Faculty Profiles - TSUKAHARA Hirokazu

MISC - TSUKAHARA Hirokazu

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肺炎球菌による敗血症に伴い壊死性腸炎および急性腎不全をきたした早産児例

冨田直子, 塚原宏一, 平城徹, 小野合歓子, 木村宏輝, 平岡政弘, 眞弓光文

日本小児腎不全学会雑誌 : 小児腎不全研究会記事 20 163 - 165 2000.8

Role of nitric oxide in human pulmonary microvascular endothelial cell adhesion

H Tsukahara, E Noiri, MZ Jiang, M Hiraoka, M Mayumi

LIFE SCIENCES 67 ( 1 ) 1 - 11 2000.5

Language：English Publisher：PERGAMON-ELSEVIER SCIENCE LTD

We examined the effect of nitric oxide (NO) on cell adhesion using cultured human pulmonary microvascular endothelial cells (PMVEC). Attachment of these cells to fibronectin was significantly inhibited by NO donors, spermine NONOate and S-nitroso-N-acetyl-penicillamine or L-arginine, but not 8-bromoguanosine-3',5'-cyclic-monophosphate. Similar results were obtained with the electrical cell-substrate impedance sensor (ECIS) technique. Addition of NO donors or L-arginine, but not 8-bromoguanosine-3',5' -cyclic-monophosphate or N-2,2'-O-dibutyrylguanosine-3',5'-cyclic-monophosphate, to confluent PMVEC monolayers resulted in a transient decrease in cell adhesion, which was quantitated by the ECIS, Exposure to 1 U/ml alpha-thrombin reduced the monolayer electrical resistance by similar to 50%. The observed response was significantly suppressed by pretreatment of cells with intracellular calcium chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- acid or NO synthase inhibitor, NG-nitro-L-arginine methyl ester, but not guanylate cyclase inhibitor, 6-anilino-5,8-quinoline-quinone. Selective knockout of endothelial NO synthase with antisense oligodeoxynucleotides also significantly reduced thrombin-induced decrease in monolayer resistance. Our findings indicate that thrombin stimulates calcium-dependent release of NO from PMVEC, which mediates the retraction of endothelial cells via a cGMP-independent pathway. Our results suggest that NO modulates cell-matrix and/or cell-cell adhesion in PMVEC and that this molecule might modify microvascular permeability in the human lune. (C) 2000 Elsevier Science Inc. All rights reserved.

DOI： 10.1016/S0024-3205(00)00598-1

塚原宏一, 冨田直子, 平城徹, 古畑律代, 川満徹, 木村宏輝, 平岡政弘, 眞弓光文

小児科臨床 53 262 - 266 2000.2

Language：Japanese Publisher：日本小児医事出版

新生児とくに早期産児の免疫系の機能は未熟で病原微生物に対しての防御能に劣る。一方、新生児医療の高度先進化は新生児感染症の頻度を低下させるには至らず、むしろその様相を複雑化させ、com-promised host を増加させている。これらの児の感染症羅患の危険性はとくに高い。以上の理由から、新生児集中治療室（NICU）での感染防御対策は極めて重要な臨床上のテーマであるといえる。本稿では、NICUでの感染防御対策についての基本的な考え方と当院 NICU における具体的な感染防御対策およびその成果についてまとめた。

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Other Link： http://search.jamas.or.jp/link/ui/2000153093

Increased oxidative stress in rats with chronic nitric oxide depletion: measurement of urinary 8-hydroxy-2 '-deoxyguanosine excretion

H Tsukahara, M Hiraoka, R Kobata, Hata, I, Y Ohshima, MZ Jiang, E Noiri, M Mayumi

REDOX REPORT 5 ( 1 ) 23 - 28 2000

Language：English Publisher：W S MANEY & SONS LTD

Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) has been reported to serve as a sensitive biomarker of oxidative stress. We examined the effect of chronic blockade of nitric oxide (NO) on urinary excretion of 8-OHdG in rats. Two types of NO synthase inhibitor were used: N-G-nitro-L-arginine methyl ester (L-NAME) as a non-selective inhibitor and aminoguanidine (AG) as a selective inhibitor of the inducible isoform. Oral administration of L-NAME (20, 50 and 80 mg/dl of drinking water), but not AG (400 mg/dl), for 4 weeks induced systemic hypertension and a significant reduction in urinary excretion of NO2-/NO3-. Rats treated with L-NAME also showed a significant increase in urinary 8-OHdG excretion compared with the control animals. The effects of L-NAME (50 mg/dl) on blood pressure and urinary excretion of NO2-/NO3- and 8-OHdG were restored by a large dose of L-arginine (2.0 g/dl). Chronic AG administration did not significantly alter urinary 8-OHdG excretion. On combining all the data, there was a significant negative correlation between urinary NO2-/NO3- and 8-OHdG. These observations suggest the importance of constitutive NO synthase activity in the maintenance of oxidant buffering capacity in rats. Oral administration of L-NAME may serve as a model of hypertension due to chronic NO deficiency with increased oxidative stress.

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一酸化窒素によるヒト肺微小血管内皮細胞接着の制御

塚原宏一

67 ( 1 ) 1 - 11 2000

一酸化窒素合成阻害ラットにおける酸化ストレスの増強 : 尿中8(OH)dG排泄による評価

塚原宏一

5 ( 1 ) 23 - 28 2000

Gas-phase oxidation of nitric oxide : Chemical kinetics and rate constant

H.Tsukahara

Nitric oxide : Biology and Chemistry 3 1999

Gas-phase oxidation of nitric oxide: Chemical kinetics and rate constant

H Tsukahara, T Ishida, M Mayumi

NITRIC OXIDE-BIOLOGY AND CHEMISTRY 3 ( 3 ) 191 - 198 1999

Language：English Publishing type：Book review, literature introduction, etc. Publisher：ACADEMIC PRESS INC

Inhaled nitric oxide (NO) is gaining popularity as a selective pulmonary vasodilator. Because of the potential toxicity of NO and its oxidizing product nitrogen dioxide (NO2), any system for the delivery of inhaled NO must aim at predictable and reproducible levels of NO and at as low concentrations of NO2 as possible. This review describes the chemical kinetics and rate constant values k for the reaction 2NO + O-2 = 2NO(2). This reaction has been well established as a third-order homogeneous reaction. Published data support two equally plausible two-step mechanisms for the reaction between NO and O-2 over a wide range of temperature and pressure. The Arrhenius equation k (L-2 . mol(-2) . s(-1)) = 1.2 x 10(3) e(530/T) (=1.2 x 10(3) x 10(230/T)) gives the best fit to the experimental values of the rate constant thus far reported in a temperature range of 273 to 600 K. Using the reaction mechanism and the rate constant k, one can make reliable predictions about NO2 formation in any set of NO inhalation therapy conditions. It is also pointed out that NO2 the intermediate of one of the two mechanisms, deserves serious attention in NO inhalation therapy. (C) 1999 Academic Press.

DOI： 10.1006/niox.1999.0232

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Endothelin subtype A receptor antagonist induces osteopenia in growing rats

H Tsukahara, C Hori, M Hiraoka, K Yamamoto, Y Ishii, M Mayumi

METABOLISM-CLINICAL AND EXPERIMENTAL 47 ( 11 ) 1403 - 1407 1998.11

Language：English Publisher：W B SAUNDERS CO

Previous studies suggested that endothelin (ET) peptides are involved in bone metabolism. We examined the effects of long-term blockade of the ETA, receptor, a receptor subtype primarily involved in the anabolic actions of ET, on bone mineral status in growing rats. Eight-week-old rats injected intraperitoneally with FR139317 50 mg/kg body weight, a specific ETA receptor antagonist, for 2 or 41 weeks were compared with control rats injected with vehicle only. Treatment with FR139317 caused a significant decrease in bone mass in the lumbar spine as determined by dual-energy x-ray absorptiometry (DXA). FR139317-induced osteopenia was associated with a significant decrease in the serum osteocalcin concentration but no change in the urinary excretion of pyridinium cross-links of collagen. Our findings indicate that long-term blockade of the ETA receptor reduces bone formation and induces osteopenia in growing rats. Our results suggest that Ei produced by vascular endothelial cells plays an important role in bone growth and metabolism in vivo. Copyright (C) 1998 by W.B. Saunders Company.

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Role of endothelin in erythropoietin-induced hypertension in rats

H Tsukahara, C Hori, S Tsuchida, M Hiraoka, K Fujisawa, M Mayumi

NEPHRON 79 ( 4 ) 499 - 500 1998.8

Experimentally-induced acute hyperinsulinemia stimulates endogenous nitric oxide production in humans: Detection using urinary NO2-/NO3- excretion.

H Tsukahara, K Kikuchi, Hata, I, C Hori, M Hiraoka, M Mayumi

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 8 A1570 - A1570 1997.9

Nitric oxide modulation of erythropoiesis in rats

H Tsukahara, C Nori, M Hiraoka, M Mayumi, T Okada, F Gejyo

BLOOD 90 ( 1 ) 473 - 474 1997.7

Use of ultrasonography in the detection of ureteric reflux in children suspected of having urinary infection

M Hiraoka, G Hashimoto, C Hori, H Tsukahara, Y Konishi, M Sudo

JOURNAL OF CLINICAL ULTRASOUND 25 ( 4 ) 195 - 199 1997.5

Language：English Publisher：JOHN WILEY & SONS INC

The present study investigated whether ultrasonography was effective in detecting ureteric reflux in children suspected of having urinary infection. Seventeen children with febrile episodes and pyuria were enrolled. The ultrasound examination revealed ballooning of the renal pelvis during bladder contraction in 4 children, dilatation of the distal ureters in 6, and small kidney in 2. Cystography was performed on the 6 children with these ultrasound abnormalities and 1 child with two episodes of suspected urinary infection. Four children showed reflux. All of the 4 children had been found to have renal pelvic ballooning on ultrasound. None of the 10 children who did not undergo cystography had recurrence of urinary infection or significant bacteriuria during a median follow-up period of 12 months. Thus, scanning during bladder contraction was effective in detecting significant ureteric reflux. (C) 1997 John Wiley & Sons, Inc.

DOI： 10.1002/(SICI)1097-0096(199705)25:4<195::AID-JCU7>3.0.CO;2-9

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Experimentally induced acute hyperinsulinemia stimulates endogenous nitric oxide production in humans: Detection using urinary NO2-/NO3- excretion

H Tsukahara, K Kikuchi, K Tsumura, K Kimura, Hata, I, M Hiraoka, M Sudo

METABOLISM-CLINICAL AND EXPERIMENTAL 46 ( 4 ) 406 - 409 1997.4

Language：English Publisher：W B SAUNDERS CO

Insulin-mediated glucose metabolism in skeletal muscle is associated with a proportional increase in muscle perfusion. The vasodilatory effect of insulin is thought to be mediated in part by endothelium-derived nitric oxide (NO), The present study was performed to determine whether acute hyperinsulinemia has any stimulatory effect on endogenous NO production in humans, Bolus intravenous injection of insulin (0.1 IU/kg body weight) caused a significant increase in urinary excretion of NO2-/NO3- together with a significant decrease in blood pressure, whereas saline infusion alone had no effect on these parameters. The increased NO response to insulin was almost comparable to that obtained with infusion of 30 g L-arginine. The acute effect of hyperinsulinemia on endogenous NO formation supports the concept that NO may mediate the vasodilatory action of insulin in humans. Copyright (C) 1997 by W.B. Saunders Company.

DOI： 10.1016/S0026-0495(97)90056-1

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Urinary nitrite versus nitrate excretion in children

H Tsukahara, Hata, I, M Sudo

JOURNAL OF PEDIATRICS 130 ( 1 ) 161 - 161 1997.1

未熟児慢性肺疾患に対する生後早期デキサメサゾン療法--最近の臨床試験から

塚原宏一

小児科診療 59 ( 12 ) 2077 - 2083 1996.12

Renal functional measurements in young rats with chronic inhibition of nitric oxide synthase

TSUKAHARA H

Acta Paediatrica Japonica 38 ( 6 ) 614 - 618 1996.12

Effect of nitric oxide synthase inhibitors on bone metabolism in growing rats

H Tsukahara, M Miura, S Tsuchida, Hata, I, K Hata, K Yamamoto, Y Ishii, Muramatsu, I, M Sudo

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM 270 ( 5 ) E840 - E845 1996.5

Language：English Publisher：AMER PHYSIOLOGICAL SOC

We examined the effects of chronic nitric oxide (NO) blockade on bone mineral status in growing rats. Oral administration of N-G-nitro-L-arginine methyl ester (L-NAME) for 4 wk caused hypertension and a significant reduction in urinary NO2- and NO3- excretion. Four-week oral aminoguanidine (AG, 400 mg/dl of drinking water) did not alter blood pressure but caused a significant decrease in urinary NO2- and NO3-. Rats treated with L-NAME at doses of 20 and 50 mg/dl had normal bone mineral mass in the lumbar spine, but the highest dose (80 mg/dl) caused a slight decrease in bone mass. Chronic AG induced a significant spine osteopenia. This effect of AG was abolished by the simultaneous administration of L-arginine (2.0 g/dl). AG-induced osteopenia was associated with a significant increase in urine excretion of collagen cross-links with normal serum osteocalcin. These findings indicate that chronic AG administration can cause an imbalance between bone resorption and formation, resulting in a decrease in bone mass in growing rats, and suggest that NO produced by inducible NO synthase plays an important role in basal osteoclast bone degradation activity in vivo.

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Urinary excretion of pyridinium cross-links of collagen in infancy

H Tsukahara, M Miura, C Hori, M Hiraoka, K Nosaka, K Hata, Y Konishi, M Sudo

METABOLISM-CLINICAL AND EXPERIMENTAL 45 ( 4 ) 510 - 514 1996.4

Language：English Publisher：W B SAUNDERS CO

This cross-sectional study evaluated urinary excretion of pyridinium cross-links of collagen, specific markers of ongoing hone resorption, in infants aged 1 week to 7 months and examined the relationship between urinary cross links and individual renal function. Spot urines from a total of 100 infants were analyzed. The collagen cross-links, pyridinoline (Pyd) and deoxypyridinoline (D-Pyd), were assayed by fluorescence detection after high-performance liquid chromatography (HPLC). beta(2)-Microglobulin (beta(2)M), an index of renal tubular function, was determined by radioimmunoassay. In healthy term infants, urinary collagen cross-links were several times higher than the reported data for older children, with peak values seen at 1 month of age. Excretion of Pyd and D-Pyd was also markedly elevated in 1-month-old preterm infants, despite poor somatic growth. Such high excretion of collagen cross-links probably reflects the state of accelerated bone turnover in infancy. The postnatal change in the doss-links was different from that in urinary beta(2)M, and the values obtained did not correlate with beta(2)M in either term or preterm infants. These results indicate that cross-link excretion is not influenced directly by individual renal function. (C) 1996 by W.B. Saunders Company

DOI： 10.1016/S0026-0495(96)90228-0

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Ultrasonographic findings of acute tubulointerstitial nephritis

M Hiraoka, C Hori, S Tsuchida, H Tsukahara, M Sudo

AMERICAN JOURNAL OF NEPHROLOGY 16 ( 2 ) 154 - 158 1996.3

Language：English Publisher：KARGER

Three children were diagnosed as having acute renal failure due to acute tubulointerstitial nephritis (TIN) associated with Yersinia pseudotuberculosis infection. The kidneys were observed ultrasonically during the disease course. The subjects presented with remittent fever, vomiting or diarrhea, and nonoliguric acute renal failure with sterile pyuria and tubular reabsorptive dysfunction. Ultrasound examination delineated marked enlargement of the kidneys with diffuse hyperechogenicity in the cortex, suggesting the diagnosis of TIN. The renal swelling was marked in the descending order of width, depth and length, respectively, and reached more than 200% in volume in 1 of the children who was examined at the culminating stage of acute renal failure. The enlarged kidneys reduced in size in parallel as the elevated serum creatinine levels decreased. However, the enlarged kidneys did not seem to return to their original sizes: the kidney size in 1 of the children remained well above the upper allowance limit of the body-height-related normals and in the other 2 they were only a little smaller than the upper limits. These ultrasound findings should help with the diagnosis and follow-up of the disease.

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