrenomedullin and proAdrenomedullin N-terminal 20 peptide (PAMP). Knockout of the Admgene is lethal in the homozygous form. The phenotype of the Admknockout mouse might be associated with a failure of normal vessel development. Knockout of the Adm –PAMP gene increases blood pressure whereas overexpression of Adrenomedullin lowers blood pressure. The effects of injury on blood vessels are enhanced in both Admknockout mice but are reduced in mice overexpressing Adrenomedullin. Complement factfactor H is an Adrenomedullin binding protprotein that enhances Adrenomedullin-receptor-mediated effects.

  • Adrenomedullin a multifunctional regulatory peptide
    Endocrine Reviews, 2000
    Co-Authors: J P Hinson, Supriya Kapas, David M Smith
    Abstract:

    Since the discovery of Adrenomedullin in 1993 several hundred papers have been published regarding the regulation of its secretion and the multiplicity of its actions. It has been shown to be an almost ubiquitous peptide, with the number of tissues and cell types synthesizing Adrenomedullin far exceeding those that do not. In Section II of this paper we give a comprehensive review both of tissues and cell lines secreting Adrenomedullin and of the mechanisms regulating gene expression. The data on circulating Adrenomedullin, obtained with the various assays available, are also reviewed, and the disease states in which plasma Adrenomedullin is elevated are listed. In Section III the pharmacology and biochemistry of Adrenomedullin binding sites, both specific sites and calcitonin gene-related peptide (CGRP) receptors, are discussed. In particular, the putative Adrenomedullin receptor clones and signal transduction pathways are described. In Section IV the various actions of Adrenomedullin are discussed: its actions on cellular growth, the cardiovascular system, the central nervous system, and the endocrine system are all considered. Finally, in Section V, we consider some unresolved issues and propose future areas for research.

J P Hinson – One of the best experts on this subject based on the ideXlab platform.

  • Adrenomedullin a multifunctional regulatory peptide
    Endocrine Reviews, 2000
    Co-Authors: J P Hinson, Supriya Kapas, David M Smith
    Abstract:

    Since the discovery of Adrenomedullin in 1993 several hundred papers have been published regarding the regulation of its secretion and the multiplicity of its actions. It has been shown to be an almost ubiquitous peptide, with the number of tissues and cell types synthesizing Adrenomedullin far exceeding those that do not. In Section II of this paper we give a comprehensive review both of tissues and cell lines secreting Adrenomedullin and of the mechanisms regulating gene expression. The data on circulating Adrenomedullin, obtained with the various assays available, are also reviewed, and the disease states in which plasma Adrenomedullin is elevated are listed. In Section III the pharmacology and biochemistry of Adrenomedullin binding sites, both specific sites and calcitonin gene-related peptide (CGRP) receptors, are discussed. In particular, the putative Adrenomedullin receptor clones and signal transduction pathways are described. In Section IV the various actions of Adrenomedullin are discussed: its actions on cellular growth, the cardiovascular system, the central nervous system, and the endocrine system are all considered. Finally, in Section V, we consider some unresolved issues and propose future areas for research.

  • local production and action of Adrenomedullin in the rat adrenal zona glomerulosa
    Journal of Endocrinology, 1998
    Co-Authors: Alfredo Martinez, Frank Cuttitta, J P Hinson
    Abstract:

    : This study was designed to investigate the synthesis and action of Adrenomedullin in the rat adrenal gland. The results obtained from in situ hybridization and immunocytochemical studies suggest that Adrenomedullin is synthesized not only in the medulla, but also within the zona glomerulosa of the rat adrenal cortex. Findings from in situ hybridization and binding studies also suggested that specific Adrenomedullin receptors are expressed in the zona glomerulosa, and that low levels are present in the inner zones of the cortex. The Kd of the zona glomerulosa Adrenomedullin receptor (5.5 nmol/l) suggests that it may respond to locally produced Adrenomedullin rather than circulating concentrations of the peptide, which are in a lower range. It was found that Adrenomedullin acted on zona glomerulosa cells in vitro to stimulate aldosterone release and cAMP formation, but in this tissue did not stimulate inositol phosphate turnover. The effect of Adrenomedullin on aldosterone secretion was significantly attenuated by a protein kinase A inhibitor, suggesting that cAMP mediates the effects of Adrenomedullin on aldosterone secretion. Adrenomedullin did not significantly affect the response of zona glomerulosa cells to stimulation by either ACTH or angiotensin II. Adrenomedullin did not affect the release of catecholamines, either adrenaline or noradrenaline, by intact adrenal capsular tissue. These data suggest that both Adrenomedullin and its specific receptor are expressed in the rat adrenal zona glomerulosa, leading to the hypothesis that Adrenomedullin may have an autocrine/paracrine role in the regulation of the rat adrenal zona glomerulosa.

  • Actions of Adrenomedullin on the rat adrenal cortex
    Endocrine research, 1996
    Co-Authors: Supriya Kapas, J P Hinson
    Abstract:

    The actions of Adrenomedullin on cAMP and aldosterone secretion have been investigated using an intact rat adrenal capsular preparation incubated in vitro. Adrenomedullin was found to cause a dose-dependent increase in aldosterone secretion, with a parallel increase in cAMP release. The minimum concentration of Adrenomedullin required for significant stimulation of aldosterone secretion was 10nmol/1. Adrenomedullin did not affect ACTH-stimulated aldosterone secretion, but significantly inhibited endothelin-1 stimulated aldosterone secretion. We conclude that Adrenomedullin is an aldosterone stimulant in the rat adrenal gland, acting through cAMP generation.