論文 - 北村 和雄
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Expression and immunohistochemical localization of adrenomedullin in the mouse cochlea 査読あり
Tono T., Shimozono M., Kawano H., Asada Y., Kitamura K., Komune S.
ORL 64 ( 3 ) 169 - 172 2002年6月
掲載種別：研究論文（学術雑誌） 出版者・発行元：ORL
Adrenomedullin (AM) is a novel hypotensive and vasodilator peptide. It has been shown that AM is biosynthesized in various organs and cells and is suggested to play multiple roles including electrolyte homeostasis and body fluid control. The present study describes for the first time the presence of mRNA for AM and AM-like immunoreactivity in the cochlea. A reverse transcription-polymerase chain reaction (RT-PCR) performed with gene-specific AM primer on total RNA extracted from mouse cochlea revealed a PCR product of the expected size. Immunohistochemical examination showed positive immunostaining in vascular smooth muscle cells of the modiolar arterioles and in the stria vascularis of the cochlea. These results suggest that AM may play a role in the regulation not only of cochlear hemodynamics but also of cochlear fluid dynamics. Copyright © 2002 S. Karger AG, Basel.
DOI： 10.1159/000058020
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Uemura T., Kato J., Kuwasako K., Kitamura K., Kangawa K., Eto T.
Journal of Hypertension 20 ( 6 ) 1209 - 1214 2002年6月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Hypertension
Objective: Both adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP), processed from the same precursor of prepro-adrenomedullin (preproAM), have differential biological properties; AM dilates blood vessels and presumably affects the vascular remodeling, while PAMP inhibits catecholamine secretion. Since aldosterone has been shown to be involved in vascular remodeling, we examined the effects of aldosterone on AM and PAMP secretion and preproAM gene expression in human aortic vascular smooth muscle cells (VSMC). Methods: AM and PAMP secreted from human VSMC incubated with aldosterone were measured by radioimmunoassay, and preproAM gene expression was evaluated by quantitative polymerase chain reaction. Results: Cultured human VSMC secreted both AM and PAMP into the media, while the secretion rate of AM was much higher than that of PAMP. Aldosterone increased preproAM gene expression in the cultured VSMC in a dose-dependent fashion following incubation for 48 h, with a concomitant increase in AM secretion from the cells, but PAMP secretion remained unchanged. Aldosterone-stimulated AM secretion was significantly reduced by spironolactone. Reverse-phase high-performance liquid chromatography analyses showed that immunoreactive AM secreted from the VSMC untreated or treated with aldosterone emerged at the point of human AM(1-52)-NH2. Conclusions: AM production was stimulated by aldosterone in cultured human VSMC without an increase in PAMP secretion, suggesting a possible role of AM in modulating vascular remodeling by aldosterone. © 2002 Lippincott Williams & Wilkins.
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Rat RAMP domains involved in adrenomedullin binding specificity 査読あり
Kuwasako K., Kitamura K., Onitsuka H., Uemura T., Nagoshi Y., Kato J., Eto T.
FEBS Letters 519 ( 1-3 ) 113 - 116 2002年5月
掲載種別：研究論文（学術雑誌） 出版者・発行元：FEBS Letters
When coexpressed with receptor activity-modifying protein (RAMP)2 or -3, calcitonin receptor-like receptor (CRLR) functions as an adrenomedullin (AM) receptor (CRLR/RAMP2 or -3). Coexpression of rat (r)CRLR with rRAMP deletion mutants in HEK293T cells revealed that deletion of residues 93-99 from rRAMP2 or residues 58-64 from rRAMP3 significantly inhibits high-affinity [125I]AM binding and AM-evoked cAMP production, despite full cell surface expression of the receptor heterodimer. Apparently, these two seven-residue segments are key determinants of high-affinity agonist binding to rAM receptors and of receptor functionality. Consequently, their deletion yields peptides that are able to serve as negative regulators of AM receptor function. © 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.
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Hirano S., Imamura T., Onitsuka H., Matsuo T., Kitamura K., Koiwaya Y., Eto T.
Circulation Journal 66 ( 4 ) 397 - 402 2002年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Circulation Journal
To determine whether acute pressure overload (POL) can stimulate adrenomedullin (AM) production, the response of ventricular AM gene expression and plasma AM concentration to aortic banding was investigated in the rat. Furthermore, any link between AM expression and the renin-angiotensin system (RAS) enhanced by acute POL was examined using: a Ca channel blocker (manidipine), an angiotensin II type I receptor antagonist (candesartan), and an angiotensin-converting enzyme inhibitor (quinapril). Rats with acute POL produced by suprarenal aortic banding were studied 1, 5 and 14 days after surgery. Plasma AM concentrations in banded rats at day 1 increased 1.49-fold (p<0.01), then gradually declined to near the control level at day 14. Plasma AM concentrations correlated with plasma renin activity (PRA) (p<0.001). Adrenomedullin mRNA expression in the left ventricle (LV) increased 1.35-fold (p<0.05) at day 1. This increase was not significant at either 5 or 14 days after surgery. Adrenomedullin mRNA expression in the right ventricle on days 1 and 5 increased by 1.46-fold (p<0.05) and 1.52-fold (p<0.05), respectively. Candesartan, quinapril and manidipine reduced systolic blood pressure equally and activated PRA at day 1. However, augmented LV AM gene expression was suppressed completely by candesartan and quinapril, but remained unaffected by manidipine. In conclusion, POL induces a rapid increase in cardiac AM gene expression and in plasma AM concentrations. Cardiac AM transcription could therefore be partly regulated by RAS in suprarenal aortic banding rats.
DOI： 10.1253/circj.66.397
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Recovery process of arthritis induced by 6-sulfanilamidoindazole (6SAI) in rats 査読あり
Y Ohmachi 1, H Fujimura, E Otsuka, T Miyazaki, W Toriumi, K Kitamura, K Doi
Histol Histopathol 17 ( 2 ) 437 - 444 2002年4月
掲載種別：研究論文（学術雑誌）
DOI： 10.14670/HH-17.437
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Adrenomedullin and PAMP: Discovery, structures, and cardiovascular functions 査読あり
Kitamura K., Kangawa K., Eto T.
Microscopy Research and Technique 57 ( 1 ) 3 - 13 2002年4月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Microscopy Research and Technique
We discovered adrenomedullin (AM) from human pheochromocytoma tissue by monitoring the elevating activity of intracellular cyclic AMP (cAMP) in rat platelets in 1993. Since the discovery of AM, it has attracted intense interest from cardiovascular researchers because AM elicits multiple biological activities, including a potent and powerful hypotensive activity caused by dilatation of resistance vessels. AM is biosynthesized and secreted from tissues, including cardiovascular organs. In addition to AM, "proadrenomedullin N-terminal 20 peptide (PAMP)," another biologically active peptide, was found to be processed from the AM precursor. Plasma AM levels are increased in various cardiovascular and renal diseases. AM, therefore, seems to function as a novel system that controls circulation and body fluid, and may be involved in pathophysiological changes in cardiovascular diseases. Therefore, in this review we will focus on the structure of AM and its gene, distribution, receptor, and the physiological and pathological roles of AM in cardiovascular disease. © 2002 Wiley-Liss, Inc.
DOI： 10.1002/jemt.10052
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Adrenomedullin, an endogenous peptide, counteracts cardiovascular damage 査読あり
Shimosawa T., Shibagaki Y., Ishibashi K., Kitamura K., Kangawa K., Kato S., Ando K., Fujita T.
Circulation 105 ( 1 ) 106 - 111 2002年1月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Circulation
Background - Adrenomedullin (AM), a potent vasodilator peptide, is produced by posttranslational splicing of proadrenomedullin together with proadrenomedullin N-terminal 20 peptide (PAMP), another hypotensive peptide. Although both AM and PAMP have the potential not only to decrease blood pressure but also to protect organs from damage, there is no direct evidence for their individual physiological roles in vivo. Methods and Results - Using knockout mice with the disruption of AM peptide alone, we investigated the organ-protective effect of AM. Although the AM-/- mutation in mice was embryonic lethal without any apparent phenotypic changes, AM+/- mice were viable and fertile; plasma and organ AM concentrations were almost half of those in AM+/+ mice. With the administration of angiotensin II (Ang II) on a high-salt diet for 12 days, marked perivascular fibrosis and intimal hyperplasia were found in coronary arteries of Ang II/salt-treated AM+/- mice, without the AM upregulation that was observed in Ang II/salt-treated AM+/+ mice. In AM+/- mice, Ang II/salt loading increased both urinary excretion of 8-hydroxydeoxyguanosine and isoprostane, markers of oxidative stress. Consistently, immunostaining of both p67phox and gp91phox, subunits of NAD(P)H oxidase and 3-nitrotyrosine, the metabolites of reactive oxygen species (ROS), and the generation of ROS measured by electron spin resonance spectroscopy apparently increased in the Ang II/salt-treated heart. These data suggested that the overproduction of oxidative stress might be involved in the cardiovascular changes induced by Ang II/salt loading. Conclusions - The evidence presented supports the hypothesis that endogenous AM possesses a protective action against cardiovascular damage, possibly through the inhibition of oxidative stress production.
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Yuchi H., Suganuma T., Sawaguchi A., Ide S., Kawano J.I., Aoki T., Kitamura K., Eto T.
Histochemistry and Cell Biology 118 ( 3 ) 259 - 265 2002年
掲載種別：研究論文（学術雑誌） 出版者・発行元：Histochemistry and Cell Biology
We reappraised the precise immunohistochemical localization of adrenomedullin (AM) by means of the combined use of the catalyzed signal amplification (CSA) system and plunge freezing (PF)/freeze substitution (FS) for light microscopy or high-pressure freezing (HPF)/FS for electron microscopy, focusing on the rat adrenal gland and heart. In the case of adrenal glands, the PF processing showed that almost all medullary cells were intensively immunoreactive, while the cortical cells showed weak immunoreaction. In the heart, almost all cardiac muscle cells of the atria were also vividly stained with the PF/FS and the CSA enhancement. On the contrary, traces of immunoreactions were seen in most of the ventricular cells. These results are consistent with the previous reports of AM radioimmunoassays and the expression of AM mRNA. However, the chemical fixation processing revealed heterogeneous immunostaining in the atrial and ventricular myocardium as well as the adrenal medulla. Intensity of the immunostaining in the chemically fixed tissues was not likely to correspond with that of AM radioimmunoassays. The HPF/FS processing clearly demonstrated the immunogold labeling on secretory granules of adrenal medullary cells as well as cardiac muscle cells of the right auricles. Immunogold labeling intensity of the cryofixed specimens was 3- to 25-fold higher than that of the chemically fixed ones.
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アドレノメデュリン中枢投与による昇圧反応における交感神経系の関与および心血管反射調節系としての延髄最後野の役割 査読あり
斉田光彦、北村和雄、江藤胤尚、河南洋
日本内分泌学会雑誌 78 ( 2 ) 454 - 454 2002年
掲載種別：研究論文（学術雑誌）
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培養骨芽細胞, 軟骨細胞におけるアドレノメデュリンの成長因子としての作用 査読あり
濱田浩朗、北村和雄、田島直也、帖佐悦男
日本内分泌学会雑誌 78 ( 2 ) 452 - 452 2002年
掲載種別：研究論文（学術雑誌）
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CRLR/RAMP1複合体はCGRP-(8-37)に感受性の高いアドレノメデュリン受容体として機能する 査読あり
名越康子、桑迫健二、加藤丈司、北村和雄、江藤胤尚
日本内分泌学会雑誌 78 ( 2 ) 452 - 452 2002年
掲載種別：研究論文（学術雑誌）
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アドレノメデュリンと心血管病 査読あり
北村和雄、北俊弘、加藤丈司、江藤胤尚
日本内分泌学会雑誌 78 ( 2 ) 444 - 444 2002年
掲載種別：研究論文（学術雑誌）
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慢性糸球体腎炎患者における血漿・尿中Adrenomedullin(AM),Proadrenomedullin N-temina120peptide(PAMP)の動態 査読あり
藤元昭一、木下浩、戸倉健、北村和雄、江藤胤尚
Therapeutic Research 23 ( 5 ) 799 - 804 2002年
掲載種別：研究論文（学術雑誌）
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心筋梗塞後リモデリングに対するアドレノメデュリン長期投与の有効性 査読あり
中村亮斉、加藤丈司、北村和雄、鬼塚久充、今村卓郎、寒川賢治、江藤胤尚
日本内分泌学会雑誌 78 ( 2 ) 451 - 451 2002年
掲載種別：研究論文（学術雑誌）
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高食塩食によるラットアドレノメデュリンとその受容体遺伝子発現の上昇 査読あり
曹遠寧、北村和雄、加藤丈司、桑迫健二、江藤胤尚
日本内分泌学会雑誌 78 ( 2 ) 452 - 452 2002年
掲載種別：研究論文（学術雑誌）
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Kuwasako K., Kitamura K., Ito K., Uemura T., Yanagita Y., Kato J., Sakata T., Eto T.
Journal of Biological Chemistry 276 ( 52 ) 49459 - 49465 2001年12月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Biological Chemistry
When co-expressed with a receptor activity-modifying protein (RAMP) accessory protein, calcitonin receptor-like receptor (CRLR) can function as a calcitonin gene-related peptide receptor (CRLR-RAMP1) or an adrenomedullin (AM) receptor (CRLR-RAMP2/3). Here we report on the structural domain(s) involved in selective AM binding that were examined using various RAMP chimeras and deletion mutants. Co-expression of chimeric RAMPs and CRLR in HEK293 cells revealed that residues 77-101, situated in the extracellular N-terminal domain of human RAMP2 (hRAMP2), were crucial for selective AM-evoked cAMP production. More detailed analysis showed that deletion of hRAMP2 residues 86-92 significantly attenuated high-affinity 125I-AM binding and AM-evoked cAMP production despite full cell surface expression of the receptor heterodimer and that deletion of hRAMP3 residues 59-65 had a similar effect. There is little sequence identity between hRAMP3 residues 59-65 and hRAMP2 residues 86-92; moreover, substituting alanine for Trp86 (Ala 87), Met88, Ile89, Ser90, Arg 91, or Pro92 of hRAMP2 had no effect on AM-evoked cAMP production. It thus seems unlikely that any one amino acid residue is responsible for determining selective AM binding or that AM binds directly to these peptide segments. Instead these findings suggest that the respective seven-amino acid sequences confer selectivity either by directly contributing to the structure of ligand binding pocket or by allosteric modulation of the conformation of CRLR.
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Action sites of adrenomedullin in the rat brain: Functional mapping by Fos expression 査読あり
Ueta Y., Hara Y., Kitamura K., Kangawa K., Eto T., Hattori Y., Yamashita H.
Peptides 22 ( 11 ) 1817 - 1824 2001年12月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Peptides
The effects of intracerebroventricular (icv) administration of adrenomedullin (AM) and proadrenomedullin NH2-terminal 20 peptide (PAMP) on the expression of Fos in the central nervous system (CNS) were examined in conscious rats, using immunohistochemistry. Fos-like immunoreactivity (LI) was detected in various brain areas of the rats, including the supraoptic nucleus, the paraventricular nucleus, the locus coeruleus, the area postrema and the nucleus of the tractus solitarius 90 min after icv administration of AM. Few cells with Fos-LI were found in the CNS 90 min after icv administration of saline. Fos-LI was also detected in the various hypothalamic areas after icv administration of PAMP. These results suggest that centrally administered AM and PAMP may cause physiological responses through the activation of a neural network in the hypothalamus and the brainstem. © 2001 Elsevier Science Inc. All rights reserved.
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Adrenomedullin (11-26): A novel endogenous hypertensive peptide isolated from bovine adrenal medulla 査読あり
Kitamura K., Matsui E., Kato J., Katoh F., Kita T., Tsuji T., Kangawa K., Eto T.
Peptides 22 ( 11 ) 1713 - 1718 2001年12月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Peptides
Adrenomedullin (AM) is a potent hypotensive peptide originally isolated from pheochromocytoma tissue. Both the ring structure and the C-terminal amide structure of AM are essential for its hypotensive activity. We have developed an RIA which recognizes the ring structure of human AM. Using this RIA, we have characterized the molecular form of AM in bovine adrenal medulla. Gel filtration chromatography revealed that three major peaks of immunoreactive AM existed in the adrenal medulla. The peptide corresponding to Mr 1500 Da was further purified to homogeneity. The peptide was determined to be AM (11-26) which has one intramolecular disulfide bond. Amino acid sequences of bovine AM and its precursor were deduced from the analyses of cDNA encoding bovine AM precursor. The synthetic AM (11-26) produced dose-dependent strong pressor responses in unanesthetized rats in vivo. The hypertensive activity lasted about one minute, and a dose dependent increase in heart rate was also observed. The present data indicate that AM (11-26) is a major component of immunoreactive AM in bovine adrenal medulla and shows pressor activity. © 2001 Elsevier Science Inc. All rights reserved.
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Matsui E., Kitamura K., Yoshida M., Kato J., Asada Y., Sumiyoshi A., Eto T.
Hypertension Research 24 ( 5 ) 543 - 549 2001年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Hypertension Research
To study the biosyntheses and pathophysiological roles of adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in septic shock, we compared the time course of plasma concentrations of these peptides and blood pressure in rats injected with either 0.9% saline (control group) or lipopolysaccharide (LPS group). The plasma AM concentration in the LPS group did not increase 30 and 60 min after LPS injection, at which time points the blood pressure remained low. Thereafter, AM rapidly increased, and it amounted to 35 times the basal value 4 h after injection, when the blood pressure returned to the basal level. The increment of plasma PAMP in the LPS group was lower than that of AM. We also examined the tissue concentration of AM and PAMP - as well as the tissue expression of proadrenomedullin (proAM) mRNA - in the LPS and control groups. LPS significantly increased the tissue concentrations of AM and PAMP in the lung, but decreased them in the adrenal gland and cardiac atrium. The LPS injection augmented proAM gene transcription in the lung, adrenal gland and aorta. In an immunohistochemical examination, AM staining was intense in alveolar endothelial cells of the lung in the LPS group. Thus, this septic shock model had high plasma levels of PAMP as well as AM, while the biosynthesis and secretion of the two peptides may have been differentially regulated in various tissues of rats injected with LPS. The present results suggest that these two bioactive peptides may play different roles in the pathophysiology of septic shock.
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Adrenomedullin and its role in renal diseases 査読あり
Eto T., Kitamura K.
Nephron 89 ( 2 ) 121 - 134 2001年9月