1997 Fiscal Year Annual Research Report

活性酵素による哺乳類血圧維持機構の分子論的解析

Research Project

Project/Area Number	09877028
Research Institution	Osaka City University
Principal Investigator	井上正康大阪市立大学, 医学部, 教授 (80040278)
Co-Investigator(Kenkyū-buntansha)	佐藤英介大阪市立大学, 医学部, 助手 (60211942)
Keywords	血圧制御 / 高血圧 / 活性酸素 / スーパーオキシド / 一酸化窒素 / 動脈硬化 / グルタチオン / 酸化ストレス
Research Abstract	これまでに、ヘパリンに特異的に結合する血管内皮細胞指向性SOD(HB-SOD)を開発し、高血圧病態では抵抗性血管壁で発生するス-パ -オキシドとNOのバランスが崩壊し、酸化ストレス傾向にあることから、本疾患が活性酸素病であるという新概念を提唱した。さらに、マンノースレセプター含有細胞にSODをターゲッティングすることにより血圧が極度に低下することが判明した。この所見から、正常の血圧維持機構にもスーパーオキシド代謝が関与する事を明らかにした。動脈硬化Watanabe兎、及び高血圧ラット(SHR)では、組織のGSH濃度には有意な差が見られないが、その代謝回転量は著明に低下していることが判明した。このことから、循環制御機構には全身組織の酸化ストレスと抗酸化分子群のバランスが深く関与していることが明らかになった。上記の降圧現象に関与するmannose receptor含有細胞を同定すべく、放射性標識したmannose-linked SOD(MAN-SOD)を調製し、その生体内分布を解析した。解析の結果、放射活性の90%以上は肝Kupffer細胞と脾マクロファージに集積することが判明した。しかし、両組織を摘出してもMAN-SODによる降圧反応が誘起されることから、本現象に関与するmannose receptor含有細胞は肝脾以外の細胞群であることが示唆された。動力学的解析の結果、本降圧反応はウレタン痲酔下では阻害され、頚動脈結紮ラットでは発現しにくいことが判明し、この現象に関与する責任細胞は興奮性細胞である可能性が示唆された。現在、mannose receptor含有細胞内に集積するスーパーオキシド発生系(Mannose結合Xanthine Oxidase)を開発し、これにより逆に昇圧反応が誘起されるか否かを検討する実験系を準備しつつある。

Research Products

(26 results)

All Other

All Publications (26 results)

[Publications] Minamiyama,Y.;Takemura,S.;Kawada,N.;Inoue,M.: "Role of nitric oxide in extracellular nucleotide-induced contractile status of assorted vessels including parts of portal vasculature" J. Hepatology. 28:314-319. 314-319 (1998)
[Publications] Nishikawa,M.; Sato,EF. ; Kuroki,T. ; Utsumi,K.Inoue,M.: "Role of glutathione in energy metabolism of tumor cells" Hepatology. (in press). (1998)
[Publications] Nakanishi,K.;Nishi,Y.;Sato,EF.;Ishii,M.;Hamada,T,;Inoue,M.: "Termal injury induces thymoyte apoptosis in the rat" J.Trauma. (in press). (1998)
[Publications] Nakahara,H.;Sato,EF.;Ishihara,R.;Yabuki,M.;Inoue,M.;Utsumi,K.: "Biochemical properties of human neutrophils" Free Radic.Res.(in press). (1998)
[Publications] Nishikawa,M.;Takeda,K.;Sato,EF.;Kuroki.T.Inoue,M.: "Nitric oxide regulates energy metabolism and bcl-2 expression in rat intestional epithelial cells" Am.J.Physiol.(in press). (1998)
[Publications] Morishita,S.;Sato,EF.;Takahashi,YP.;Manabe,M.;Inoue,M.: "Hypoglycemia-induced apoptosis in rat thymocytes in vivo" Dyabetes Res.Clin.Prac.(in press). (1998)
[Publications] Nagata,K.;Yu,H.;Sato,EF.;Kasahiba,M.;Tamura,T.;Inoue,M.: "Irreversible inhibition of respiration of Helicobacter pylori by nitric oxide" J.Biol.Chem.(in press). (1998)
[Publications] Kawada,N.;Seki,S.;Inoue,M.;Kuroki,T.: "Effect of antioxidants,resveratol,quercetin and N-acetyl cysteine on the function of hepatic stellate cells and Kupffer cells" Hepatology. (in press). (1998)
[Publications] Dunlap,WC.;Yamamoto,Y.;Inoue,M.;Kashiba,M.;Yamaguchi,M.;Tomita,K.: "Uric acid photo-oxidation assay : in vitro comparison of sunscreening agents" Int.I.Cosmetic Sci.20:1-8. 1-8 (1998)
[Publications] I.Shiraishi,;E.F.Sato;M.Nishikawa.;F.Sendo.;M.Inoue: "Mechanism of hypotensive shock induced by anti-neutrophil monoclonal antibody" Pathopysiology. 4:197-204. 197-204 (1997)
[Publications] H.Yu.;E.F.Sato.;T.Arakawa.;K.Kobayashi,.;M.Inoue: "Protective action of lipopolysaccharide against stress-induced gastric mucosal injury" Digestion. 58:311-318. 311-318 (1997)
[Publications] Hirai,A.;Minamiyam,Y.;Hamada,T.;Ishii,M.:Inoue,M.: "Dynamic aspects of glutathione metabolism in mice with hapten-induced allergic and irritant contact" J.Invest.Dermatol.109:314-318. 314-318 (1997)
[Publications] Minamiyam,Y.;Takemura,S.Inoue,M.: "Effect of thiol status on nitric oxide metabolism in the circulation" Arch.Biochem.Biophys.341:186-192. 186-192 (1997)
[Publications] Yabuki,M.;Inai,Y.;Yoshioka,T.;Hamazaki,K.;Yasuda,T.;Inoue,M.:Utsumi.K.: "Oxygen-dependent fragmentation of cellular DNA by nitric oxide" Free Rad.Res.26:245-255. 245-255 (1997)
[Publications] Uno,H.;Arakawa,T.;Fukuda,T.;Yu,H.;Fujiwara,,Y.;Higuchi,K.;Inoue,M.;Kobayashi.K.: "Nitric oxide stimulates prostaglandin synthesis in cultured rabbit gastric cells" Prostaglandins. 53:153-162. 153-162 (1997)
[Publications] Yu,H.Sato,EF.;Nagata,K.;Nishikawa,M.Kashiba,M.Arakawa,T.:Kobayashi.K.Inoue.M: "Oxygen-dependent regulation of the respiration and growth of Escherichia coli by nitric oxide" FEBS Letters. 409:161-165. 161-165 (1997)
[Publications] Yamamasu,S..;Sato,EF.;Ogita,S.;Inoue,M.: "Role of glutathione metabolism and apoptosis in the regression of liver hemopoiesis" Free Radical Biol.& Med.23:100-109. 100-109 (1997)
[Publications] Kashiba,M.;Miyamoto,M.;Inoue,M.: "Effect of nitric oxide on the ligand binding activity of albumin" Arch.Biochem.Biophys.345:237-242. 237-242 (1997)
[Publications] Morishita,S.;Nishi,Y.;Sato,EF.;Yamaoka,K.Manabe,M.;Inoue,M.: "Cold-stress induces thymocyte apoptosis in the rat" Pathophysiology. 4:213-219. 213-219 (1997)
[Publications] Hanada,H.;Kashiwagi,A.;Takehara,Y.;Kanno,T.;Yabuki,M.;Sasaki,J.:Inoue.M.:Utsumi.K.: "Do reactive oxygen species underlie the mechanism of apoptosis in the tadpole tail?" Free Radical Biol.& Med.23:294-301. 294-301 (1997)
[Publications] Nishikawa,M.;Sato,EF.;Kuroki,T.;Inoue,M.: "Role glutathione in the energy metabolism of mitochondria" FEBS Letters. 415:341-345. 341-345 (1997)
[Publications] Kashiba,M.;Kitoh,K.;Yu,H.;Kasahara,E.;Nishikawa,M.;Matsuo,M.:Inoue.M.: "Ascorbic Acid and reducing agents regulates the fates and functions of S-nitrospthiols" J.Biochem.122:1208-1214. 1208-1214 (1997)
[Publications] Minamiyama,Y.;Takemura,S.;Imaoka,S.;Funae,Y.;Tanimoto,Y.;Inoue,M.: "Irreversible inhibition of cytochrome P450 by nitric oxide" J.Phaemacol.Exp.Ther.283:1479-1485. 1479-1485 (1997)
[Publications] Yamada,T.;Yukioka,H.Asada,A.;Inoue,M.: "Effect of inhaled nitric oxide on platelet-activating factor induced pulmonary hypertension in dogs" Acta Anesthesiol.Scand.41. (1997)
[Publications] Kashiba,Iwasuki.M.Kitoh,K.Nishikawa,M.Sato F.F.Inoue M.: "Oxygen Homeostasis and its dynamics" Springer-Verlag,Tokyo(Ishimura,Y.,Suematsu,M.,Shimada,H), 7 (1998)
[Publications] Utsumi,K.,Takehara,Y.,Inai,Y.,Yabuki,M.,Kanno,T.,Nishikawa,M.,Sato EF.Inoue M.: "Mitochondria,Oxydants,and Aging" Academic Press(L.Packer Cadenas)(in press), (1998)

1997 Fiscal Year Annual Research Report

活性酵素による哺乳類血圧維持機構の分子論的解析

Principal Investigator

井上 正康 大阪市立大学, 医学部, 教授 (80040278)

Research Products

[Publications] Minamiyama,Y.;Takemura,S.;Kawada,N.;Inoue,M.: "Role of nitric oxide in extracellular nucleotide-induced contractile status of assorted vessels including parts of portal vasculature" J. Hepatology. 28:314-319. 314-319 (1998)

[Publications] Nishikawa,M.; Sato,EF. ; Kuroki,T. ; Utsumi,K.Inoue,M.: "Role of glutathione in energy metabolism of tumor cells" Hepatology. (in press). (1998)

[Publications] Nakanishi,K.;Nishi,Y.;Sato,EF.;Ishii,M.;Hamada,T,;Inoue,M.: "Termal injury induces thymoyte apoptosis in the rat" J.Trauma. (in press). (1998)

[Publications] Nakahara,H.;Sato,EF.;Ishihara,R.;Yabuki,M.;Inoue,M.;Utsumi,K.: "Biochemical properties of human neutrophils" Free Radic.Res.(in press). (1998)

[Publications] Nishikawa,M.;Takeda,K.;Sato,EF.;Kuroki.T.Inoue,M.: "Nitric oxide regulates energy metabolism and bcl-2 expression in rat intestional epithelial cells" Am.J.Physiol.(in press). (1998)

[Publications] Morishita,S.;Sato,EF.;Takahashi,YP.;Manabe,M.;Inoue,M.: "Hypoglycemia-induced apoptosis in rat thymocytes in vivo" Dyabetes Res.Clin.Prac.(in press). (1998)

[Publications] Nagata,K.;Yu,H.;Sato,EF.;Kasahiba,M.;Tamura,T.;Inoue,M.: "Irreversible inhibition of respiration of Helicobacter pylori by nitric oxide" J.Biol.Chem.(in press). (1998)

[Publications] Kawada,N.;Seki,S.;Inoue,M.;Kuroki,T.: "Effect of antioxidants,resveratol,quercetin and N-acetyl cysteine on the function of hepatic stellate cells and Kupffer cells" Hepatology. (in press). (1998)

[Publications] Dunlap,WC.;Yamamoto,Y.;Inoue,M.;Kashiba,M.;Yamaguchi,M.;Tomita,K.: "Uric acid photo-oxidation assay : in vitro comparison of sunscreening agents" Int.I.Cosmetic Sci.20:1-8. 1-8 (1998)

[Publications] I.Shiraishi,;E.F.Sato;M.Nishikawa.;F.Sendo.;M.Inoue: "Mechanism of hypotensive shock induced by anti-neutrophil monoclonal antibody" Pathopysiology. 4:197-204. 197-204 (1997)

[Publications] H.Yu.;E.F.Sato.;T.Arakawa.;K.Kobayashi,.;M.Inoue: "Protective action of lipopolysaccharide against stress-induced gastric mucosal injury" Digestion. 58:311-318. 311-318 (1997)

[Publications] Hirai,A.;Minamiyam,Y.;Hamada,T.;Ishii,M.:Inoue,M.: "Dynamic aspects of glutathione metabolism in mice with hapten-induced allergic and irritant contact" J.Invest.Dermatol.109:314-318. 314-318 (1997)

[Publications] Minamiyam,Y.;Takemura,S.Inoue,M.: "Effect of thiol status on nitric oxide metabolism in the circulation" Arch.Biochem.Biophys.341:186-192. 186-192 (1997)

[Publications] Yabuki,M.;Inai,Y.;Yoshioka,T.;Hamazaki,K.;Yasuda,T.;Inoue,M.:Utsumi.K.: "Oxygen-dependent fragmentation of cellular DNA by nitric oxide" Free Rad.Res.26:245-255. 245-255 (1997)

[Publications] Uno,H.;Arakawa,T.;Fukuda,T.;Yu,H.;Fujiwara,,Y.;Higuchi,K.;Inoue,M.;Kobayashi.K.: "Nitric oxide stimulates prostaglandin synthesis in cultured rabbit gastric cells" Prostaglandins. 53:153-162. 153-162 (1997)

[Publications] Yu,H.Sato,EF.;Nagata,K.;Nishikawa,M.Kashiba,M.Arakawa,T.:Kobayashi.K.Inoue.M: "Oxygen-dependent regulation of the respiration and growth of Escherichia coli by nitric oxide" FEBS Letters. 409:161-165. 161-165 (1997)

[Publications] Yamamasu,S..;Sato,EF.;Ogita,S.;Inoue,M.: "Role of glutathione metabolism and apoptosis in the regression of liver hemopoiesis" Free Radical Biol.& Med.23:100-109. 100-109 (1997)

[Publications] Kashiba,M.;Miyamoto,M.;Inoue,M.: "Effect of nitric oxide on the ligand binding activity of albumin" Arch.Biochem.Biophys.345:237-242. 237-242 (1997)

[Publications] Morishita,S.;Nishi,Y.;Sato,EF.;Yamaoka,K.Manabe,M.;Inoue,M.: "Cold-stress induces thymocyte apoptosis in the rat" Pathophysiology. 4:213-219. 213-219 (1997)

[Publications] Hanada,H.;Kashiwagi,A.;Takehara,Y.;Kanno,T.;Yabuki,M.;Sasaki,J.:Inoue.M.:Utsumi.K.: "Do reactive oxygen species underlie the mechanism of apoptosis in the tadpole tail?" Free Radical Biol.& Med.23:294-301. 294-301 (1997)

[Publications] Nishikawa,M.;Sato,EF.;Kuroki,T.;Inoue,M.: "Role glutathione in the energy metabolism of mitochondria" FEBS Letters. 415:341-345. 341-345 (1997)

[Publications] Kashiba,M.;Kitoh,K.;Yu,H.;Kasahara,E.;Nishikawa,M.;Matsuo,M.:Inoue.M.: "Ascorbic Acid and reducing agents regulates the fates and functions of S-nitrospthiols" J.Biochem.122:1208-1214. 1208-1214 (1997)

[Publications] Minamiyama,Y.;Takemura,S.;Imaoka,S.;Funae,Y.;Tanimoto,Y.;Inoue,M.: "Irreversible inhibition of cytochrome P450 by nitric oxide" J.Phaemacol.Exp.Ther.283:1479-1485. 1479-1485 (1997)

[Publications] Yamada,T.;Yukioka,H.Asada,A.;Inoue,M.: "Effect of inhaled nitric oxide on platelet-activating factor induced pulmonary hypertension in dogs" Acta Anesthesiol.Scand.41. (1997)

[Publications] Kashiba,Iwasuki.M.Kitoh,K.Nishikawa,M.Sato F.F.Inoue M.: "Oxygen Homeostasis and its dynamics" Springer-Verlag,Tokyo(Ishimura,Y.,Suematsu,M.,Shimada,H), 7 (1998)

[Publications] Utsumi,K.,Takehara,Y.,Inai,Y.,Yabuki,M.,Kanno,T.,Nishikawa,M.,Sato EF.Inoue M.: "Mitochondria,Oxydants,and Aging" Academic Press(L.Packer Cadenas)(in press), (1998)

井上正康大阪市立大学, 医学部, 教授 (80040278)