| Project/Area Number |
16K08559
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Toho University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
中村 裕二 東邦大学, 医学部, 助教 (10614894)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 拡張不全型心不全 / 収縮不全型心不全 / ONO-AE1-329 / caldaret / EP4受容体 / 細胞内Ca2+ / SERCA / Caldaret / HFpEF / HFrEF / 慢性房室ブロック犬 / EP4受容体刺激 / 左室圧容積関係 / 拡張性心不全 / 左室等容性弛緩能 / 充満期拡張能 |
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| Outline of Final Research Achievements |
EP4 receptor stimulation by ONO-AE1-329 showed the positive inotropic and lusitopic effects in addition to the increase of left ventricular end-diastolic volume and the decrease of end-systolic volume in normal dogs. The positive inotropic action of ONO-AE1-329 was also confirmed in the chronic heart failure model induced by chronic atrioventricular block, but the lusitropic action were various and bidirectional. Furthermore, intracellular Ca2+ modulation by caldaret was assessed in normal dogs, showing that it can exert various kinds of electropharmacologic actions as well as the positive inotropic and lusitropic effects. Elucidation of the further mechanism at the cellular level may be necessary for analyzing how the change in the intracellular Ca2+ dynamics may affect each of ionic channels in the heart.
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| Academic Significance and Societal Importance of the Research Achievements |
拡張不全型心不全は全心不全患者の半数以上を占め、予後不良である。拡張不全型心不全に対して、収縮不全型心不全の治療において予後改善が認められた薬物（レニン・アンジオテンシン系抑制薬およびβ遮断薬など）の有用性が評価されたが、同様の効果は認められず左室拡張機能を修復できる薬物の開発が強く求められていた。本研究では正常犬および拡張不全型心不全モデル犬を用いて新規作用点（EP4受容体刺激および細胞内Ca2+動態修飾）を有する化合物の心血管作用を評価した。得られた知見は、拡張不全型心不全に対しする薬物治療の突破口になることが期待できる。
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