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Pathophysiological Role of Arachidonic Acid Metabolites in the Regulation of Cardiac and Vascular Smooth Muscle Cell Function.

Research Project

Project/Area Number 02454253
Research Category

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

Allocation TypeSingle-year Grants
Research Field Circulatory organs internal medicine
Research InstitutionFaculty of Medicine, University of Tokyo

Principal Investigator

SUGIMOTO Tsuneaki  Faculty of Medicine, Univ. of Tokyo, Professor, 医学部(病), 教授 (60019883)

Co-Investigator(Kenkyū-buntansha) NAKAJIMA Toshiaki  Faculty of Medicine, Univ. of Tokyo, Associate, 医学部(病), 助手 (50227790)
UEHARA Yoshio  Faculty of Medicine, Univ. of Tokyo, Associate, 医学部(病), 助手 (40184965)
TOYOOKA Teruhiko  Health Center, Univ. of Tokyo, Professor, 保健センター, 教授 (00146151)
Project Period (FY) 1990 – 1991
Project Status Completed (Fiscal Year 1991)
Budget Amount *help
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 1991: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1990: ¥5,000,000 (Direct Cost: ¥5,000,000)
Keywordsarachidonic acid / muscarinic K+ channel / single cardiac cells / GTP-binding protein / vascular smooth muscle cells / cell growth / hypertension / cytoskeleton protein / 単離心筋細胞 / ムスカリン性Kチャネル / プロスタグランジン / トロンボキサン / カルシウム動態 / インスリン
Research Abstract

1) Acetylcholine activates a specific population of cardiac channels (IK. Ach) via the pertussis-toxin sensitive G proteins (GK). The major aim of the present study was to clarify. the modulation of IK. Ach channel by arachidonic metabolites and also the regulatory mechanisms of G-proteins on the IK. Ach.
The intracellular anions, Cl- ion, were found to play an important role on the activation of IK. Ach. The effects of Cl- ion were thought to be due to the inhibitory action on the GTPase activity of GK. Besides the direct gating of the IK. Ach channel by G protein, we found that the G-protein-gated channel system can be modulated in a stimulatory manner by arachidonic acid and its metabolites. The IK. Ach channel activity could be also stimulated by alpha-adrenergic agonis and platelet activating factor via the arachidonic metabolic pathway.
Thus, it was suggested that archidonic acid metabolites are possibly new common intracellular messengers to the IK. Ach channel in a variety of phy … More siological and pathophysiological regulations of cardiac excitation.
2) We designed experiments to reveal the role of endogenous eicosanoid system in the regulation of vascular smooth muscle cell(VSMC)growth and assess the implication in the vascular and organ injuries in hypertensive state. Prostacyclin regulated the GO/GI transit in cell cycle via a short loop circuit. This mechanism-was mediated by de novo phospholipase A2 synthesis. Thromboxane stimulated the formation of cytoskeleton xprotein, leading to rapid cell growth with a short G2/M transit.
Impaired prostacyclin generation is responsible for the rapid cell growth seen in VSMC from spontaneously hypertensive rats. An increase in endogenous prostacyclin in vivo is found to attenuate the vascular and renal injuries in salt-induced hypertension in Dahl salt-sensitive rats, whereas blood pressure reduction by thiazide diuretic results in a decrease in endogenous eicosanoid synthesis and failure of regression of the vascular and renal injuries.
3)The study elucidated the role of arachidonic metabolites in the intracellular regulatory mechanisms of cellular electrical acitivity and also cellular proliferation. This understanding would contribute to the further study of signal transduction modification mediating the interaction in the receptor and effector systems. Less

Report

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

    (28 results)

All Other

All Publications (28 results)

  • [Publications] Tanaka,H.et al.: "Votage-gated K+ channels in the mouse interleukin 3-dependent cell line,FDC-P2." J.Membrane Biol.120. 185-190 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Nakajima,T.et al.: "Platelet-activating factor activates cardiac GK via arachidonic acid metabolites." FEBS Letters. 289. 239-243 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Ito,H.et al.: "On the mechanism of basal and agonist-induced activation of the G protein-gated muscarinic K channel in atrial myocytes of guinea pig heart." J.Gen.Physiol.98. 517-533 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Nagata,T.et al.: "Regulatory effects of thromobxane on proliferation of vascular smooth muscle cells of rats." Am.J.Physiol.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Ueahra,Y.et al.: "Antihypertensive effects of cicletanine and renal protection in Dahl salt-sensitive rats." J.Hypertension.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Kurachi, Y. et al: "Effects of Anions on G-protein-mediated Activation of the Muscarinic K Channel in the Cardiac Atrial Cell Membrane" J. Gen. Physiol.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Itoh, H. et al.: "On the Mechanism of G Protein beta, gamma Subunits-activation of the Muscarinic K channel in guinea pig Atrial Cell Membrane ; Comparison with the ATP Sensitive K channel." J. Gen. Physiol.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Nakajima, T. et al.: "Effects of Calcitonin-gene Related Peptide on Membrane Currents in Mammalian Cardiac Myocytes." Pfluegers Arch.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Tanaka, H., et al.: "Voltage-gated K+ channels in the Mouse Interleukin 3-dependent Cell Line, FDC-P2." J. Membrane Biol.120. 185-190 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Nakajima, T. et al.: "Platelet-Activating Factor Activates Cardiac GK via Arachidonic Acid Metabolites." FEBS Let.289. 239-243 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Ito, H. et al.: "On the Mechanism of Basal and Agonist-induced Activation of the G Protein-gated Muscarinic K Channel in Atrial Myocytes of Guinea Pig heart." J. Gen. Physiol.98. 517-533 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Uehara, Y. et al.: "Alterations in receptor-mediated activation of phospholipase A2 in Dahl salt-sensitive rats." Hypertension.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Ishimitsu, T. et al.: "Antihypertensive Effects of Interferon gamma and renal Protection." Hypertension.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Uehara, Y. et al.: "Desparate Response of Urinary Eicosanoid System to Norepinephrine Infusion in Patients with Essential Hypertension." Prostaglandins Leukotri. Essent Fatty Acid.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Nagata, T. et al.: "Regulatory Effect of Thromboxane on Proliferation of Vascular Smooth Muscle Cells of Rats." Am. J. Physiol.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Uehara, Y. et al: "Antihypertensive Effects of Cicletanine and Renal Protection in Dahl salt-sensitive rats." J. Hypertension.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1991 Final Research Report Summary
  • [Publications] Kurachi,Y.et al.: "Effectc of anions on G proteinーactivation of the muscarinic K channel in the cardiac atrial cell membrane." J.Gen.Physiol.

    • Related Report
      1991 Annual Research Report
  • [Publications] Itoh,H.et al.: "On the mechanism of G protein beta,gamma subunits activation of the muscarinic K channel in guinea pig atrial cell membrane." J.Gen Physiol.

    • Related Report
      1991 Annual Research Report
  • [Publications] Nakajima,T.et al.: "Effects of calcitonin gene related peptide on membrane currents in mammalian cardiac myocytes." Pfluegers Arch.

    • Related Report
      1991 Annual Research Report
  • [Publications] Uehara,Y.et al.: "Alterations in receptor medicated activation of phospolipase A2 in Dahl saltーsensitive rats." Hypertension.

    • Related Report
      1991 Annual Research Report
  • [Publications] Ishimitsu,T.et al.: "Antihypertensive effects of interferon gamma and renal protection." Hypertension.

    • Related Report
      1991 Annual Research Report
  • [Publications] Uehara,Y.et al.: "Desparate response of urinary eicosanoid system to norepinephrine infusion in patients with essential hypertension." Prostaglandins Leukotri.Essent.Fatty Acid.

    • Related Report
      1991 Annual Research Report
  • [Publications] Takikawa,R.et al.: "Adenosineー5ーtriphosphateーinduced sinus tachycardia mediated by prostaglandin synthesis via phospholipase C in the rabbit heart." Pfluegers Archiv.417. 13-20 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] YanagisawaーMiwa,A.et al.: "Effects of insulin on vasoconstriction induced by thromboxane A_2 in porcine coronary artery." Circulation. 81. 1654-1659 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Kurachi,Y.et al.: "Positive cooperativity in activation of the cardiac muscarinic K^+ channel by intracellular GTP." Pfluegers Archiv. 416. 216-218 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Hamada,E.et al.: "Glibenclamide specifically blocks ATPーsensitive K^+ channel current in atrial myocytes of guinea pig heart." Japan.J.Pharmacol.54. 473-477 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Ito,H.et al.: "Heparin uncouples the muscarinic receptors from G_k protein in the atrial cell membrane of the guinea pig heart." Pfluegers Archiv.417. 126-128 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Naitoh,T.et al.: "An endogenous Ca^<++> cahnnel agonist,endothelinー1,does not directly activate partially purified dihydropyridineーsensitive Ca^<++> channel from cardiac muscle in a recostituted system." Biochem.Biophys.Res.Comm.171. 1205-1210 (1990)

    • Related Report
      1990 Annual Research Report

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Published: 1990-04-01   Modified: 2016-04-21  

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