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Pathophysiological implications of adenosine in the regulatory mechanism of cardiovascular function.

Research Project

Project/Area Number 61440098
Research Category

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

Allocation TypeSingle-year Grants
Research Field Circulatory organs internal medicine
Research InstitutionUniversity of Tokyo

Principal Investigator

SUGIMOTO Tsuneaki  University of Tokyo, Faculty of Medicine, Professor, 医学部, 教授 (60019883)

Co-Investigator(Kenkyū-buntansha) TOYOOKA Teruhiko  University of Tokyo, Health Care Center, Assistant Professor, 保健管理センター, 講師 (00146151)
KURACHI Yoshihisa  University of Tokyo, Faculty of Medicine, Associate, 医学部, 助手 (30142011)
MOMOMURA Shinichi  University of Tokyo, Faculty of Medicine, Associate, 医学部, 助手 (10190985)
MATSUOKA Hiroaki  University of Tokyo, Faculty of Medicine, Associate Professor, 医学部, 講師 (20111544)
IIZUKA Masahiko  University of Tokyo, Faculty of Medicine, Associate Professor, 医学部, 講師 (70010379)
芹沢 剛  東京大学, 医学部, 助手 (90143429)
内田 康美  東京大学, 医学部, 講師 (60010419)
Project Period (FY) 1986 – 1988
Project Status Completed (Fiscal Year 1988)
Budget Amount *help
¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 1988: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1987: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 1986: ¥7,000,000 (Direct Cost: ¥7,000,000)
KeywordsPurinergic Receptors / Single Cardiac Myocyte / GTP-binding Proteins / Muscarinic K^+ Channel / Arachidonic Acid / Phospholipase C / Prostaglandins / 平滑筋細胞 / 単一心筋細胞 / G蛋白サブユニット / ムスカリン性カリウムチャネル / リポキシゲナーゼ / ロイコトリエン / アデノシン / GTP結合タンパク / 心筋収縮・拡張特性 / 心筋保護 / 血管 / 平滑筋 / 高血圧 / アルドステロン / 胃壁酸分泌 / 冠動脈攣縮 / 血管平滑筋 / 心筋収縮 / 拡張特性 / 気管支平滑筋
Research Abstract

The results of the study during these three years will be summarized as follows:
1. The Study on cardiac purinergic receptors. 1) The cardiac purinergic receptors are divided into two major categories; i.e.P1 and P2. P1 receptor was found to cause negative chronotropic and dromotropic effects by activating a K^+ channel via pertussis toxin-sensitive G proteins. On the other hand, P2 receptor caused positive chronotropic action, which might be due to production of prostaglandins and possibly IP3 via phospholipase C. The P1 action was much more prominent than that of P2 in the physiological conditions. P2 action was noted to play an important role in various pathophysiological states of the heart. 2) P1 and m-Ach receptors are linked to a specific K^+ channel via pertussis toxin-sensitive G proteins in the cell membrane. Intracellular Mg^<2+> is essential for GTP to activate the G protein. It was found that exogenous G protein subunits can activate the K^+ channel current. Based on these … More observations, we proposed a model for the molecular mechnisms underlying purinergic and muscarinic activation of the K^+ channel in atrial cell membrance. 3) The study of the molecular mechanisms of the short-term desensitization of purinergic and muscarinic activated K^+ channel current demonstrated that G protein also plays an essential role in the desensitization. 4) The model of the molecular mechanism which we proposed clarified the subcellular processes underlying the anti-cholinergic effects of various anti-arrhythmic agents. 5) Recently, we found that arachidonic acid metabolites work as intracellular modulators of the G protein-gated K^+ channel. Alpha-adrenergic agonists can activate the K^+ channel using this modulatory pathway, which suggests the importance of this novel modulation of the K^+ channel in various physiological and pathophysiological conditions of the heart. 6) We also confirmed that adenosine can be used as a very useful drug to terminate the supraventricular tachycardia, which involves atrio-ventricular node in its reentrant circuit. This is attributed to the transient inhibition of atrio-ventricular conduction due to the activation of the K^+ channel current as disclosed by ourselves.
2. The study on the smooth muscle cell purinergic receptors. 1) We succeeded in preparing single smooth muscle cell preparation from rabbit ileum and guinea-pig trachea. With these preparations, we examined the effects of a contrcting substance, Ach, and a relaxant substance, adenosine, on the contractile and electrical properties of smooth muscle cells. At present, we are preparing single vascular smooth muscle cells and planning to examine the effects of adenosine and ATP on the membrane currents of the cells. Less

Report

(4 results)
  • 1988 Annual Research Report   Final Research Report Summary
  • 1987 Annual Research Report
  • 1986 Annual Research Report

Research Products

(36 results)

All Other

All Publications

  • [Publications] Yoshihisa Kurachi et al.: American Journal of Physiology. 251. H681-H684 (1986)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa Kurachi et al.: Pfluegers Archiv,European Journal of Physiology. 407. 264-274 (1986)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa Kurachi et al.: Pfluegers Archiv,European Journal of Physiology. 407. 572-574 (1986)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Diomedes Logothetis et al.: Nature. 325. 216-218 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa Kurachi et al.: Naunyn-Schmiedeberg's Archives of Pharmacology. 325. 216-218 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa Kurachi et al.: Pfluegers Archiv,European journal of Physiology. 410. 227-233 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa Kurachi et al.: Biomedical Journal. 8(Suppl.). 135-142 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa Kurachi et al.: Pfluegers Archiv,European Journal of Physiology. (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Toshiaki Nakajima et al.: Circulation Research. (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Hiroyuki Ito et al.: Naunyn-Schmiedeberg's Archives of Pharmacology. (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa KUrachi et al.: Nature. (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa Kurachi: News in Physiological Sciences. (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa,Kurachi;et al.: "Acetylcholine activation of K^+ channels in cell-free membrane of atrial cells." American Journal of Physiology. 251. H681-H684 (1986)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa,Kurachi;et al.: "On the mechanism of activation of muscarinic K^+ channels by adenosine in isolated atrial cells: Involvement of GTP-binding proteins." Pfluegers Archiv, European Journal of Physiology. 407. 264-274 (1986)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa,Kurachi;et al.: "Role of intracellular Mg^<2+> in the activation of muscarinic K^+ channel in cardiac atrial cell membrane." Pfluegers Archiv, European Journal of Physiology. 407. 572-574 (1986)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Diomedes,Logothe tis;et al.: "The beta-gamma subunits of GTP-binding proteins activate the muscarinic K^+ channels in heart." Nature. 325. 216-218 (1987)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa,Kurachi;et al.: "Quinidine inhibition of the muscarinic receptor-activated K^+ channel current in atrial cells of guinea pig." Naunyn-Schmiedeberg's Archives of Pharmacology. 325. 216-218 (1987)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa,Kurachi;et al.: "On the molecualr regulation of muscarinic K^+ channel by GTP-binding proteins in cardiac atrial myocytes." Biomedical Journal. 8(Suppl.). 135-142 (1987)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa,Kurachi;et al.: "Activation of atrial muscarinic K^+ channels by low concentrations of beta-gamma subunits of rat brain G protein." Pfluegers Archiv, European Journal of Physiology. in press. (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Toshiaki,Nakajima;et al.: "Anti-cholinergic effects of quinidine, disopyramide, and procainamide in isolated atrial myocytes: Mediation by different molecular mechanisms." Circulation Research.in press. (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Hiroyuki,Ito;et al.: "Anti-cholinergic effect of verapamil on the muscarinic acetylcholine receptor-gated K^+ channel in isolated guinea-pig atrial myocytes." Naunyn-Schmiedeberg's Archives of Pharmacology. in press. (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa,Kurachi;et al.: "Arachidonic acid metabolites as intracellular modulators of G protein-gated cardiac K^+ channel." Nature. in press. (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa,Kurachi;et al.: Short-term desensitization of muscarinic K^+ channel current in isolated atrial myocytes and possible role of GTP-binding proteins.Pfluegers Archiv, European Journal of Physiology, 227-233 (1987)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshihisa,Kurachi: Regulation of G protein-gated K^+ channels.News in Physiological Sciences, (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1988 Final Research Report Summary
  • [Publications] Yoshisa,Kurachi;et al.: Pfluegers Archiv,European Journal of Physiology. (1989)

    • Related Report
      1988 Annual Research Report
  • [Publications] Toshiaki,Nakajima;et al.: Circulation Research. (1989)

    • Related Report
      1988 Annual Research Report
  • [Publications] Hiroyuki,Ito;et al.: Naunyn-Schmiedeberg's Archives of Pharmacology. (1989)

    • Related Report
      1988 Annual Research Report
  • [Publications] Yoshihisa,Kirachi;et al.: Nature. (1989)

    • Related Report
      1988 Annual Research Report
  • [Publications] Yoshihisa,Kurachi: News in Physiological Sciences. (1989)

    • Related Report
      1988 Annual Research Report
  • [Publications] Yoshihisa,Kurachi: "Muscarinic acetylcholine receptor-gated K^+ channel in mammalian hearts.in "Regulation of Potassium Transport Across Biological Membranes"edited by L.Reuss,J.Russell and G.Szabo" The University of Texas Press, (1989)

    • Related Report
      1988 Annual Research Report
  • [Publications] 倉智嘉久: 治療学. 17(3). 378-380 (1986)

    • Related Report
      1987 Annual Research Report
  • [Publications] Kurachi,Y. et al.: Proceedings of International-Symposium on Cardiac Arrhythmias -1986 (Excerpta Medica). 23-26 (1987)

    • Related Report
      1987 Annual Research Report
  • [Publications] Nakajima,T. et al.: Proceedings of International-Symposium on Cardiac Arrhythmias -1986 (Excerpta Medica). 27-32 (1987)

    • Related Report
      1987 Annual Research Report
  • [Publications] Kurachi,Y.et al.: Pluegers Arch.Europ.J.Physiol.407. 264-274 (1986)

    • Related Report
      1986 Annual Research Report
  • [Publications] Kurachi,Y.et al.: Pluegers Arch.Europ.J.Physiol.407. 572-574 (1986)

    • Related Report
      1986 Annual Research Report
  • [Publications] Uchida,Y.et al.: Jap.Heart J.27. 727-740 (1986)

    • Related Report
      1986 Annual Research Report

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Published: 1987-03-30   Modified: 2016-04-21  

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