| Project/Area Number |
61440098
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | University of Tokyo |
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Principal Investigator |
SUGIMOTO Tsuneaki University of Tokyo, Faculty of Medicine, Professor, 医学部, 教授 (60019883)
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| 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)
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| Project Period (FY) |
1986 – 1988
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| Project Status |
Completed (Fiscal Year 1988)
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| 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)
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| Keywords | Purinergic 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 |
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| 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
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