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IDENTIFICATION OF ENDOGENOUS DIGITALIS AND THE ROLE IN WATER-ELETROLYTES BALANCES AND BLOOD PRESSURE REGULATION

Research Project

Project/Area Number 10557253
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section展開研究
Research Field Laboratory medicine
Research InstitutionKANSAI MEDICAL UNIVERSITY

Principal Investigator

TAKAHASHI Hakuo  KANSAI MEDICAL UNIVERSITY, FACULTY OF MEDICINE, PROFESSOR, 医学部, 教授 (80094431)

Co-Investigator(Kenkyū-buntansha) KOBAYASHI Kouji  SEKISUI CHEMICALS CO.LTD., MEDICAL INSTITUTION, SENIOR INVESTIGATOR, メディカル研究所, 副主任研究員
MASUDA Midori  KANSAI MEDICAL UNIVERSITY, FACULTY OF MEDICINE, ASSOCIATE PROFESSOR, 医学部, 講師 (50173753)
KOMIYAMA Yutaka  KANSAI MEDICAL UNIVERSITY, FACULTY OF MEDICINE, ASSOCIATE PROFESSOR, 医学部, 講師 (40140264)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2000: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1999: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1998: ¥2,500,000 (Direct Cost: ¥2,500,000)
KeywordsENDOGENOUS DIGITALIS / OUABAIN / CULTURED CELLS / ADRENAL MEDULLA / NEURONAL TISSUE / PROGESTERONE / MASS SPECTROMETRY
Research Abstract

Ouabainlike factor (OLF) has been suggested to be a steroid, and may be produced in adrenals. Thereby, progesterone could be a substrate for the OLF.However, there is no evidence that OLF is endogenously produced in mammalian cells. We have found Ouabainlike immunoreactivity in the adrenal medulla by immunohistochemistry, the pheochromocytoma tissue, adrenal cortex and medulla by enzyme-linked immunosorbent assay for ouabain. Since PC12 cells are of rat pheochromocytoma origin, we explored the possible production of OLF by using cultured PC12 cells by adding progesterone in the culture medium. Progesterone increased Ouabainlike immunoreactivity in the culture medium of PC12 cells dose-dependently. OLI in the culture medium was purified by 5 steps of high-performance liquid chromatography (HPLC). The final fraction of OLI was applied to HPLC/mass spectrometry (LC/MS) to analyze the molecular structure, and the OLI was found to be identical to authentic ouabain. This is the first direct evidence to show that mammalian cells produce ouabain, identical to that of plant origin, because the culture system is apparently out of contamination of ouabain of plant origin. It may be a novel finding that cells of neuronal origin can produce biologically active steroids.
Furthermore, we are trying to develop a sensitive and selective assay method by using LC/MS with a selected ion mode. So far, it became possible to measure OLF and a digoxinlike factor from 5ml of plasma. To explore the possible existence of other digitalislike factors, we are developing a novel biological assay system for digitalislike bioactivity by measuring intracellular calcium ions in endothelial cells.

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (44 results)

All Other

All Publications (44 results)

  • [Publications] Nishimura M,Takahashi H, et al.: "Role of FMRF amide-Activated Brain Sodium Channel in Salt-Sensitive Hypertension. Hypertension (Suppl.) 35 : 443-450, 2000"Hypertension. 35. S443-S450 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kiyozuka Y,Takahashi H. et al.: "Establishment of Novel Human Esophageal Caner Cell Line in Relation to Telomere Dynamics and Telomerase Activity."Digestive Diseases and Sciences. 45/5. 870-879 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Komiyama Y,Takahashi H, et al.: "Identification of endogenous ouabain in culture supernatant of pcl2 cells."Journal of Hypertension. 19. 229-236 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Komiyama Y,Takahashi H. et al.: "Liquid chromatography mass spectrometric analysis of Ouabainlike factor in biological fluid."Hypertension Research. 23. S21-S27 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takahashi H.: "Endogenous digitalislike factor : An update."Hypertension Research. 23. S1-S5 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takahashi H.,Komiyama Y.: "Na/K ATPase and Related ATPases."Elsevier Science B.V.Amsterdam, The Netherland. 663-670 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 高橋伯夫: "高血圧ナビゲーター"メディカルレビュー社、東京. 106-107 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishimura M, Takahashi H, et al.: "Increased Serum Concentrations of Human Hepatocyte Growth Factor in Proliferative Diabetic Retinopathy."Journal of Clinical Endocrinology and Metabolism. 83. 195-198 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masaki H, Takahashi H, et al.: "Cardiac-specific Overexpression of Angiotensin II AT2 Receptor Causes Attenuated Response to AT1 Receptor-mediated Pressor and Chronotropic Effects."Journal of Clinical Investigation. 101. 527-535 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Komiyama Y, Takahashi H, et al.: "Purification and characterization of ouabain-binding protein in human plasma."Clinical and Experimental Hypertension. 20 (5&6). 683-690 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishimura M, Takahashi H, et al.: "Enhanced Production of Nitric Oxide May Be Involved in Acute Hypotension During Maintenance Hemodialysis."American Journal of Kidney Diseases. 31. 809-817 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishimura M, Takahashi H, et al.: "Benzamil blockade of brain Na^+ channels averts Na^+-induced hypertension in rats."American Journal of Physiology.. 274. R635-R644 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nanbu A, Takahashi H, et al.: "Lower than normal expression of brain nitric oxide synthase gene in the hypothalamus of deoxycorticosterone acetate-salt hypertensive rats."Journal of Hypertension. 16. 495-502 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kagawa H, Komiyama Y, Takahashi H, et al.: "Expression of functional tissue factor on small vesicles of lipopolysaccharide-stimulated human vascular endothelial cells."Thrombosis Research. 91. 297-304 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Masaki H, Takahashi H, et al.: "Cardiac-specific over expression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects."The Journal of Clinical Investigation. 101 (3). 527-35 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishimura M, Takahashi H, et al.: "Roles of brain angiotensin II and C-type natriuretic peptide in deoxycorticosterone acetate-salt hypertension in rats."Journal of Hypertension. 16. 1175-1185 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Komiyama Y, Takahashi H.et al.: "Increases in Plasma Ouabainlike Immunoreactivity during Surgical Extirpation of Pheochromocytoma."Hypertension Research. 22 (2). 135-13 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishimura M, Takahashi H, et al.: "Regulation of brain renin-angiotensin system by benzamil-blockable sodium channels."American Journal of Physiology. 276. R1416-1424 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Sakamoto M, Nishimura M, Takahashi H: "Brain atrial natriuretic peptide family abolishes cardiovascular haemodynamic alterations caused by hypertonic saline in rats."Clincal and Experimental Pharmacology and Physiology. 26. 684-690 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Tsutsumi Y, Takahashi H, et al.: "Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilatation."The Journal of Clinical Investigation. 104 (7). 925-935 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishimura M, Ohtsuka K, Takahashi H, Yoshimura M: "Role of FMRF amide-Activated Brain Sodium Channel in Salt-Sensitive Hypertension."Hypertension. (Suppl.) 35. 443-450 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishimura M, Takahashi H, et al.: "Eicosapentanoic acid stimulates nitric oxide production and decreases cardiac noradrenaline in diabetic rats."Clinical and Experimental Pharmacology and Physiology. 27. 618-624 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Satoi S, Takahashi H.et al.: "Nitric oxide production and hepatic dysfunction in patients with postoperative sepsis."Clinical and Experimental Pharmacology and Physiology. 27. 197-201 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Komiyama Y, Masuda M, Takahashi H.et al.: "Liquid chromatography mass spectrometric analysis of Ouabainlike factor in biological fluid."Hypertension Research. 23 (Suppl). S21-S27 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takahashi H: "Endogenous digitalislike factor : An update."Hypertension Research. 23 (Suppl). S1-S5 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Komiyama Y, Takahashi H.et al: "Identification of endogenous ouabain in cultures supernatant of PC12 cells."Journal of Hypertension. 16. 229-236 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Takahashi H, Komiyama Y: "Ouabain is endogenously produced in cultured PC 12 cells with pregesterone as the substrate."In : Na/K ATPase and Related ATPases. (Eds. K.Taniguchi and S.Kaya), Elsevier Science B.V.Amsterdam, The Netherland. 663-670 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nishimura M,Takahashi H, et al.: "Role of RMRF amide-Activated Brain Sodium Channel in Salt-Sensitive Hypertension. Hypertension (Suppl.) 35 : 443-450, 2000"Hypertension. 35. S443-S450 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kiyozuka Y,Takahashi H. et al.: "Establishment of Novel Human Esophageal Caner Cell Line in Relation to Telomere Dynamics and Telomerase Activity."Digestive Diseases and Sciences. 45/5. 870-879 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Komiyama Y,Takahashi H, et al.: "Identification of endogenous ouabain in culture supernatant of PC12 cells."Journal of Hypertension. 19. 229-236 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Komiyama Y,Takahashi H. et al.: "Liquid chromatography mass spectrometric analysis of Ouabainlike factor in biological fluid."Hypertension Research. 23. S21-S27 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takahashi H.: "Endogenous digitalislike factor : An update."Hypertension Research. 23. S1-S5 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takahashi H.,Komiyama Y.: "Na/K ATPase and Related ATPases."Elsevier Science B.V.Amsterdam, The Netherland. 663-670 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 高橋伯夫: "高血圧ナビゲーター"メディカルレビュー社、東京. 106-107 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nishimura M,Takahashi H,et al.: "Regulation of brain renin-angiotensin system by benzamil-blockable sodium channels"American Journal of Physiology. 276. R1416-R1424 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sakamoto M,Nishimura M,Takahashi H.: "Brain atrial natriuretic peptide family abolishes cardiovascular haemodynamic alterations caused by hypertonic saline in rats. Clin. And Experimental Pharmacology and Physiology 26:684-690"Clinical and Experimental Pharmacology and Physiology. 26. 684-690 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tsutsumi Y,Takahashi H,et al.: "Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodialation"The Journal of Clinical Investigation. 104・7. 925-935 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hara K,Takahashi H.Et al.: "Measurement of urinary amino acids using high-performance liquid chromatography equipped with a strong cation exchange resin pre-column"Annals of Clinical Biochemistry. 36. 202-206 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Satoi S,Takahashi H.Et al: "Different responses to surgical stress between extra domain A+ and plasma fibronectins"Clinical and Experimental Pharmacology and Physiology. 26. 225-229 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sakai M,Takahashi H.et al.: "Stimulation of nitric oxide release from rat spinal cord by prostaglandin E2." British Journal of Pharmacology. 123. 890-894 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Satoi S,Takahashi H.et al.: "Prolonged decreases in plasma nitrate levels at early postoperative phase after hepato-pancreato-biliary surgery." Journal of Laboratory and Clinical Medicine. 131. 236-242 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nishimura M,Takahashi H.et al.: "Enhanced Production of Nitric Oxide May Be Involved in Acute Hypotension During Maintenance Hemodialysis." American Journal of Kidney Diseases. 31(5). 809-817 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Masaki H,Takahashi H,et al.: "Cardiac-specific Overexpression of Angiotensin II AT2 Receptor Causes Attenuated Response to AT1 Receptor-mediated Pressor and Chronotropic Effects." Journal of Clinical Investigation. 101. 527-535 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nishimura M,Takahashi H.et al.: "Benzamil blockade of brain Na^+ channels averts Na^+-induced hypertenshion in rats." American Journal of Physiology. 274(43). R635-R644 (1998)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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