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Characterization, localization and quantification of neutral metalloendopeptidase, the degradative enzyme for atrial natriuretic peptide

Research Project

Project/Area Number 04670511
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Circulatory organs internal medicine
Research InstitutionTohoku University

Principal Investigator

YASUJIMA Minoru  Tohoku University School of Medicine, Associate Professor, 医学部, 助教授 (90142934)

Co-Investigator(Kenkyū-buntansha) KOHZUKI Masahiro  Tohoku University School of Medicine, Assistant Professor, 医学部・附属病院, 助手 (70234698)
Project Period (FY) 1992 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1993: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1992: ¥1,400,000 (Direct Cost: ¥1,400,000)
Keywordsneutral metalloendopeptidase / NEP inhibitor / radio-labeled NEP inhibitor / radioinhibitory binding assay / in vitro autoradiography / rat kidney / neutral metalloendopeptidase(NEP)
Research Abstract

Atrial natriuretic peptide (ANP) is rapidly degraded by neutral metalloendopeptidase (NEP), with the kidney being a major site of ANP clearance. NEP has been anatomically localized in the rat kidney by in vitro autoradiography and the active site studied by a radioinhibitory binding assay (RIBA) using a newly developed radioinhibitor as a radioligand. SCH47896 is a phenolic derivative of SCH39370, a potent specific inhibitor of NEP, which can be radioiodinated with ^<125>I.NEP catalytic activity in the rat kidney was inhibited by SCH47896 and its di-iodo analog SCH48446. Specific binding of [^<125>I]SCH47896 to renal plasma membranes fitted a single-site model with Kd = 43.3 nM and maximal binding site density = 13.8 pmol/mg protein. Thus, [^<125>I]SCH47896 retains full enzymatic inhibitory activity and full binding to the active site of the NEP.Autoradiographs using [^<125>I]SCH47896 demonstrated maximal binding to deep proximal renal tubules. This binding was displaced in a dose-dependent manner by NEP inhibitors. The present studies suggest that degradation of ANP by NEP occurs mainly in the deep proximal tubules, and that the proximal convoluted tubule in the outer cortex is not a major site of location of NEP.These properties enable [^<125>I]SCH47896 to be used as a radioligand for RIBA and in vitro autoradiography. Using these methods, investigation of the regulation of NEP under different physiological and pathophysiological conditions is possible. Furthermore, this method of radioinhibitor binding is applicable to any enzyme, provided a suitable radioligand can be constructed.

Report

(3 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • Research Products

    (27 results)

All Other

All Publications (27 results)

  • [Publications] 金澤雅之: "ラット腎atrial natriuretic peptide(ANP)代謝酵素neutral metalloendopeptidase(EC3.4.24.11)(NEP)活性とその局在" 日本腎臓学会誌. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 金澤雅之: "ラットにおけるAngiotensin IIの血圧上昇作用に対するCicletanineの抑制効果" 脈管学. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Minoru Yasujima: "Urinary Active Kallikrein Excretion and Diabetic Renal Impairments in Streptozotocin-Treated Rats" Tohoku J.Exp.Med.171. 135-144 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Minoru Yasujima: "The Augmented Blood Pressure Response to Chronic Angiotensin II Infusion in Partially Nephrectomized Rats" Tohoku J.Exp.Med.169. 271-277 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masahiro Kohzuki: "Antihypertensive and renal protective effects of losartan in spontaneously hypertensive rats with chronic renal failure" Hypertension Research. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kazunori Yoshida: "Endothelin-1 augments pressor response to angiotensin II infusion in rats" Hypertension. 20. 292-297 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masayuki Kanazawa: "Activity and localization of neutral metalloendopeptidase (EC 3.4.24.11)(NEP), the degradative enzyme for atrial natriuretic peptide (ANP), in rat kidney" The Japanese Journal of Nephrology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masayuki Kanazawa: "Effects of cicletanine on the blood pressure response to chronic infusion of *angiotensin II in rats" The Journal of Japanese College of Angiology. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masahiro Kohzuki: "The kidney protecting effect of trandolapril in normotensive and hypertensive diabetic rats" Pharmacometrics. 44. 309-315 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Makito Sato: "Effect of sulindac of prostaglandin synthesis in human and in cultured rat renal and vascular smooth muscle cells" Tohoku J.Exp. Med.166. 185-200 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kazuhisa Takeuchi: "Phosphoinositide hydrolysis and calcium mobilization induced by vasopressin and angiotensin II in cultured vascular smooth muscle cells" Tohoku J.Exp. Med.166. 107-122 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kazunori Yoshida: "Endothelin-1 augments pressor response to angiotensin II infusion in rats" Hypertension. 20. 292-297 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Minoru Yasujima: "Chronic treatment with anti-endothelin antibodies fails to modify the development of hypertension in stroke-prone spontaneously hypertensive rats and DOCA-salt hypertensive rats" Tohoku J.Exp. Med.169. 43-50 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Minoru Yasujima: "The augmented blood pressure response to chronic angiotensin II infusion in partially nephrectomized rats" Tohoku J.Exp. Med.169. 271-277 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Minoru Yasujima: "Urinary active kallikrein excretion and diabetic renal impairments in streptozotocin-treated rats" Tohoku J.Exp. Med.171. 135-144 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Masahiro Kohzuki: "Angiotensin converting enzyme inhibitors and progression of chronic renal failure in rats with reduced renal mass" Inhibition of the renin-angiotensin system -- Recent Advances. eds by Sever P and MacGregor. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Kazunori Yoshida: "The effects of chronic treatment of calcium channel blockers and angiotensin converting enzyme inhibitors on renal function in the streptozotocin diabetic rats" Hypertension Research. (in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 金澤雅之: "ラット腎atrial natriuretic peptide(ANP)代謝酵素neutral metalloendopeptidase(EC3.4.24.11)(NEP)活性とその局在" 日本腎臓学会誌. (印刷中).

    • Related Report
      1993 Annual Research Report
  • [Publications] 金澤雅之: "ラットにおけるAngiotensinIIの血圧上昇作用に対するCicletanineの抑制効果" 脈管学. (印刷中).

    • Related Report
      1993 Annual Research Report
  • [Publications] Minaru Yasujima: "Urinary Active Kallikrein Excretion and Diabetic Renal Impairments in Streptozotocin-Treated Rats" Tohoku J.Exp.Med.171. 135-144 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Minaru Yasujima: "The Augmented Blood Pressure Response to Chronic Angiotensin II Infusion in Partially Nephrectomized Rats" Tohoku J.Exp.Med.169. 271-277 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Masahiro Kohzuki: "Antihypertensive and renal protective effects of losartan in spontaneously hypertensive rats with chronic renal failure." Hypertension Research. (印刷中).

    • Related Report
      1993 Annual Research Report
  • [Publications] Kazuhisa Takeuchi: "Phosphoinositide hydrolysis and calcium mobilization induced by vasopressin and angiotensin II in cultured vascular smooth musele cells." Tohoku J.Exp.Med.166. 107-122 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Makito Sato: "Effect of sulindac of prostaglandin synthesis in human and in cuetured rat renal and vascular smooth muscle cells." Tohoku J.Exp.Med.166. 185-200 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Masahiro Kohzuki: "The Kidney protecting effect of trandolapril in.normotensive and hypertensive diabetic rats." Pharmacometrics. 44. 309-315 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Kazunori Yoshida: "Endothelin-1 augments pressor response to angiotensin 2 infusion in rats." Hypertension. 20. 292-297 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Minoru Yasujima: "Chronic treatment with anti-endothelin antibodies fails to modify the development of hypertension in stroke prone spontaneously hypertensive rats and DOCA-salt hypertensive rats." Tohoku J.Exp.Med.

    • Related Report
      1992 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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