1998 Fiscal Year Annual Research Report

ポジトロン断層法による高感度内皮機能評価法の確立と新しい動脈硬化早期診断法の確立

Research Project

Project/Area Number	10557050
Research Institution	Kyoto University
Principal Investigator	伊藤裕京都大学, 医学研究科, 助手 (40252457)
Co-Investigator(Kenkyū-buntansha)	塚田秀夫浜松ホトニクス株式会社, 中央研究所, 専任部員西村伸太郎藤沢薬品工業株式会社, 基盤技術研究室, 主任研究員
Keywords	内皮細胞 / 一酸化窒素 / ポジトロン断層法 / 動脈硬化症
Research Abstract	高血圧症、糖尿病、高脂血症等の成人病による血管合併症の早期発見は臨床上極めて重要な課題である。これまで、動脈硬化症の臨床診断法は、動脈硬化病変がかなり進展した段階で初めて検出される点、手法によっては侵襲性がかなり高い点等の数多くの問題点を有している。そこで本研究は、動脈硬化病変の早期異常としてNO合成酵素(NOS)活性の低下に注目し、最近新しい核医学診断法として脚光を浴びているポジトロン断層法(PET)によるNOS活性の評価という新しいアプローチにより、動脈硬化病変の早期診断法の開発を目指すものである。本年度は、NOの基質であるL-アルギニンの関連化合物の内皮細胞への取り込み動態とNOS活性及び内皮細胞機能の相関の検討を行った。ポジトロン核種^<11>C-Lアルギニンあるいは^<11>C-L-NAME(NOS阻害剤)取り込みによる血管機能評価を目指したPET測定の基礎実験として、半減期の長い^3H標識化合物を用いたin vitro内皮細胞機能の評価を行った。まず、^3H標識L-NAMEの合成に成功した。更に、この^3H-L-NAMEを培養血管平滑筋細胞及び培養内皮細胞に投与し、その取り込みを検討したところ、誘導型NOSの刺激物質であるインターロイキン、TGF-β投与により^3H-L-NAME取り込みの有意の上昇を認めた。今後更に培養血管内皮細胞に投与し、その取り込みとNO産生量・NOS遺伝子発現量、及び内皮機能との相関を既に確立しているずり応力負荷装置、及び血管細胞共存培養系を用いて検討する予定である。

Research Products
(19 results)

All Other

All Publications (19 results)

[Publications] K.Masatsugu et al.: "Physiologic shear stress suppresses endothelin-converting enzyme-1 expression in vascular endothelial cells." J.Cardiovasc.Pharmacol.31,SUPPL1. S42-S45 (1998)
[Publications] T.Saito et al.: "Oxidative stress suppresses the endothelial secretion of endothelin." J.Cardiovasc.Pharmacol.31,SUPPL1. S45-S47 (1998)
[Publications] T.Igaki et al.: "Effects of intravenously administered C-type natriuretic peptide in humans --Comparison with atrial natriuretic peptide." Hypertens.Res.21. 7-13 (1998)
[Publications] S.Suga et al.: "Regulation of endothelial production of C-type natriuretic peptide by interaction between endothelial cells and macrophages." Endocrinology. 139. 1920-1926 (1998)
[Publications] M.Suda et al.: "Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide." Proc.Natl.Acad.Sci.U.S.A.95. 2337-2342 (1998)
[Publications] N.Azuma et al.: "The significance of the Trp 64 Arg mutation of the b3-adrenergic receptor gene in impaired glucose tolerance,non-insulin-dependent diabetes mellitus,and insulin resistance in Japanese subjects" Metabolism. 47. 456-460 (1998)
[Publications] M.Inoue et al.: "Vascular endothelial growth factor(VEGF)expression in human coronary atherosclcrotic lesions:Possible pathophysiological significance of VEGF in progression of atherosclerosis." Circulation. 98. 2108-2116 (1998)
[Publications] Y.Miyamoto et al.: "Endothelial nitric oxide synthase gene is positively associated with essential hypertension." Hypertension. 32. 3-8 (1998)
[Publications] J.Matsuda et al.: "Increased adipose expression of uncoupling protein-3 gnene by thiazolidinediones in Wistar fatty rats and in cultured adipocytes." Diabetes. 47. 1809-1814 (1998)
[Publications] M.Yamaguchi et al.: "Effect of neutral endopeptidase inhibition on the natriuresis and renal clearance of atrial natriuretic peptide in perfused rat kidney." Pharmaceutical Research. 15. 1499-1502 (1998)
[Publications] K.Doyama et al.: "Expression and distribution of brain natriuretic peptide in human right atria." J.Am.Coll.Cardiol.32. 1832-1838 (1998)
[Publications] H.Itoh et al.: "Hypertension and insulin resistance-The role of peroxisome proliferator-activated receptor-γ(PPARγ)-" Clinical and Experimental Pharmacology and Physiology. (in press). (1999)
[Publications] Y.Numata et al.: "Immunoradiometric assay for the N-terminal fragment of proatrial natriuretic peptide in human plasma." Clinical Chemistry. 44. 1008-1013 (1998)
[Publications] M.Harada et al.: "Interaction of myocytes and nonmyocytes is necessary for mechanical stretch to induce ANP/BNP production in cardiocyte culture." J.Cardiovasc.Pharmacol.31 SUPPL1. S357-S359 (1998)
[Publications] G.Takemura et al.: "Expression of atrial and brain natriuretic peptides and their genes in hearts of patients with cardiac amyloidosis." J.Am.Coll.Cardiol.31. 254-265 (1998)
[Publications] J.Yamashita et al.: "Identification of cis-element of the human endothelin-A receptor gene and inhibition of the gene expression by the decoy strategy." J.Biol.Chem.273. 15993-15999 (1998)
[Publications] H.Nanno et al.: "Plasma nitric oxide metabolite levels are decreased in pre-eclamptic women complicated with fetal distress." Prenat.Neonat Med.3. 222-226 (1998)
[Publications] H.Nanno et al.: "Nitric oxide metabolite concentrations in maternal plasma decrease during parturition: possible transient down-regulation of nitric oxide synthesis." Molecular Human Reproduction. 4. 609-616 (1998)
[Publications] T.Tanaka et al.: "Down-regulation of peroxisome proliferator-activated receptorg expression by inflammatory cytokines and its reversal by thiazolidinediones." Diabetologia. (in press). (1999)

1998 Fiscal Year Annual Research Report

ポジトロン断層法による高感度内皮機能評価法の確立と新しい動脈硬化早期診断法の確立

Principal Investigator

伊藤 裕 京都大学, 医学研究科, 助手 (40252457)

Research Products

[Publications] K.Masatsugu et al.: "Physiologic shear stress suppresses endothelin-converting enzyme-1 expression in vascular endothelial cells." J.Cardiovasc.Pharmacol.31,SUPPL1. S42-S45 (1998)

[Publications] T.Saito et al.: "Oxidative stress suppresses the endothelial secretion of endothelin." J.Cardiovasc.Pharmacol.31,SUPPL1. S45-S47 (1998)

[Publications] T.Igaki et al.: "Effects of intravenously administered C-type natriuretic peptide in humans --Comparison with atrial natriuretic peptide." Hypertens.Res.21. 7-13 (1998)

[Publications] S.Suga et al.: "Regulation of endothelial production of C-type natriuretic peptide by interaction between endothelial cells and macrophages." Endocrinology. 139. 1920-1926 (1998)

[Publications] M.Suda et al.: "Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide." Proc.Natl.Acad.Sci.U.S.A.95. 2337-2342 (1998)

[Publications] N.Azuma et al.: "The significance of the Trp 64 Arg mutation of the b3-adrenergic receptor gene in impaired glucose tolerance,non-insulin-dependent diabetes mellitus,and insulin resistance in Japanese subjects" Metabolism. 47. 456-460 (1998)

[Publications] M.Inoue et al.: "Vascular endothelial growth factor(VEGF)expression in human coronary atherosclcrotic lesions:Possible pathophysiological significance of VEGF in progression of atherosclerosis." Circulation. 98. 2108-2116 (1998)

[Publications] Y.Miyamoto et al.: "Endothelial nitric oxide synthase gene is positively associated with essential hypertension." Hypertension. 32. 3-8 (1998)

[Publications] J.Matsuda et al.: "Increased adipose expression of uncoupling protein-3 gnene by thiazolidinediones in Wistar fatty rats and in cultured adipocytes." Diabetes. 47. 1809-1814 (1998)

[Publications] M.Yamaguchi et al.: "Effect of neutral endopeptidase inhibition on the natriuresis and renal clearance of atrial natriuretic peptide in perfused rat kidney." Pharmaceutical Research. 15. 1499-1502 (1998)

[Publications] K.Doyama et al.: "Expression and distribution of brain natriuretic peptide in human right atria." J.Am.Coll.Cardiol.32. 1832-1838 (1998)

[Publications] H.Itoh et al.: "Hypertension and insulin resistance-The role of peroxisome proliferator-activated receptor-γ(PPARγ)-" Clinical and Experimental Pharmacology and Physiology. (in press). (1999)

[Publications] Y.Numata et al.: "Immunoradiometric assay for the N-terminal fragment of proatrial natriuretic peptide in human plasma." Clinical Chemistry. 44. 1008-1013 (1998)

[Publications] M.Harada et al.: "Interaction of myocytes and nonmyocytes is necessary for mechanical stretch to induce ANP/BNP production in cardiocyte culture." J.Cardiovasc.Pharmacol.31 SUPPL1. S357-S359 (1998)

[Publications] G.Takemura et al.: "Expression of atrial and brain natriuretic peptides and their genes in hearts of patients with cardiac amyloidosis." J.Am.Coll.Cardiol.31. 254-265 (1998)

[Publications] J.Yamashita et al.: "Identification of cis-element of the human endothelin-A receptor gene and inhibition of the gene expression by the decoy strategy." J.Biol.Chem.273. 15993-15999 (1998)

[Publications] H.Nanno et al.: "Plasma nitric oxide metabolite levels are decreased in pre-eclamptic women complicated with fetal distress." Prenat.Neonat Med.3. 222-226 (1998)

[Publications] H.Nanno et al.: "Nitric oxide metabolite concentrations in maternal plasma decrease during parturition: possible transient down-regulation of nitric oxide synthesis." Molecular Human Reproduction. 4. 609-616 (1998)

[Publications] T.Tanaka et al.: "Down-regulation of peroxisome proliferator-activated receptorg expression by inflammatory cytokines and its reversal by thiazolidinediones." Diabetologia. (in press). (1999)

伊藤裕京都大学, 医学研究科, 助手 (40252457)