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Pharmacological and biological studies of an endothelium-derived vasoconstrictive peptide, endothelium.

Research Project

Project/Area Number 01440022
Research Category

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

Allocation TypeSingle-year Grants
Research Field General pharmacology
Research InstitutionKyoto University (1991)
University of Tsukuba (1989-1990)

Principal Investigator

MASAKI Tomoh  Kyoto University Pharmacology Professor, 医学部, 教授 (60009991)

Co-Investigator(Kenkyū-buntansha) YANAGISAWA Masashi  Kyoto University Pharmacology Instructor, 医学部, 講師 (20202369)
GOTO Katsutoshi  University of Tsukuba Pharmacology Professor, 基礎医学系, 教授 (30012660)
Project Period (FY) 1989 – 1991
Project Status Completed (Fiscal Year 1991)
Budget Amount *help
¥30,300,000 (Direct Cost: ¥30,300,000)
Fiscal Year 1991: ¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1990: ¥7,800,000 (Direct Cost: ¥7,800,000)
Fiscal Year 1989: ¥15,900,000 (Direct Cost: ¥15,900,000)
Keywordsendothelin / vasoconstriction / endothelin receptor / intracellular free calcium ion / カルシュウムチャンネル / ホスホリパ-ゼのリン酸化 / 平滑筋収縮機構 / 平滑筋収縮 / 内皮細胞 / エンドセリンのcDNA / エンドセリンのアイソペプチド / エンドセリンのmRNA
Research Abstract

Aim of this project is to elucidate mechanism of vasoconstriction elicited by endothelin (ET). Since ET widely distributes in various tissues as well as in endothelium, elucidation of structure and function of ET-receptor is important. At the first step of this project, three distinct ET-isotypes were discovered. Subsequently, distribution of those isotypes in different tisuues was investigated. On the other hand, multiple functions of ET in various tissues were reported, suggesting the existence of subtypes of ET-receptor. We reported cDNA cloning of ET-receptor from rat lung and human jejunum cDNA libraries. As a result, those ET-receptors were classified into two subtypes, designated ETA and ETB. Both types belong to a type of receptor of seventurned G-protein coupled receptor. We made chimeric receptors of two subtypes of human ET-receptor and analyzed them with reference to structure-activity relationship. It was demonstrated that both types of the receptor activated by agonist, stimulate phosphoinositol turnover, to increase intracellular free calcium concentration. In addition, it was also demonstrated that, in various types of cell, ET stimulates opening of calcium channel and induces increase in calcium influx. Particularly in porcine coronary smooth muscle, voltage dependent calcium channel was opened by ET. This process is sensitive to pertussis toxin. Additionally, we demonstrated that vascular bed of spontaneous hypertensive rat is sensitive to ET. Causes of increase in the sensitivity to ET were analyzed and discussed. Further, we analyzed various pharmacological actions of ET in various tissues. Moreover, measurement of human plasma concentration of ET has added a great deal of clinical data regarding ET. Thus, research in this project has greatly progressed in accumulating knowledge of physiological and pathophysiological meaning of ET.

Report

(4 results)
  • 1991 Annual Research Report   Final Research Report Summary
  • 1990 Annual Research Report
  • 1989 Annual Research Report
  • Research Products

    (42 results)

All Other

All Publications (42 results)

  • [Publications] A.Saito: "Endothelins:vasoconstrictor effects and localization in canine cerebral arteris" Br.J.Pharmacology. 103. 1129-1135 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T.Sakurai: "cDNA cloning,sequence analysis and tissue distribtuion of rat preproendothelin-1 mRNA" Biochem.Biophys.Res.Commun.175. 44-47 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T.Sawamura: "Phosphoramidon inhibits the intracellular conversion of big endothelin-1 to endothelin-1 in cultured endothelial cells" Biochem.Biophys.Res.Commun.174. 779-784 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Y.Tomobe: "Mechanism of altered sensivity to endothelin-1 between aortic smooth muscles of spontaneously hypertensive and Wistar-Kyoto rats" J.Pharmacol.Exp.Ther.257. 555-561 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] A.Sakamoto: "Cloning and functional expression of human cDNA for the ET_B endothelin receptor" Biochem.Biophys.Res.Commun.178. 656-663 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T.Ishikawa: "Characteristics of binding of endothelin-1 and endothelin-3 to rat hearts:Developmental changes in mechanical responses and receptor subtypes" Circ.Res.49. 918-926 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T.Masaki: "J.Cardiovascul.Pharmacol." Raven Press, 4 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T.Masaki: "Circulation" American Heart Association, 6 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T. Miyauchi, Y. Tomobe, R. Shiba, T. Ishikawa, M. Yanagisawa, S Kimura, Y. Sugishita, I. Ito, K. Goto, T. Masaki: "Envolvement of endothelin in the regulation of human vascular tonus." Circulation. 81. 1874-1880 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T. Sawamura, S. Kimura, O. Shinmi, Y. Sugita, M. Yanagisawa, K. Goto, T. Masaki: "Purification and characterization of putative endothelin converting enzyme in bovine adrenal medulla : evidence for a cathepsin D-like enzyme." Biochem. Biophys. Res. Commun. 168. 1230-1236 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T. Sakurai, M. Yanagisawa, Y. Takuwa, H. Miyazaki, S. Kimura, K. Goto, T. Masaki: "cDNA cloning of a cDNA encoding a nonisopeptide-selective subtype of endothelin receptor." Nature. 348. 732-735 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T. Sawamura, S. Kimura, O. Shinmi, Y. Sugita, M. Kobayashi, Y. M. Yanagisawa, K. Goto, T. Masaki: "Characterization of endothelin concerting enzyme activities in soluble fraction of bovine cultured endothelial cells." Biochem. Bioophys. Res. Commun. 169. 1138-1144 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T. Sawamura, O. Shinmi, N. Kishi, Y. Sugita, M. Yanagisawa, K. Goto, T. Masaki, S. Kimura: "Analysis of big endothelin-1 digestion by cathepsin D." Biochem. Biophys. Res. Commun. 172. 883-889 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] A. Saito, R. Shiba, M. Yanagisawa, T. Masaki, S. Kimura, K. Yamada, T. Mima, T. Shigeno, K. Goto: "Endothelins : vasoconstrictor effects and localization in canine cerebral arteris." Br. J. Pharmacol.103. 1129-1135 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T. Miyauchi, N. Suzuki, T. Kurihara, I. Yamaguchi, Y. Sugishita, H. Matsumoto, K. Goto, T. Masaki: "Endothelin-1 and endothelin-3 play different roles in acute and chronic alterations of blood pressure in patients with chronic hemodialysis." Biochem. Biophys. Res. Commun.178. 276-281 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T. Sakurai, M. Yanagisawa, A. Inoue, U. S. Ryaan, S. Kimura, Y. Mitusi, K. Goto, T. Masaki: "cDNA cloning, sequence analysis and tissue distribution of rat preproendothelin-1 mRNA." Biochem. Biophys. Res. Commun.175. 44-47 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T. Sawamura, Y. Kasuya, Y. Matsushita, N. Suzuki, O. Shinmi, N. Kishi, Y. Sugita, M. Yanagisawa, K. Goto, T. Masaki, S. Kimura: "Phosphoramidon inhibits the intracellular conversion of big endothelin-1 to endothelin-1 in cultured endothelial cells." Biochem. Biophys. Res. Commun.174. 779-784 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Y. Tomobe, T. Ishikawa, M. Yanagisawa, S. Kimura, T. Masaki, K. Goto: "Mechanism of altered sensitivity to endothelin-1 between aortic smooth muscle of spontaneously hypertensive and Wistar-Kyoto rats." J. Pharmacol. Exp. Ther.257. 555-561 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] A. Sakamoto, M. Yanagisawa, T. Sakurai, Y. Takuwa, H. Yanagisawa, T. Masaki: "Cloning and functional expression of human cDNA for the ETB endothelin receptor." Biochem. Biophys. Res. Commun.178. 656-663 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] T. Ishikawa, L. Li, O. Shinmi, S. Kimura, M. Yanagisawa, K. Goto T. Masaki: "Characteristics of binding of endothelin-1 and endothelin-3 to rat hearts : Developmental changes in mechanical responses and receptor subtypes" Circ. Res.49. 918-926 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] A.Saito: "Endothelins:vasoconstrictor effects and localization in canine cerebral arteris" Br.J.Pharmacology. 103. 1129-1135 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] T.Sakurai: "cDNA cloning,sequence analysis and tissue distribtuion of rat preproendothelinー1 mRNA" Biochem.Biophys.Res.Commun.175. 44-47 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] T.Sawamura: "Phosphoramidon inhibits the intracellular conversion of big endothelinー1 to endothelinー1 in cultured endothelial cells" Biochem.Biophys.Res.Commun.174. 779-784 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Y.Tomobe: "Mechanism of altered sensivity to endothelinー1 between aortic smooth muscles of spontaneously hypertensive and WistarーKyoto rats" J.Pharmacol.Exp.Ther.257. 555-561 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] A.Sakamoto: "Cloning and functional expression of human cDNA for the ET_B endothelin receptor" Biochem.Biophys.Res.Commun.178. 656-663 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] T.Ishikawa: "Characteristics of binding of endothelinー1 and endothelinー3 to rat hearts:Developmental changes in mechanical responses and receptor subtypes" Circ.Res.49. 918-926 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] T.Masaki: "J.Cardiovascul.Pharmacol." Raven Press, 4 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] T.Masaki: "Circulation" American Heart Association, 6 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] T.Sakurai,M.Yanagisawa,Y.Takuwa,H.Miyazaki,S.Kimura,K.Goto,T.Masaki: "cDNA cloning of nonーisopeptide selective subtype of endothelin receptor." Nature. 648. 732-735 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Y.Tomobe,T.Ishikawa,M.Yanagisawa,S.Kimura: "Mechanism of alfered sensitivity to endothelinー1 aortic smooth muscles of spontaneously hypertensive and WistarーKyoto rats." J.Pharmacol.Exp.Ther.

    • Related Report
      1990 Annual Research Report
  • [Publications] T.Sawamura,O.Shinmi,N.Kishi,Y.Sugita,M.Yanagisawa,K.Goto,T.Masaki,S.Kimura: "Analysis of big endothelinー1 digestion by cathepsin D." Biochem.Biophys.Res.Commun.172. 883-889 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] T.Masaki,M.Yanagisawa,K.Goto,S.Kimura: "Role of endothelin in mechanisms of local pressure control." J.Hypertension. 8(suppl.7). S108-S112 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Y.Takuwa,T.Masaki,K.Yamashita: "The effects of the endothelin family peptides on cultured on cultured osteoblastic cells from rat calvariae." Biochem.Biophys.Res.Commun.170. 998-1005 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] S.Usuki,T.Saitoh,T.Sawamura,N.Suzuki,S.Shigemitsu,M.Yanagisawa,K.Goto,H.Onda,M.Fujino,T.Masaki: "Increased maternal plasma concentration of endothelinー1 during labor pain or on delivery and the existence of a large amount of endothelinー1 in amnotic fluid." Gynecol.Endocrinol.4. 85-97 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] T.Masaki: "Influence of Molecular Biology on Drug Discovery" W.Zuckschwerdt Verlag, 134 (1989)

    • Related Report
      1990 Annual Research Report
  • [Publications] T.Masaki,M.Yanagisawa,Y.Takuwa,Y.Kasuya,S.Kimura,K.Goto: "The Biology and Medicine of Signal Transduction" Raven Press, 750 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] A.Inoue,M.Yanagisawa,S.Kimura,Y.Kasuya,T.Miyauchi,K.Goto,T.Masaki: "The human endothelin family:Three structurally and pharmacologically distinct isopeptides predicted by three separate genes." Proc.Natl.Acad.Sci.USA. 86. 2863-2867 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Y.Kasuya,T.Ishikawa,M.Yanagisawa,S.Kimura,K.Goto,T.Masaki: "Mechanism of contraction to endothelin in the isolated porcine coranary artery." Am.J.Physiol.257. H1828-H1835 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] K.Goto,Y.Kasuya,N.Matsuki,Y.Takuwa,H.Kurihara,T.Ishikawa,S.Kimura,M.Yanagisawa,T.Masaki: "Endothelin activates dihydropyridineーsensitive,voltageーdependent Ca^<2+>channel in vascular smooth muscle." Proc.Natl.Acad.Sci.USA. 86. 3915-3918 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] A.Inoue,M.Yanagisawa,Y.Mitsui,M.Kobayashi: "The human preproendothelinー1 gene:complete nucleotide sequence and regulation of expression." J.Biol.Chem.264. 14954-14959 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Y.Kasuya,Y.Takuwa,M.Yanagisawa,S.Kimura,K.Goto,T.Masaki: "Endothelinー1 induces vasoconstriction through two functionally distinct pathways in porcine coronary artery:contribution of phosphoinositide turnover." Biochem.Biophys.Res.Commun.161. 1049-1055 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] T.Miyauchi,M.Yanagisawa,T,Tomizawa,Y.Sugishita,N.Suzuki,M.Fujino,R.Ajisaka,K.Goto,T.Masaki: "Increased plasma concentrations of endothelinー1 and big endothelinー1 in acute myocardial infarction." The Lancet. ii. 53-54 (1989)

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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