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Effects of natriuretic peptides on the mechanisms of atherosclerosis

Research Project

Project/Area Number 05670622
Research Category

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

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

Principal Investigator

KUGIYAMA Kiyotaka  Kumamoto University school of medicine, Division of Cardiology, Assistant Professor, 医学部, 講師 (00225129)

Co-Investigator(Kenkyū-buntansha) YASUE Hirofumi  Kumamoto University school of medicine, Division of Cardiology, Professor, 医学部, 教授 (40174502)
Project Period (FY) 1993 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsNatriuretic Peptides / Neutral Endopeptidase / Atherosclerosis / Endothelial cell / Oxysterol / Oxidized LDL, / Lysophosphatidylcholine / Oxidized LDL / Endothelial cells / Oxidized IDL
Research Abstract

Neutral Endopeptidase 24.11 (NEP), widely distributed in the body, hydrolyzes and inactivates a number of endogenous vasoactive peptides, some of which could alter the functions of smooth muscle cell or macrophage in the arterial wall. The aim of this study was to assess the influence of chronic NEP inhibition by daily administration of UK79300 (Candoxatril ; UK), an orally active inhibitor of NEP,on the development of atherosclerotic changes in high cholesterol-fed rabbits. Male New Zealand White rabbits were fed for 8 weeks : normal rabbit diet (Nor, n=15), 1.5% cholesterol diet (Chol, n=15), or 1.5% choresterol diet containing UK (20 mg/kg/day) (UK +Chol, n=15). At the end of dietary period, UK-treatment suppressed surface area of the aorta covered by plaques (% surface area : Chol 48 + 7% vs UK + chol 11 + 3, p<0.05) and decreased contents of cholesterol and cholesterol ester in the aortas. UK also reduced plasma total cholesterol by 15 + 4% of Chol (1680 + 180 mg/dl). UK-treatment preserved endothelium-dependent relaxation of the isolated thoracic aortic rings suspended in the organ chamber in response to acetylcholine (ACh) (EC50, nM ; concentrations of ACh causing 50% inhibition of contractions with 0.3 mM of phenylephrine : Nor 12 + 4, Chol 360 + 20 +, UK + Chol 56 + 9^*, +p<0.01 vs Nor, ^*p<0.01 vs Chol). UK-treatment decreased plasma NEP enzymatic activity by 27 + 3% of Chol and prevented the atherosclerotic impairment of relaxation of the isolated thoracic aortic rings in the organ chamber in response to atrial natriuretic peptide, one of NEP substrates (EC50, pM : Nor 50 + 4, Chol 290 + 20 +, UK + Chol 65 + 8, +p<0.01 vs Nor, ^*p<0.01 vs Chol). The results suggest that NEP plays a significant role in atherogenesis and NEP inhibitors might be therapeutically useful in the prevention of atherosclerosis.

Report

(3 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Toyoaki Murohara: "Cigarette Smoke Extract Contracts Isolated Porcine Coronary Arteries by Superoxide Anion-mediated Degradation of EDRF" Am J Physiol. 266. H874-H880 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hirofumi Yasue: "Localization and Mechanisms of Secretion of B-type Natriuretic Peptide (BNP) in Comparison With Those of A-type Natriuretic Peptide (ANP) in Normal Subjects and Patients With Heart Failure" Circulation. 90. 195-203 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Toyoaki Murohara: "LPC in Oxidized LDL Elicits Vasocontraction and Inhibits Endothelium-Dependent Relaxation" Am J Physiol. 267. H2441-H2449 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Toyoaki Murohara, Kiyotaka Kugiyama, et al.: "Cigarette smoke extract contracts isolated porcine coronary arteries by superoxide anion-mediated degradation of EDRF." Am J Physiol. 266. H874-H880 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Hirofumi Yasue, Kiyotaka Kugiyama, et al.: "Localization and mechanisms of secretion of B-type natriuretic peptide (BNP) in comparison with those of A-type natriuretic peptide (ANP) in normal subjects and patients with heart failure." Circulation. 90. 195-203 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Toyoaki Murohara, Kiyotaka Kugiyama, et al.: "LPC in oxidized LDL elicits vasoconstriction and inhibits endothelium - dependent relaxation." Am J Physiol. 267. H2441-H2449 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Toyoaki Murohara: "Cigarette Smoke Extract Contracts Isolated Porcine Coronary Arteries by Superoxide Anion-mediated Degradation of EDRF" Am J Physiol. 266. H874-H880 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hirofumi Yasue: "Localization and Mechanisms of Secretion of B-type Natriuretic Peptide(BNP)in Comparison Peptide(ANP)in Normal Subjects and Patients With Heart Failure" Circulation. 90. 195-203 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Toyoaki Murohara: "LPC in Oxidized LDL Elicits Vasocontraction and Inhibits Endothelium-Dependent Relaxation" Am J Physiol. 267. H2441-H2449 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kiyotaka Kugiyama: "Transferable lipids in oxidized low-density lipoprotein stimulate plasminogen activator inhibitor-1 and inhibit tissue-type plasminogen activator release from endothelial cells" Circulation Research. 73. 335-343 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Masamichi Ohgushi: "Protein kinase C inhibitors prevent impairment of endothelium-dependent relaxation by oxidatively modified LDL" Arteriosclerosis and Thrombosis. 13. 1525-1532 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Earl L.Mangin Jr.: "Effects of lysolipids and oxidatively modified low density lipoprotein on endothelium-dependent relaxtion of rabbit aorta" Circulation Research. 72. 161-166 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Toyoaki Murohara: "Activated human polymorphonuclear leukocytes elicit endothelium-dependent contraction in isolated pig coronary arteies" Journal of Cardiovascular Pharmacology. 21. 760-766 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Masamichi Ohgushi: "Contraction and endothelium dependent relaxation via alpha adrenoreceptors are variable in various pig arteries" Cardiovascular Research. 27. 779-784 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Seigo Sugiyama: "Lysophosphatidylcholine in oxidized low-density lipoprotein increases endothelial susceptibility to polymorphonuclear leukocyte-induced endothe-lial dysfunction in porcine coronary arteries:role of protein kinase C" Circulation Research. 74,(in press). (1994)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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