2016 Fiscal Year Final Research Report
Drug discovery platform for improvement of positive inotropic effect in septic myocardium
Project/Area Number |
15K15661
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Research Category |
Grant-in-Aid for Challenging Exploratory Research
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Allocation Type | Multi-year Fund |
Research Field |
Emergency medicine
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Research Institution | Nagoya University |
Principal Investigator |
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Project Period (FY) |
2015-04-01 – 2017-03-31
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Keywords | 敗血症 / β受容体 / ホスホジエステラーゼ / PDE4 / ドブタミン |
Outline of Final Research Achievements |
We weighed the effects of dobutamine and milrinone as inotropes in BALB/c mice with cecal ligation and puncture (CLP)-induced sepsis. Surface expression levels of β1-adrenoceptors and alpha subunits of three main G protein families in myocardium were unaffected by CLP-induced sepsis. Plasma cyclic adenosine monophosphate (cAMP) levels were significantly elevated in both sham-operated and CLP mice in response to milrinone but only in sham-operated controls in response to dobutamine. Of phosphodiesterase (PDE) isoforms, PDE4D, but not PDE3A, both of which are responsible for cardiac cAMP hydrolysis, was significantly upregulated in CLP mouse myocardium. We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support.
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Free Research Field |
救急医学
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