the correlation of serotonin receptor and bladder remodeling in clinical stage of partial bladder outlet obstruction

• Project/Area Number: 17K16767
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: University of Yamanashi (2019); Hokkaido University (2017-2018)
• Principal Investigator: KAKIBUCHI Yukiko 山梨大学, 大学院総合研究部, 臨床助教 (70735183)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 下部尿路閉塞膀胱 / セロトニン受容体 / 夜間頻尿 / サーカディアンリズム / 神経因性膀胱 / 前立腺肥大症 / 膀胱虚血 / 膀胱リモデリング / 日内リズム / α１ブロッカー / 下部尿路閉塞 / 膀胱の線維化 / ナフトピジル / 膀胱機能 / 下部尿路症状 / メタボリックシンドローム

Outline of Final Research Achievements

We reproduced benign prostate hyperplasia (BPH) with partial bladder outlet obstruction(pBOO) mice. The increase in inactive-period micturition frequency was observed in pBOO mice compared to intact mice. And micturition frequency of inactive-period was significantly decreased in pBOO + NAF group compared to pBOO.The mRNA-expression levels of 5-HT2A was significantly decreased in pBOO mice compared to intact mice (p < 0.05), which was canceled by long-termed naftopidil administration.
Naftopidil behaves as 5-HT2 antagonists and this phenomenon could be the certain background mechanisms of relieving storage symptoms in BPH patient.

Academic Significance and Societal Importance of the Research Achievements

我が国の超高齢化社会への変容に伴い、加齢性に排尿蓄尿障害を呈する疾患である前立腺肥大症に悩む人口は将来的に増加すると予想される。本研究では、長期の部分的下部尿路閉塞状態が排尿の日内リズムにどのような変化を及ぼすか、また、前立腺肥大症の国産治療薬の一つであるナフトピジルの長期投与によってその変化をどのようなメカニズムで改善させるかに主眼を置いた研究であり、社会的にも国民へ貢献できたと考える。
学術的には、長期の下部尿路閉塞状態、治療薬の長期投与での経過を追った基礎的研究は数少なく、その点についても評価されうると考える。

Research Products

• [Journal Article] Dopaminergic urethral closure mechanisms in a rat model of Parkinson's disease. (2019)
  • Author(s): Ouchi M, Kitta T, Kanno Y, Higuchi M, Togo M, Takahashi Y, Moriya K, Shinohara N.
  • Journal Title: Neurourol Urodyn. Volume: - Issue: 5 Pages: 1203-1211
  • DOI: 10.1002/nau.23989
  • Peer Reviewed
• [Journal Article] Risk factors affecting post-pubertal high serum follicle-stimulating hormone in patients with hypospadias. (2019)
  • Author(s): Moriya K, Nakamura M, Kon M, Nishimura Y, Kanno Y, Kitta T, Shinohara N.
  • Journal Title: World J Urol. Volume: - Issue: 12 Pages: 2795-2799
  • DOI: 10.1007/s00345-019-02687-w
  • Peer Reviewed / Open Access
• [Journal Article] Long-term Outcome of Adenosine A2A Receptor Antagonist on Lower Urinary Tract Symptoms in Male Parkinson Disease Patients. (2018)
  • Author(s): Kitta T, Yabe I, Kanno Y, Higuchi M, Ouchi M, Togo M, Moriya K, Takahashi I, Matsushima M, Sasaki H, Shinohara N.
  • Journal Title: Clin Neuropharmacol Volume: 41 Issue: 3 Pages: 98-102
  • DOI: 10.1097/wnf.0000000000000281
  • Peer Reviewed / Open Access
• [Journal Article] Effect of a 5-HT2c receptor agonist on urethral closure mechanisms in female rats. (2018)
  • Author(s): Ouchi Mifuka, Kitta Takeya, Kanno Yukiko, Higuchi Madoka, Togo Mio, Moriya Kinmihiko, Sinohara Nobuo
  • Journal Title: Neurourol Urodyn. Volume: - Issue: 8 Pages: 2382-2388
  • DOI: 10.1002/nau.23586
  • Peer Reviewed / Open Access
• [Journal Article] Benefits and limitations of animal models in partial bladder outlet obstruction for translational research (2017)
  • Author(s): Kitta Takeya、Kanno Yukiko、Chiba Hiroki、Higuchi Madoka、Ouchi Mifuka、Togo Mio、Moriya Kimihiko、Shinohara Nobuo
  • Journal Title: Int J Urol. Volume: 25 Issue: 1 Pages: 36-44
  • DOI: 10.1111/iju.13471
  • Peer Reviewed / Open Access
• [Presentation] Long-term administration of alpha-1 blocker reverses the micturition pattern in bladder outlet obstruction mice (2019)
  • Author(s): Kitta T, Chiba H, Kanno Y, Shinohara N et al.
  • Organizer: the 49th International Continence Society Annual Meeting
  • Int'l Joint Research
• [Presentation] 長期間の下部尿路閉塞は夜間頻尿とメタボリックシンドロームを惹起する (2019)
  • Author(s): 千葉博基、橘田岳也、垣渕由岐子、篠原信雄ら
  • Organizer: 第84回日本泌尿器科学会東部総会
• [Presentation] Bladder outlet obstruction causes nocturia and metabolic syndrome in mice. (2019)
  • Author(s): Chiba H, Kitta T, Kanno Y, Shinohara N et al.
  • Organizer: the 49th International Continence Society Annual Meeting
  • Int'l Joint Research
• [Presentation] .Long-term administration of alpha-1 blocker reverses the micturition pattern in bladder outlet obstruction mice. (2019)
  • Author(s): Kitta T, Kanno Y, Higuchi M, Ouchi M, Moriya K, Shinohara N
  • Organizer: 49th International Continence Society annual meeting
  • Int'l Joint Research
• [Presentation] 下部尿路閉塞は排尿における日内リズムを障害する (2017)
  • Author(s): 発表者名 菅野由岐子、橘田岳也、樋口まどか、築山 真由子、大内みふか、東郷未緒、西村陽子、中村美智子、守屋仁彦、篠原信雄
  • Organizer: 第24回日本排尿機能学会総会