2021 Fiscal Year Final Research Report
Mutual adjustment of autonomic nervous system and nitric oxide biosynthesis via tetrahydrobiopterin
| Project/Area Number |
19K07331
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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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| Review Section |
Basic Section 48030:Pharmacology-related
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| Research Institution | Fujita Health University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | テトラヒドロビオプテリン / セピアプテリン還元酵素 / 持続勃起症 (Priapism) / チロシン水酸化酵素 / 一酸化窒素 / 自律神経 |
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| Outline of Final Research Achievements |
Sepiapterin reductase gene disrupted (Spr-/-) mice suffer from severe priapism. The total biopterin, tetrahydrobiopterin (BH4), and norepinephrine (NE) contents and the tyrosine hydroxylase (TH) protein level in the penile homogenate of Spr-/- mice were significantly reduced compared with those in wild type (Spr+/+) mice. Neuronal nitric oxide (NO) synthase (nNOS) was increased and cGMP was greatly accumulated in Spr-/- mice with priapism. The symptom was relieved by repeated administration of BH4 accompanied by an increase in total biopterin, BH4, and NE. The TH protein level tended to increase, whereas NO metabolites were decreased. We conclude that priapism in Spr-/- mice is caused by sympathetic nervous system hypofunction, and NO/cGMP signaling disturbance from disinhibition of nNOS-containing neurons and/or abnormal catabolism of cyclic nucleotides is strongly suggested.
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| Free Research Field |
薬理学
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| Academic Significance and Societal Importance of the Research Achievements |
Spr-/-マウスで交感神経機能が低下する一方NO/cGMP系が亢進することは、BH4を通じて自律神経系とNO合成系の間に巧妙な調節が働くことを示唆する。BH4の反復投与でPriapismの緩解まで時間を要するのは、THたんぱく質量の増加だけでなくシナプスレベルでの変化が生じるためかもしれない。Priapismはヒトでは鎌状赤血球症の男性患者の約40%に合併するほか悪性腫瘍、脊髄損傷、向精神薬の副作用などで生じることがあるが、不明な点が多い。Spr-/-マウスは血流の維持される非虚血性Priapismのモデルであり、勃起不全症(ED)の治療法へのヒントを与える。
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