論文 - 北村 和雄
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高血圧とアドレノメデュリン 査読あり
北村和雄
Geriatric Medicine（老年医学） 38 ( 10 ) 1467 - 1473 2000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関連ペプチド 査読あり
北村和雄。江藤胤尚
日本臨牀 58 ( 1 ) 121 - 125 2000年
担当区分：筆頭著者 掲載種別：研究論文（学術雑誌）
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心筋細胞におけるアドレノメデュリン(AM)分泌機序の検討 査読あり
加藤丈司、鶴田敏博、北村和雄、桑迫健二、三嶋和也、江藤胤尚
日本内分泌学会雑誌 76 ( 2 ) 471 - 471 2000年
掲載種別：研究論文（学術雑誌）
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培養心筋細胞および非心筋細胞におけるproadrenomedullin N-terminal 20 peptide(PAMP)の産生 査読あり
加藤丈司、鶴田敏博、三嶋和也、北村和雄、江藤胤尚
日本内分泌学会雑誌 76 ( 2 ) 471 - 471 2000年
掲載種別：研究論文（学術雑誌）
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Marked increase of guanylin secretion in response to salt loading in the rat small intestine 査読あり
Kita T., Kitamura K., Sakata J., Eto T.
American Journal of Physiology - Gastrointestinal and Liver Physiology 277 ( 5 40-5 ) 1999年11月
掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Physiology - Gastrointestinal and Liver Physiology
Guanylin and uroguanylin are intestinal peptides that stimulate guanylate cyclase C and cause chloride secretion. These peptides show topological instability due to two disulfide bonds. The disulfide bonds were reduced and S-carboxymethylated to cleave the bonds and obtain stable and sole derivatives. We established a new and reliable RIA system for the stable derivatives from both peptides. With the use of this system, the response of the peptides to salt loading of the rat small intestine was evaluated. The lumen of the small intestines of Sprague-Dawley rats was perfused in vivo with Krebs-Ringer solution containing different concentrations of salt or mannitol. Mature guanylin, proguanylin, and mature uroguanylin were found in the perfusate in the basal state. The highest salt loading (200 mM NaCl for 20 min) increased the guanylin secretion about threefold (1.9 ± 0.2 vs. 5.4 ± 0.5 pmol/min), with the effect lasting for 60 min. The uroguanylin secretion was less affected. Hyperosmolar mannitol also caused a significant but smaller increase of guanylin secretion. Increased guanylin could lead to increased salt and water secretion of the intestine; thus members of the guanylin family have potential roles in the regulation of water and salt metabolism in the small intestine.
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Novel distribution of adrenomedullin-immunoreactive cells in human tissues 査読あり
Asada Y., Hara S., Marutsuka K., Kitamura K., Tsuji T., Sakata J., Sato Y., Kisanuki A., Eto T., Sumiyoshi A.
Histochemistry and Cell Biology 112 ( 3 ) 185 - 191 1999年10月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Histochemistry and Cell Biology
Adrenomedullin (AM) is a novel hypotensive and vasodilator peptide. We previously examined the localization of AM in human, rat, and porcine tissues using a polyclonal antibody against synthetic human AM[40-52]. We demonstrated that AM is widely distributed in the endocrine and neuroendocrine systems, but not in the heart, kidney, or blood vessels, although high levels of AM mRNA were detected in the latter tissues. In this study, we further investigated the distribution of AM by using two newly developed monoclonal antibodies against synthetic human AM peptides, [12-25] and [46-52]. AM immunoreactivity was observed in cardiac myocytes, vascular smooth muscle cells, endothelial cells, and renal distal and collecting tubules. In addition, AM-immunoreactive (IR) cells were found in mucosal and glandular epithelia of the digestive, respiratory, and reproductive systems, as well as the endocrine and neuroendocrine systems. These findings indicate that AM-IR cells are more widely distributed in human tissues and suggest that AM might play multiple biological roles in humans.
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An autocrine or a paracrine role of adrenomedullin in modulating cardiac fibroblast growth 査読あり
Tsuruda T., Kato J., Kitamura K., Kawamoto M., Kuwasako K., Imamura T., Koiwaya Y., Tsuji T., Kangawa K., Eto T.
Cardiovascular Research 43 ( 4 ) 958 - 967 1999年9月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Cardiovascular Research
Objective: The aim of the present study was to determine the role of adrenomedullin (AM) in cardiac fibroblasts. Methods: The production and secretion of AM were examined in cultured neonatal rat cardiac fibroblasts, and the effects of AM on proliferation and protein synthesis of these cells were assessed by [3H]thymidine and [3H]phenylalanine incorporation, respectively. Results: Cultured cardiac fibroblasts secreted AM into the medium time-dependently at a rate of 20.3±3.0 fmol/5x104 cells/48 h, mean±S.D. Northern blot analysis showed expression of preproAM mRNA of 1.6 kb in these cells. In addition, 10-6 mol/l of angiotensin II (Ang II) and endothelin-1 (ET-1) significantly increased the AM secretion by 55 and 48%, respectively. Synthetic AM significantly reduced 10-6 mol/l Ang II- or 10-7 mol/l ET-1-stimulated [3H]thymidine and [3H]phenylalanine incorporation in a dose-dependent manner, and these effects were attenuated by a calcitonin gene-related peptide (CGRP) type 1 receptor antagonist, CGRP(8-37). Synthetic AM also had a dose-dependent stimulatory effect on cAMP accumulation in these cells, which was significantly attenuated by CGRP(8-37). A cAMP analogue, 8-bromo-cAMP, mimicked the AM effects, inhibiting the Ang II-stimulated [3H]thymidine and [3H]phenylalanine incorporation. Blockage of the effect of endogenous AM by anti-AM monoclonal antibody not only significantly reduced the basal level of intracellular cAMP, but also enhanced the [3H]thymidine and [3H]phenylalanine incorporation into the cells. Conclusions: Cultured neonatal rat cardiac fibroblasts produce and secrete AM, and the secreted AM may inhibit proliferation and protein synthesis of these cells. AM may exert these inhibitory effects partly by elevating intracellular cAMP. It is suggested that AM has an important role in modulating the growth of cardiac fibroblasts in an autocrine or a paracrine manner. Copyright (C) 1999 Elsevier Science B.V.
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Ohta H., Tsuji T., Asai S., Tanizaki S., Sasakura K., Teraoka H., Kitamura K., Kangawa K.
Clinica Chimica Acta 287 ( 1-2 ) 131 - 143 1999年9月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Clinica Chimica Acta
We developed a one-step two-site immunoradiometric assay (IRMA) using two kinds of monoclonal antibodies, which enables us to directly measure the entire molecules of adrenomedullin (AM) (the sum of mature-type AM (abbreviated, m-AM) amidated at the C-terminus and Gly-extended non-amidated AM) in human plasma using a small amount of sample (100 μl) without prior extraction. The detection limit of this assay was 0.5 pmol/l for a 100-μl sample. Intra- and inter-assay precisions were 3.4-7.3% and 5.8-7.6%, respectively. The dilution curves of plasma samples showed good linearity and analytical recovery was 89-118%. The mean total AM in plasma of healthy subjects was 9.00±2.13 pmol/l, whereas m-AM was 1.05±0.24 pmol/l. This method, together with our previously reported simplified method to specifically measure m-AM (Ohta et al., Clin Chem 1999;45:244-251), allows facile estimation of the plasma concentration of AM-Gly by subtracting m-AM from the total AM measured by the procedure described in this paper. We were able to show that the concentration of total AM in patients with sepsis was markedly higher than that in the healthy controls and that the ratios of m-AM/total AM were significantly different between the controls and patients. Copyright (C) 1999 Elsevier Science B.V.
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Kobayashi H., Yamamoto R., Kitamura K., Niina H., Masumoto K., Minami S.i., Yanagita T., Izumi F., Aunis D., Tanenao E., Wada A.
European Journal of Biochemistry 263 ( 3 ) 702 - 708 1999年8月
掲載種別：研究論文（学術雑誌） 出版者・発行元：European Journal of Biochemistry
Adrenomedullin and proadrenomedullin N-terminal 20 peptide are peptides with multiple physiological functions and are most abundant in adrenal medulla. We studied whether the cAMP-dependent pathway is involved in the regulation of synthesis and release of adrenomedullin and proadrenomedullin N-terminal 20 peptide in cultured bovine adrenal chromaffin cells. Exposure of the cells to dibutyryl cAMP (dbcAMP) increased a progressive accumulation of immunoreactive-adrenomedullin and immunoreactive-proadrenomedullin N- terminal 20 peptide in the extracellular medium, while reciprocally decreasing their cellular content in a time-dependent manner. The decrease of levels of both peptides in the cells was much greater in extent than the increase of the peptides in the medium. H89, an inhibitor of cAMP-dependent protein kinase attenuated these changes, induced by dbcAMP. The resulting changes by dbcAMP and H89 were similar to those of chromogranin B, a marker peptide of chromaffin granule. Northern blot analysis showed that the mRNA encoding these peptides, detected as a band of 1.6 kb, was decreased by the treatment with dbcAMP. The effect of dbcAMP on mRNA was attenuated by H89, and was reversible as the decreased mRNA level caused by dbcAMP could be returned to control levels by culturing cells after removal of dbcAMP. These results suggest that the cAMP-dependent protein kinase pathway stimulates the release of adrenomedullin and proadrenomedullin N-terminal 20 peptide, whereas it lowers synthesis of these peptides via the reduction of their transcript level.
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Increased plasma levels of mature form of adrenomedullin in patients with chronic renal failure 査読あり
T Ishihara 1, N Yokota, S Hisanaga, S Fujimoto, N Hirayama, J Kato, K Kitamura, T Eto
Clin Nephrol 52 ( 2 ) 119 - 123 1999年8月
掲載種別：研究論文（学術雑誌）
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Biological and clinical roles of adrenomedullin in circulation control and cardiovascular diseases 査読あり
Eto T., Kitamura K., Kato J.
Clinical and Experimental Pharmacology and Physiology 26 ( 5-6 ) 371 - 380 1999年7月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Clinical and Experimental Pharmacology and Physiology
1. Adrenomedullin (AM) is found ubiquitously in tissues and organs, especially in cardiovascular tissues and in the kidney, lung and endocrine glands. It has multifunctional biological properties, of which, its effects on the control of circulation and body fluid volume regulation seem to be the most outstanding and characteristic. 2. Acute administration of a high dose of AM induces a vasodilator depressor response, cardiac inotropic effects, diuresis and suppression of aldosterone secretion in experimental animals. 3. Long-term continuous administration of a very low dose of AM causes vasodilation in sheep (0.5 μg/kg per h) and hypotension in rats (0.8 μg/kg per h). 4. The plasma concentration of AM increases under pathological conditions such as congestive heart failure, myocardial infarction and hypertensive and renal diseases. Under these disease conditions, AM may be produced in vascular endothelial and smooth muscle cells and in cardiac myocytes in response to volume expansion, hypertension and activated humoral factors, such as catecholamine and the renin-angiotensin system. 5. Increased AM in the circulating blood and cardiovascular tissues may counteract pathological deviation in the system that controls circulation and body fluid volume, acting against cardiovascular damage and disease. 6. Because of these beneficial properties in the cardiovascular system, AM and its pharmaceutical ligands should prove useful in the treatment of cardiovascular diseases.
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Secretion and clearance of the mature form of adrenomedullin in humans 査読あり
Hirayama N., Kitamura K., Imamura T., Kato J., Koiwaya Y., Eto T.
Life Sciences 64 ( 26 ) 2505 - 2509 1999年5月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Life Sciences
In the biosynthesis of adrenomedullin (AM), glycine-extended AM, an intermediate form (iAM) processed from proAM is converted to AM[1-52]-NH2, the bioactive mature form of AM (mAM), by enzymatic amidation. We earlier showed that both molecular forms of AM circulate in human plasma. In the present study, to investigate the secretion and clearance sites of mAM and iAM in humans, we examined the plasma mAM and iAM concentrations in the femoral artery and vein (FA and FV), the aortic root and coronary sinus (AO and CS), and the pulmonary artery and capillary (PA and PC) of patients with ischemic heart disease. Plasma mAM in FV was significantly (p<0.001) higher than in FA. There also was a significant (p<0.001) step-up in the plasma mAM of the CS as compared to the AO. In contrast, plasma mAM was significantly (p<0.001) reduced in the PC as compared to the PA. However, such differences were not observed in plasma iAM levels. These findings suggest that in humans the vasculature of the lower extremities and the heart produce and secrete roAM and that the lung is a clearance site of circulating mAM.
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Plasma adrenomedullin and natriuretic peptides in patients with essential or malignant hypertension 査読あり
Kato J., Kitamura K., Matsui E., Tanaka M., Ishizaka Y., Kita T., Kangawa K., Eto T.
Hypertension Research - Clinical and Experimental 22 ( 1 ) 61 - 65 1999年3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 - Clinical and Experimental
Adrenomedullin (AM), a potent vasodilator and natriuretic peptide, is found in human blood. To investigate the pathophysiological role of AM in essential and malignant hypertension (EHT and MHT), we measured the plasma concentrations of AM in patients with EHT of WHO stage I or II (n = 42) and in those with MHT (n = 9) by a specific radioimmunoassay, and compared these concentrations with those in normotensive controls (n = 46). The plasma concentrations of atrial and brain natriuretic peptides (ANP and BNP) in these subjects were also measured by immunoradiometric assays, and their relations to plasma AM were examined. The plasma AM level in the EHT patients (7.15 ± 0.21 pmol/l, mean ± SEM) was significantly (p < 0.01) higher than that in the normotensive controls (6.14 ± 0.25 pmol/l), and a further elevation was observed in the MHT patients (14.1 ± 3.8 pmol/l). Similar elevations of plasma ANP and BNP were seen in the two patient groups. The plasma AM level significantly (p < 0.01) correlated with not only the systolic (r = 0.44) and diastolic (r = 0.46) blood pressures, but also with the plasma levels of ANP (r = 0.43) and BNP (r = 0.43). The elevated plasma concentration of AM in the MHT patients decreased significantly (p < 0.05) after antihypertensive treatment, and the plasma ANP and BNP levels similarly declined. These results suggest that AM may participate, along with ANP and BNP, in mechanisms counteracting a further elevation of blood pressure in patients with EHT and MHT.
DOI： 10.1291/hypres.22.61
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Kitani M., Asada Y., Sakata J., Kitamura K., Sumiyoshi A., Eto T.
Histopathology 34 ( 2 ) 134 - 139 1999年2月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Histopathology
Aims: Adrenomedullin (AM) is a novel hypotensive and vasorelaxing peptide recently isolated from human phaeochromocytoma tissue, and is widely distributed in various organs. In this study we examined the localization of AM-immunoreactive (IR) cells in the gastric mucosa and AM-IR cell density in antral atrophic gastritis. Methods and results: Gastric mucosal tissues were taken from the gastric body and antral mucosa of 52 patients (27 men, 25 women: mean age 56.0 (range 20-86) years). Immunohistochemical analysis revealed that AM-IR cells were present in the pyloric glands, but not in the fundic glands, and that AM-IR cells were stained positively for chromogranin A and gastrin. The percentage of AM-IR cells vs chromogranin A- and gastrin- IR cells was 42 and 56%, respectively. The number of AM-IR cells decreased with the progression of severity of atrophic changes in the pyloric gland, and also of mononuclear cell infiltration. There was no correlation between the number of AM-IR cells and the degree of neutrophilic infiltration. Similar findings were also obtained for gastrin-IR cells. Conclusion: AM-IR cells are present in the endocrine cells including gastrin-IR cells in the pyloric glands. These results suggest that AM may contribute to gastrin secretion in the pyloric glands.
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Molecular forms of circulating adrenomeduilin in patients with congestive heart failure 査読あり
Hirayama N., Kitamura K., Imamura T., Kato J., Koiwaya Y., Tsuji T., Kangawa K., Eto T.
Journal of Endocrinology 160 ( 2 ) 297 - 303 1999年2月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Endocrinology
In the biosynthesis of adrenomedullin (AM), an intermediate form, AM(1- 52)-glycine-COOH (iAM), is cleaved from proAM and subsequently processed to a biologically active mature form, AM(1-52)-NH2 (mAM), by enzymatic amidation. We recently reported that immunoreactive AM in human plasma consists of roAM and iAM. To clarify the pathophysiological roles of mAM and iAM in heart failure, we established an assay method to specifically detect mAM, and we determined the plasma concentrations of mAM and iAM in 68 patients with congestive heart failure (CHF). The plasma mAM concentrations of the CHF patients classified as being class I or II of New York Heart Association (NYHA) functional classification were significantly greater than those of the 28 healthy controls, and a further increase was noted in the class III or IV patients. Similar increases in plasma iAM were also observed in these patients compared with controls. The increased plasma mAM and iAM in 12 patients with exacerbated CHF were significantly reduced by treatment of their CHF for 7 days. In addition, the plasma concentrations of both mAM and iAM were significantly correlated with pulmonary capillary wedge pressure, pulmonary artery pressure, fight atrial pressure, cardiothoracic ratio, heart rate, and the plasma concentrations of atrial and brain natriuretic peptides in the CHF patients. Thus the plasma concentrations of both roAM and iAM were increased progressively in proportion to the severity of CHF. These results suggest that, though the role of iAM remains to be clarified, mAM acts against the further deterioration of heart failure in patients with CHF.
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Adrenomedullin-like immunoreactivity in the rat hypothalamo- neurohypophysial tract 査読あり
Ueta Y., Hara Y., Setiadji V.S., Isse T., Shibuya I., Kitamura K., Kangawa K., Matsuo H., Eto T., Hattori Y., Yamashitaa H.
Peptides 20 ( 2 ) 199 - 204 1999年2月
掲載種別：研究論文（学術雑誌） 出版者・発行元：Peptides
Adrenomedullin-like immunoreactivity in the hypothalamo- neurohypophysial tract in colchicine-treated and hypophysectomized rats was examined by immunohistochemistry. Adrenomedullin-like immunoreactive (AM-LI) neurons were localized in the hypothalamic areas, including the paraventricular nuclei and the supraoptic nuclei. Abundant AM-LI fibers and varicosities were found in the hypothalamoneurohypophysial tract and the internal zone of the median eminence in the colchicine-treated and hypophysectomized rats, whereas in control rats few AM-LI fibers were observed. These results suggest that the axons of the AM-LI neurons in the hypothalamus may terminate in the neurohypophysis.
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One-step direct assay for mature-type adrenomedullin with monoclonal antibodies 査読あり
H Ohta 1, T Tsuji, S Asai, K Sasakura, H Teraoka, K Kitamura, K Kangawa
Clin Chem 45 ( 2 ) 244 - 251 1999年2月
掲載種別：研究論文（学術雑誌）
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Serino R., Ueta Y., Hara Y., Nomura M., Yamamoto Y., Shibuya I., Hattori Y., Kitamura K., Kangawa K., Russell J.A., Yamashita H.
Endocrinology 140 ( 5 ) 2334 - 2342 1999年
掲載種別：研究論文（学術雑誌） 出版者・発行元：Endocrinology
The effects of intracerebroventricular (icv) administration of adrenomedullin (AM) on plasma oxytocin (OXT), c-Fos protein (Fos), and c-fos messenger RNA (mRNA) in the paraventricular (PVN) and supraoptic nuclei (SON) of the rat were investigated using RIA for OXT, immunohistochemistry for Fos, and in situ hybridization histochemistry for c-Fos mRNA. Central administration of AM caused a significant increase in the plasma OXT level. Intracerebroventricular administration of AM caused a marked induction of Fos-like immunoreactivity (LI) in the PVN and in the dorsal parts of the SON. In the PVN and SON, OXT-LI cells predominantly exhibited nuclear Fos-LI in comparison with arginine vasopressin-LI cells. In situ hybridization histochemistry revealed that the induction of c-fos mRNA in the PVN and SON was increased in a dose-related manner 30 min after icv administration of AM. This induction was reduced by pretreatment with the AM receptor antagonist, human AM-(22-52)-NH2. These results suggest that central AM is responsible for activating the neurosecretory cells in the PVN and SON via selective AM receptors, and that AM stimulates the secretion of OXT by activating hypothalamic OXT-producing cells.
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Etoh T., Kato J., Takenaga M., Imamura T., Kitamura K., Koiwaya Y., Eto T.
Clinical Cardiology 22 ( 2 ) 113 - 117 1999年
掲載種別：研究論文（学術雑誌） 出版者・発行元：Clinical Cardiology
Background: Adrenomedullin (AM) is a potent vasodilatory peptide discovered in human pheochromocytoma tissue. Proadrenomedullin N-terminal 20 peptide (PAMP) processed from an AM precursor is also a novel hypotensive peptide which inhibits catecholamine secretion from sympathetic nerve endings. Hypothesis: The present study sought to examine the relationships between the two peptides and other clinical parameters by measuring the plasma AM and PAMP concentrations in 98 patients with heart failure. Methods: In all, 98 patients [65 men and 33 women, aged 58.2 ± 11.0 years, mean ± standard deviation (SD)] with heart failure and 26 healthy volunteers (12 men and 14 women, aged 54.1 ± 8.6 years) were examined in this study. Heart failure was secondary to previous myocardial infarction in 58 patients, valvular disease in 28, cardiomyopathy in 9, and congenital heart disease in 3. All patients were classified into two groups of class I or II (Group 1) and class III or IV (Group 2) according to the New York Heart Association (NYHA) functional classification. Results: Both plasma AM and PAMP concentrations in the patients were significantly higher than those in healthy volunteers. In addition, plasma AM and PAMP concentrations in patients in class III or IV of New York Heart Association (NYHA) classification were significantly higher than those in NYHA class I or II. The elevated plasma concentrations of these peptides in patients in NYHA class III or IV significantly decreased in response to the treatment for 7 days. There was a significant correlation between plasma AM and PAMP, though the plasma concentration of PAMP was one-fifth to one-seventh of that of AM in patients and controls. The plasma AM concentration correlated significantly with the plasma concentrations of atrial and brain natriuretic peptides, epinephrine, and right atrial pressure, whereas such a relationship was not noted for the plasma PAMP concentration. Conclusions: Judging from the difference in not only the biological actions but also the hormonal profiles between AM and PAMP, they may differentially modulate the cardiovascular system in patients with heart failure, although they are processed from the same precursor.
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Kinoshita H., Fujimoto S., Kitamura K., Yokota N., Kawamoto M., Tokura T., Hisanaga S., Eto T.
American Journal of Kidney Diseases 34 ( 1 ) 114 - 119 1999年
掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Kidney Diseases
· Proadrenomedullin N-terminal 20 peptide (PAMP) is a novel hypotensive peptide present in the precursor of adrenomedullin (AM), a vasodilative and natriuretic peptide. We examined the plasma and urinary levels of these peptides in patients with chronic glomerulonephritis (CGN). The mean plasma AM concentration of the patients with CGN did not differ from that of control subjects (4.17 ± 0.17 v 3.87 ± 0.21 fmol/mL, respectively), whereas urinary AM excretion was significantly less in the patients with CGN (5.96 ± 0.95 v control, 8.93 ± 1.02 fmol/mg of creatinine; P < 0.05). Plasma concentrations and urinary excretion of PAMP were significantly less for the patients with CGN compared with control subjects (0.91 ± 0.08 v 1.23 ± 0.20 fmol/mL; P < 0.05 and 25.0 ± 3.0 v 35.0 ± 3.6 fmol/mg of creatinine, respectively; P < 0.05). The plasma AM concentration was negatively correlated with plasma renin activity (r = -0.58; P < 0.01) and aldosterone concentration (r = - 0.40; P < 0.05). Urinary excretions of AM and PAMP showed significant correlations with urine excretion of sodium (r 0.39; P < 0.05 and r = 0.49; P < 0.01, respectively). These findings suggest that AM and PAMP may have roles in the regulation of sodium in patients with CGN.