論文 - 北村 和雄
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Tanaka M., Ishizaka Y., Ishiyama Y., Kato J., Kida O., Kitamura K., Eto T., Kangawa K., Matsuo H.
Hypertension Research - Clinical and Experimental 18 ( 2 ) 159 - 166 1995年
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 - Clinical and Experimental
To determine the major stimuli for the release of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP), we measured their plasma concentrations in 14 normal subjects and 19 patients with essential hypertension during exercise with a bicycle ergometer. The plasma levels of both hormones at baseline were significantly higher in the hypertensive group than in the controls (p<0.05). The exercise raised both the plasma BNP and ANP, with concomitant increases in systolic blood pressure (SBP), heart rate (HR) and plasma norepinephrine (NE) or epinephrine (Epi) in each group. In the controls the change in ANP correlated with those in SBP, HR and NE (p<0.05), and similarly the change in BNP with those in SBP, HR, NE and Epi (p<0.05). In multivariate regression analysis only NE was found to be a significant stimulus for ANP secretion, whereas SBP or Epi was related to BNP release. In the hypertensives the change in ANP correlated with those in HR and NE, but on multivariate regression analysis the change in ANP correlated only with that in HR. The change in BNP in the hypertensives correlated only with that in HR. These findings indicate that in normal subjects the exercise-induced release of BNP and ANP is more sensitive to a similar but slightly different sympathetic stimulus, whereas in hypertensives the major stimulus for the release of both hormones is heart rate, indicating that the mediators for BNP or ANP release are altered by some factors involved in hypertension. (Hypertens Res 1995; 18: 159-166). © 1995, The Japanese Society of Hypertension. All rights reserved.
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Nishikimi T., Kitamura K., Saito Y., Shimada K.E., Ishimitsu T., Takamiya M., Kangawa K., Matsuo H., Eto T., Omae T., Matsuoka H.
Hypertension 24 ( 5 ) 600 - 604 1994年11月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Hypertension
Adrenomedullin is a novel hypotensive peptide, newly discovered in pheochromocytoma. Because immunoreactive adrenomedullin is present in human plasma, adrenomedullin may play a role in regulating blood pressure. A recent report showed that human adrenomedullin mRNA is expressed not only in pheochromocytoma but also in the normal adrenal medulla, kidney, lung, and ventricle. However, whether or not these organs actually release adrenomedullin into the circulation remains unknown. To investigate the sites of production and degradation of adrenomedullin in human subjects, we obtained blood samples from various sites and measured immunoreactive adrenomedullin concentrations. In study 1, blood samples were obtained from the infrarenal inferior vena cava, suprarenal inferior vena cava, superior vena cava, right atrium, right ventricle, pulmonary artery, pulmonary capillary, left ventricle, and aorta during cardiac catheterization in 15 patients with ischemic heart disease (67±10 years). In study 2, blood samples were taken from the infrarenal inferior vena cava, suprarenal inferior vena cava, right and left renal veins, and left adrenal vein in 5 hypertensive patients (42±14 years) suspected of having renovascular hypertension. In study 3, peripheral venous blood samples were obtained in 2 patients (males, 45 and 36 years old) with pheochromocytoma at rest and during hypertensive attacks. Plasma adrenomedullin concentrations were measured by a newly developed radioimmunoassay. In study 1, there were no significant differences in plasma adrenomedullin concentrations in various sites of the right-side circulation. There was no step-up of plasma adrenomedullin levels in the coronary sinus. However, the plasma concentration of adrenomedullin in aorta was slightly but significantly lower than in pulmonary artery. In study 2, there was no difference of plasma adrenomedullin levels between right and left renal veins and aorta. The plasma concentration of adrenomedullin in left adrenal vein tended to be higher than in aorta, but not significantly. In study 3, the plasma adrenomedullin concentration did not increase at rest or even during a hypertensive attack in patients with pheochromocytoma, even though epinephrine and norepinephrine rose markedly. These results suggest that the adrenal glands, lungs, kidneys, and heart may not be the main sources of circulating adrenomedullin, despite the fact that these organs express adrenomedullin mRNA. The pulmonary circulation, however, may be one of the sites of adrenomedullin clearance.
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Ishimitsu T., Nishikimi T., Saito Y., Kitamura K., Eto T., Kangawa K., Matsuo H., Omae T., Matsuoka H.
Journal of Clinical Investigation 94 ( 5 ) 2158 - 2161 1994年11月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Clinical Investigation
Adrenomedullin is a potent hypotensive peptide newly discovered in pheochromocytoma tissue by monitoring its elevating activity on platelet cAMP. We measured plasma concentration of adrenomedullin in patients with essential hypertension and chronic renal failure. As compared with normal subjects, plasma adrenomedullin was increased by 26% (P < 0.05) in hypertensives without organ damage and by 45% (P < 0.005) in those with organ damage. The increase in plasma adrenomedullin was more prominent in renal failure than in hypertension. Renal failure patients with plasma creatinine of 1.5-3, 3-6, and > 6 mg/dl had higher plasma adrenomedullin levels than healthy subjects by 78% (P < 0.05), 131% (P < 0.001), and 214% (P < 0.001), respectively. Moreover, adrenomedullin showed intimate correlations with norepinephrine, atrial natriuretic peptide, and cAMP in plasma (r = 0.625, P < 0.001; r = 0.656, P < 0.001; and r = 0.462, P < 0.001; respectively). Thus, plasma adrenomedullin is supposed to increase in association with changes in sympathetic nervous activity and body fluid volume in hypertension and renal failure. Considering its potent vasodilator effect, adrenomedullin may be involved in the defense mechanism preserving the integrity of the cardiovascular system in these disorders.
DOI： 10.1172/JCI117573
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Distribution and characterization of immunoreactive rat adrenomedullin in tissue and plasma 査読あり
Sakata J., Shimokubo T., Kitamura K., Nishizono M., Iehiki Y., Kangawa K., Matsuo H., Eto T.
FEBS Letters 352 ( 2 ) 105 - 108 1994年9月
掲載種別：研究論文（学術雑誌） 出版者・発行元：FEBS Letters
Adrenomedullin is a new bioactive peptide recently isolated from pheochromocytoma. We report on the rat adrenomedullin distribution and molecular forms in various tissues and plasma. Using a sensitive radioimmunoassay system for rat adrenomedullin, high concentrations of immunoreactive rat adrenomedullin were detected in adrenal gland, lung and cardiac atrium. In lung and atrium, the immunoreactivity concentration in rat was about 6-10 times higher than that in human. The mean plasma concentration of immunoreactive rat adrenomedullin was 3.60 ±0.34 fmol/ml (mean ± S.D.). Analysis in adrenal gland, lung and atrium with reverse-phase and gel-filtration high-performance liquid chromatography showed that most immunoreactive rat adrenomedullin emerged as a single peak at a position exactly identical to that of the authentic rat adrenomedullin peptide, synthesized according to the sequence predicted from the cDNA. © 1994.
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Sugo S., Minamino N., Shoji H., Kangawa K., Kitamura K., Eto T., Matsuo H.
Biochemical and Biophysical Research Communications 203 ( 1 ) 719 - 726 1994年8月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
In this study, we demonstrate production and secretion of adrenomedullin (AM) from cultured vascular smooth muscle cells (VSMCs). In addition to endothelial cells (ECs), we found immunoreactive (ir-) AM in culture media of rat and bovine VSMCs in the survey for AM-producing cells. Although the secretion level of ir-AM was at most 1/6 that of rat ECs, all the examined VSMCs were shown to produce AM. By gel filtration, reverse phase high-performance liquid chromatography, and biological characterization, ir-AM in the culture medium was identified to be rat AM of 50 residues. By RNA blot analysis, a positive band of AM mRNA was detected in cultured VSMC at an intensity 3-4 fold higher than that in adrenal gland. Gene expression and production of AM were markedly augmented by tumor necrosis factor-α. Based on these data as well as the presence of AM specific receptors on VSMCs, AM secreted from VSMC is deduced to function as an autocrine or paracrine regulatory in vascular cell communication. © 1994 by Academic Press, Inc.
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Genomic structure of human adrenomedullin gene 査読あり
Ishimitsu T., Kojima M., Kangawa K., Hino J., Matsuoka H., Kitamura K., Eto T., Matsuo H.
Biochemical and Biophysical Research Communications 203 ( 1 ) 631 - 639 1994年8月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
Adrenomedullin (AM) is a potent hypotensive peptide recently discovered from human pheochromocytoma tissue by its stimulating activity of platelet cAMP production. In this study, we have isolated the gene for human AM from a human genomic library and determined its structure. The genomic DNA of human AM consists of 4 exons and 3 introns, and the 5′ flanking region contains TATA, CAAT and GC boxes. There are also multiple binding sites for activator protein-2 (AP-2) and a cAMP-regulated enhancer element. Southern blot analyses revealed that the AM gene is situated in a single locus of chromosome 11. These indicate that the human AM gene has components for its functional expression and that the expression may be subject to the activity of protein kinase C and the feedback from cAMP level. © 1994 by Academic Press, Inc.
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Identification and hypotensive activity of proadrenomedullin N-terminal 20 peptide (PAMP) 査読あり
Kitamura K., Kangawa K., Ishiyama Y., Washimine H., Ichiki Y., Kawamoto M., Minamino N., Matsuo H., Eto T.
FEBS Letters 351 ( 1 ) 35 - 37 1994年8月
掲載種別：研究論文（学術雑誌） 出版者・発行元：FEBS Letters
Proadrenomedullin N-terminal 20 peptide (PAMP) is a candidate for a novel biologically active peptide processed from an adrenomedullin precursor. Using a radioimmunoassay for human PAMP, major and minor immunoreactive PAMPs were purified from porcine adrenal medulla and complete amino acid sequences were determined. The major immunoreactive peptide was PAMP itself with an amidated carboxy terminus. The minor one was determined to be PAMP[5-20]. An intravenous bolus injection of human PAMP in anesthetized rats caused a rapid and strong hypotensive effect in a dose dependent manner. The present data indicate that PAMP is an endogenous biologically active peptide which is processed from adrenomedullin precursor. © 1994.
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Immunoreactive proadrenomedullin N-terminal 20 peptide in human tissue, plasma and urine 査読あり
Washimine H., Kitamura K., Ichiki Y., Yamamoto Y., Kangawa K., Matsuo H., Eto T.
Biochemical and Biophysical Research Communications 202 ( 2 ) 1081 - 1087 1994年7月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
Proadrenomedullin N-terminal 20 peptide (PAMP) is a candidate for a novel biologically active peptide processed from proadrenomedullin. This study clearly demonstrates the existence of PAMP in vivo that had been deduced from analysis of cDNA. To identify PAMP in vivo, we established a radioimmunoassay for PAMP and characterized immunoreactivities in human tissue, plasma and urine. Half maximal inhibition of the assay was observed at 10 fmol/tube. A high concentration of immunoreactive PAMP was found in adrenal medulla (18.4 ± 8.95 fmol/mg, mean ± S.D.) and pheochromocytoma tissue (12.3 ± 9.82 fmol/mg) where the concentrations are comparable to that of adrenomedullin. As determined by three different kinds of chromatography, most of the immunoreactive peptide in pheochromocytoma was eluted at a position exactly identical to that of synthetic PAMP. Further, considerable concentration of immunoreactive PAMP was found in human plasma and urine. The present data indicate that PAMP as well as adrenomedullin is processed from an adrenomedullin precursor. © 1994 Academic Press, Inc.
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Katoha F., Niina H., Kitamura K., Ichiki Y., Yamamoto Y., Kangawa K., Eto T., Wada A.
FEBS Letters 348 ( 1 ) 61 - 64 1994年7月
掲載種別：研究論文（学術雑誌） 出版者・発行元：FEBS Letters
Bovine cultured adrenal medullary cells (4 × 106) contained 4266.5 ± 370.0 fmol of immunoreactive adrenomedullin and 373.4 ± 32.6 mnol of catecholamines. Nicotinic (but not muscarinic) receptors mediated the Ca2+-dependent co-secretion of adrenomedullin and catecholamines, with the molar ratio of adrenomedullin/catecholamines secreted into the medium being equal to the ratio stored in the cells. The concentration-response curve of carbachol for adrenomedullin secretion (EC50 42 μM) was similar to that for catecholamine secretion (EC50 63 μM). Reverse phase HPLC analysis showed that immunoreactive adrenomedullins in the cells and secreted into the medium were both eluted exclusively at the position almost identical to synthetic human adrenomedullin[1-52]NH2. © 1994.
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Endothelial Cells Actively Synthesize and Secrete Adrenomedullin 査読あり
Sugo S., Minamino N., Kangawa K., Miyamoto K., Kitamura K., Sakata J., Eto T., Matsuo H.
Biochemical and Biophysical Research Communications 201 ( 3 ) 1160 - 1166 1994年6月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
This study demonstrates active production of adrenomedullin (AM) in cultured vascular endothelial cells (ECs). To identify the origin of plasma AM and its functional relationship to vascular smooth muscle cells (VSMCs), we checked production of AM in a series of tissues and cell lines and found immunoreactive (ir-) AM in culture media of rat, porcine, human and bovine ECs. Ir-AM was accumulated linearly for up to 48 hours in the culture medium of rat ECs, and the secretion rate of AM was almost comparable to that of endothelin-1. By gel filtration and reverse phase high performance liquid chromatography, ir-AM in the culture medium was shown to have chromatographic behavior indistinguishable from that of synthetic rat AM. By RNA blot analysis of rat tissue, the most highly positive band was detected in cultured ECs, at an intensity 20 to 40 fold higher than that in adrenal gland. Based on these data as well as the presence of AM specific receptor on VSMCs, AM secreted from ECs is deduced to act directly on VSMCs, regulating vascular tone. © 1994 Academic Press. All rights reserved.
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Adrenomedullin stimulates cyclic amp formation in rat vascular smooth muscle cells 査読あり
Ishizaka Y., Ishizaka Y., Tanaka M., Kitamura K., Kangawa K., Minamino N., Matsuo H., Eto T.
Biochemical and Biophysical Research Communications 200 ( 1 ) 642 - 646 1994年4月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Biochemical and Biophysical Research Communications
A newly identified human peptide, adrenomedullin (AM) increased cAMP levels with dose and time dependencies in a manner similar to that of human calcitonin gene-related peptide (CGRP) in rat vascular smooth muscle cells (VSMC). The EC50 value of human AM is 2 x 10−8 M which is slightly higher than that of CGRP (8.5 x 10−9 M). In a receptor binding assay for AM in rat VSMC, the binding of [125I] AM was competitively inhibited by human AM, but not by human CGRP. Thus, AM is thought to increase intracellular cAMP in rat VSMC via its specific receptor to evoke vasodilation. © 1994 Academic Press, Inc.
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Immunoreactive adrenomedullin in human plasma 査読あり
Kitamura K., Ichiki Y., Tanaka M., Kawamoto M., Emura J., Sakakibara S., Kangawa K., Matsuo H., Eto T.
FEBS Letters 341 ( 2-3 ) 288 - 290 1994年3月
掲載種別：研究論文（学術雑誌） 出版者・発行元：FEBS Letters
A specific and sensitive radioimmunoassay for adrenomedullin has been developed. Half-maximal inhibition of binding of radioiodinated adrenomedullin was observed at 4 tool/tube. The radioimmunoassay recognized the entire adrenomedullin molecule and has little crossreactivity with adrenomedullin fragment peptides. Adrenomedullin-like immunoreactivity was found to circulate in human plasma at considerable concentration (3.3 ± 0.39 fmol ml). The immunoreactivity of adrenomedullin was eluted at almost the same position as synthetic adrenomedullin on gel-filtration chromatography and reverse-phase high-performance liquid chromatography, suggesting that circulating adrenomedullin recognized by the present radioimmunoassay is identical or very similar to authentic adrenomedullin. Plasma immunoreactive adrenomedullin significantly increased in patients with hypertension, with a progressive rise proportionate to disease severity. © 1994.
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Complete amino acid sequence of porcine adrenomedullin and cloning of cDNA encoding its precursor 査読あり
Kitamura K., Kangawa K., Kojima M., Ichiki Y., Matsuo H., Eto T.
FEBS Letters 338 ( 3 ) 306 - 310 1994年2月
掲載種別：研究論文（学術雑誌） 出版者・発行元：FEBS Letters
Porcine adrenomedullin was isolated from adrenal medulla extract and its amino acid sequence was determined. The peptide is identical to human adrenomedullin with a single replacement of Gly for Asn at position 40. The cDNA clone encoding the porcine adrenomedullin precursor was isolated and sequenced. The precursor for adrenomedullin (preproadrenomedullin) is 188 amino adds in length, including the adrenomedullin sequence, followed by a glycine (the amide donor). In addition to adrenomedullin, proadrenomedullin (proAM) contains a candidate for a unique 20-residue peptide, proAM-N20, whose carboxy-terminus may be amidated. By RNA blot analysis, porcine adrenomedullin mRNA was found to be highly expressed in several porcine tissues including lung and kidney as well as adrenal medulla. © 1994.
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Distribution and characterization of immunoreactive adrenomedullin in human tissue and plasma 査読あり
Ichiki Y., Kitamura K., Kangawa K., Kawamoto M., Matsuo H., Eto T.
FEBS Letters 338 ( 1 ) 6 - 10 1994年1月
掲載種別：研究論文（学術雑誌） 出版者・発行元：FEBS Letters
A specific and sensitive radioimmunoassay for human adrenomedullin has been developed and distribution and characterization of immunoreactive adrenomedullin in human tissue were investigated. The radioimmunoassay specifically recognizes its carboxyterminal region and half maximal inhibition of binding of radioiodinated adrenomedullin(40-52)NH2 was observed at 11 fmol tube. Immunoreactive adrenomedullin was abundant in adrenal medulla (47.7 ± 26.1 fmol mg, mean ± S.D.) and was ubiquitously found in all tissue examined. The mean plasma concentration of adrenomedullin in three normal individuals was 17.2 ± 6.4 pg ml (mean ± S.D.). By analysis with reverse-phase high-performance liquid chromatography coupled with the radioimmunoassay, most immunoreactive adrenomedullin in the adrenal medulla, atrium and lung was found to be adrenomedullin(1-52)NH2. © 1994.
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ヒトproadrenomedullin N-terminal 20 peptide (proAM-N20) の生体内分布と分子型の検討 査読あり
鷲峯久紀、北村和雄、市来能成、山本良髙、寒川賢治、江藤胤尚
日本内分泌学会雑誌 70 ( 3 ) 264 - 264 1994年
掲載種別：研究論文（学術雑誌）
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培養ウシ副腎髄質細胞におけるadrenomedullin(AM)分泌に関する検討 査読あり
加藤ふみ、北村和雄、市来能成、山本良髙、江藤胤尚、寒川賢治、和田明彦
日本内分泌学会雑誌 70 ( 3 ) 264 - 264 1994年
掲載種別：研究論文（学術雑誌）
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褐色細胞腫由来血管拡張ペプチドadrenomedullin(AM)の腎作用に関する検討 査読あり
平田恭信、北村和雄、江藤胤尚、寒川賢治、松尾壽之
日本内分泌学会雑誌 70 ( 3 ) 264 - 264 1994年
掲載種別：研究論文（学術雑誌）
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降圧ペプチド アドレノメデュリン 査読あり
北村和雄
産科と婦人科 61 ( 12 ) 1701 - 1705 1994年
掲載種別：研究論文（学術雑誌）
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新しい降圧ペプチド“adrenomedullin”(AM)の研究：発見およびその臨床的意義 査読あり
北村和雄、寒川賢治、市来能成、松尾壽之、江藤胤尚
日本内分泌学会雑誌 70 ( 3 ) 264 - 264 1994年
掲載種別：研究論文（学術雑誌）
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Plasma Concentration of Human Brain Natriuretic Peptide in Patients on Hemodialysis 査読あり
Ishizaka Y., Yamamoto Y., Fukunaga T., Yokota N., Kida O., Kitamura K., Kangawa K., Minamino N., Matsuo H., Eto T.
American Journal of Kidney Diseases 24 ( 3 ) 461 - 472 1994年
掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Kidney Diseases
The plasma concentration of immunoreactive human brain natriuretic peptide (ir-BNP) was measured in 40 patients on hemodialysis (HD) and in 12 healthy subjects. Immunoreactive human atrial natriuretic peptide (ir-ANP) was also measured. The mean (+SE) plasma it-BNP concentration in the patients before HD (18.4 + 3.4 fmol/mL) was markedly higher than that in the control group (0.39 ± 0.08 fmol/mL). The plasma it-BNP level was significantly decreased by HD from 18.4 ± 3.4 fmol/mL to 10.5 ± 2.2 fmol/mL (P < 0.001), but the latter value was still higher than the upper limit of the normal range for our laboratory. There were significant correlations between the plasma it-ANP level and the mean blood pressure before HD (P < 0.05) and between the HD-induced changes in plasma it-ANP level and mean blood pressure (P < 0.001). These correlations were not observed between the plasma it-BNP level and mean blood pressure. The plasma it-BNP level correlated with the cardiothoracic ratio and this correlation was closer to that between the plasma ir-ANP level and cardiothoracic ratio. Ultrasound echocardiographic studies in 13 patients revealed that the pre-HD state of high cardiac output was corrected by HD in association with decreases in plasma ir-BNP and ir-ANP levels. Correlations were observed between the pre-HD it-ANP level and the interventricular septal thickness index (r = 0.68, P < 0.05) and between the change in it-BNP level and that in left atria) diameter (r = 0.806, P < 0.001). In conclusion, BNP levels were high in HD patients compared with the control subjects and were decreased during HD. In addition, BNP and ANP levels correlated with several parameters of volume change and cardiac status. © 1994, National Kidney Foundation. All rights reserved. All rights reserved.