| 研究課題/領域番号 |
19K16498
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| 研究機関 | 国立研究開発法人国立循環器病研究センター |
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研究代表者 |
ワディンガム マーク.トーマス 国立研究開発法人国立循環器病研究センター, 病院, 特任研究員 (70822211)
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| 研究期間 (年度) |
2019-04-01 – 2022-03-31
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| キーワード | Pulmonary Hypertension / Heart Failure / Right Ventricle / Myofilament / Sarcomere / Sympathetic Nervous Sys. / SSRIs |
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| 研究実績の概要 |
Using the model characterisation data obtained in FY2019, the effects of a selective serotonin re-uptake inhibitor (SSRI), paroxetine, were examined in the Sugen 5416/10% O2 chronic hypoxia (SuHx) model of pulmonary hypertension (PH). Briefly, after induction of PH, rats were returned to normoxic conditions for 2 weeks. SuHx rats then received either paroxetine (5mg/kg/day) or vehicle via an osmotic pump implanted subcutaneously for 4 weeks.
It was found that paroxetine treatment was associated with improved right ventricular (RV) systolic function and pulmonary vascular compliance in the PH rats, despite no overt reduction in pulmonary pressures. Moreover, modest improvements in RV diastolic function were also observed in PH rats that received the paroxetine treatment.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
3: やや遅れている
理由
It was planned to conduct synchrotron x-ray diffraction experiments in the in situ beating rat heart to understand if the beneficial effects of paroxetine on RV function in PH is associated with changes at the level of the sarcomere. However, due to the COVID-19 global pandemic and the necessary restrictions, only limited access to SPring-8 Synchrotron (Hyogo, Japan) was offered in 2020. This precluded these experiments being conducted in FY2020 as per the experiment plan.
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| 今後の研究の推進方策 |
It is now planned to investigate if using the SSRI, paroxetine, can prevent the development of RV dysfunction throughout the development of PH. To achieve this, a prevention study will be conducted whereby rats will receive paroxetine from the time that PH is induced until the end of the study.
Moreover, biochemical analysis of RV tissues will continue to establish if paroxetine treatment in the intervention study exhibited any beneficial effects directly upon the RV myofilaments (e.g. increase in phosphorylation or reduction of oxidative modifications) or other processes within the cardiomyocytes such as energetics, metabolism or calcium handling. Analysis of lung tissue will also be conducted to establish if paroxetine could also reduce lung remodelling, inflammation and vasoconstrictor factors that are associated with the initiation and progression of PH.
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| 次年度使用額が生じた理由 |
Funds were reserved for travel and SPring-8 experiments that could not be conducted in FY2020 due to the impact of the COVID-19 pandemic. The remaining funds will be utilised in FY2021 to support SPring-8 experiments (pending approval for access) in addition to further biochemical analysis of rat heart and lung tissues collected during FY2020.
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