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The effect of Arginine/Citrulline administration on detrusor underactivity

Research Project

Project/Area Number 21K09417
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56030:Urology-related
Research InstitutionUniversity of Yamanashi

Principal Investigator

MITSUI Takahiko  山梨大学, 大学院総合研究部, 教授 (90421966)

Co-Investigator(Kenkyū-buntansha) 澤田 智史  山梨大学, 大学院総合研究部, 准教授 (70402055)
井原 達矢  山梨大学, 大学院総合研究部, 医学研究員 (90622407)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords慢性虚血 / シトルリン / アルギニン / 一酸化窒素 / 膀胱機能 / 過活動膀胱 / 低活動膀胱 / 下部尿路症状 / 排尿筋低活動 / ミトコンドリア
Outline of Research at the Start

下部尿路症状(LUTS)の病態の一つである排尿筋低活動は、有効な治療法がないのが現状である。本研究では、LUTS患者のメタボロミクス解析で関与が示唆された一酸化窒素合成に関与しているシトルリン(Cit)、アルギニン(Arg)の投与によって、排尿筋低活動に与える影響とその機序について明らかにする。
研究方法として、排尿筋低活動モデルを作成し、Cit‐Arg経路の活性化によるNOを介した排尿筋低活動への予防および治療効果、その機序として膀胱平滑筋におけるミトコンドリア機能の影響、膀胱上皮における圧受容体への作用を明らかにする。本研究の結果はLUTSにおける新規治療薬の開発の端緒となると考えられる。

Outline of Final Research Achievements

We have been conducting research under the assumption that the anti-inflammatory effects of citrulline-arginine (CitArg) mediated by NO may prevent the progression to underactive bladder. In a study of male rats in a control group and a chronic ischemia group, frequent urination was observed in cystometry and a decrease in the contractile force of bladder smooth muscle tissue was observed in experiments. These results indicate overactive bladder as well as detrusor underactivity. In the group administered CitArg to chronic ischemia, frequent urination was improved in cystometry. However, we were unable to establish an underactive bladder model by administering L-NAME to the chronic ischemia group. We hope to continue pioneering new approaches to the treatment of the pathology of underactive bladder.

Academic Significance and Societal Importance of the Research Achievements

超高齢社会を迎えた本邦では、下部尿路症状(LUTS)患者に対する治療の必要性が高くなっている。特にLUTSの原因の一つである排尿筋低活動の病態は多岐にわたり、有効な治療法がないのが現状である。過活動膀胱は病態が慢性的な虚血が進展すると低活動膀胱に移行するという病態が想定されている。本研究の結果は、シトルリン・アルギニンの投与によって排尿状態の改善が明らかとなっており、現状では治療法が確立していない排尿筋低活動の新規治療法の可能性を示唆するものである。現状では、十分な検討はできなかったが、今後も研究を続けることで低過活動膀胱の病態への新たな治療のアプローチを切り拓いていけると考えている。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (32 results)

All 2024 2023 2022 2021

All Journal Article (14 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 9 results,  Open Access: 6 results) Presentation (17 results) (of which Int'l Joint Research: 7 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Factors associated with symptomatic urinary tract infection in persons with spinal cord lesions who perform clean intermittent catheterization with single‐use catheters2024

    • Author(s)
      Sekido Noritoshi、Takahashi Ryosuke、Matsuyama Fujio、Murata Tatsunori、Matsuoka Mihoko、Sengoku Atsushi、Nomi Masashi、Kitta Takeya、Mitsui Takahiko
    • Journal Title

      LUTS: Lower Urinary Tract Symptoms

      Volume: 16 Issue: 3

    • DOI

      10.1111/luts.12515

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Optogenetic stimulation of neurons in the anterior cingulate cortex induces changes in intravesical bladder pressure and the micturition reflex2024

    • Author(s)
      Mochizuki Takanori、Manita Satoshi、Shimura Hiroshi、Kira Satoru、Sawada Norifumi、Bito Haruhiko、Sakimura Kenji、Augustine George J.、Mitsui Takahiko、Takeda Masayuki、Kitamura Kazuo
    • Journal Title

      Scientific Reports

      Volume: 14 Issue: 1 Pages: 6367-6367

    • DOI

      10.1038/s41598-024-56806-8

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Prevalence and impact on daily life of lower urinary tract symptoms in Japan: Results of the 2023 Japan Community Health Survey (<scp>JaCS</scp> 2023)2024

    • Author(s)
      Mitsui Takahiko、Sekido Noritoshi、Masumori Naoya、Haga Nobuhiro、Omae Kenji、Saito Motoaki、Kubota Yasue、Sakakibara Ryuji、Yoshida Mikako、Takahashi Satoru
    • Journal Title

      International Journal of Urology

      Volume: in press Issue: 7 Pages: 747-754

    • DOI

      10.1111/iju.15454

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Heterogeneity of Hippo signaling activity in different histopathological subtypes of renal cell carcinoma2023

    • Author(s)
      Duong NX, Le M, Kondo T, Mitsui T
    • Journal Title

      Journal of Cellular and Molecular Medicine

      Volume: 27 Issue: 1 Pages: 66-75

    • DOI

      10.1111/jcmm.17632

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cross-sectional internet survey exploring symptomatic urinary tract infection by type of urinary catheter in persons with spinal cord lesion in Japan2023

    • Author(s)
      Sekido N, Matsuoka M, Takahashi R, Sengoku A, Nomi M, Matsuyama F, Murata T, Kitta T, Mitsui T
    • Journal Title

      Spinal Cord Series and Cases

      Volume: 9 Issue: 1 Pages: 3-8

    • DOI

      10.1038/s41394-023-00559-5

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Diagnosis and treatment of Japanese children with neurogenic bladder: Analysis of data from a national health insurance database2023

    • Author(s)
      Kitta T, Mitsui, T, Izumi N
    • Journal Title

      Journal of Clinical Medicine

      Volume: 12 Issue: 9 Pages: 3191-3203

    • DOI

      10.3390/jcm12093191

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
  • [Journal Article] The prevalence and predictive factors of nocturnal polyuria in Japanese patients with nocturia: a multicentral retrospective cohort study2023

    • Author(s)
      Iinuma Koji、Nishino Yoshinori、Matsuoka Kanako、Ihara Tatsuya、Makabe Shunta、Tanji Ryo、Harigane Yuki、Ishida Kenichiro、Tamaki Masayoshi、Yokoi Shigeaki、Hoshino Hiroki、Yuhara Kazuya、Yamada Toru、Kubota Yasuaki、Miwa Kousei、Kikuchi Mina、Kojima Yoshiyuki、Mitsui Takahiko、Koie Takuya
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 18128-18135

    • DOI

      10.1038/s41598-023-45311-z

    • Related Report
      2023 Annual Research Report
  • [Journal Article] G protein-coupled receptor 55 activated by palmitoylethanolamide is associated with the development of nocturia associated with circadian rhythm disorders2023

    • Author(s)
      Ihara Tatsuya、Shinozaki Youichi、Shigetomi Eiji、Danjo Yosuke、Tsuchiya Sachiko、Kanda Mie、Kamiyama Manabu、Takeda Masayuki、Koizumi Schuichi、Mitsui Takahiko
    • Journal Title

      Life Sciences

      Volume: 332 Pages: 122072-122072

    • DOI

      10.1016/j.lfs.2023.122072

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Importance of Regular Examination and Follow-up in Pediatric Patients with Neurogenic Bladder: 24-Month Follow-up Study Using a Japanese Health Insurance Database2023

    • Author(s)
      Izumi Naoko、Kitta Takeya、Mitsui Takahiko
    • Journal Title

      Advances in Therapy

      Volume: 40 Issue: 12 Pages: 5519-5535

    • DOI

      10.1007/s12325-023-02692-x

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Effects of fatty acid metabolites on nocturia2022

    • Author(s)
      106.Ihara T, Shimura H, Tsuchiya S, Kanda M, Kira S, Sawada N, Takeda M, Mitsui T, Shigetomi E, Shinozaki Y, Koizumi S
    • Journal Title

      Sci Rep

      Volume: 12 Issue: 1 Pages: 3050-3050

    • DOI

      10.1038/s41598-022-07096-5

    • Related Report
      2022 Research-status Report 2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Outcomes of artificial urinary sphincter implantation in patients with diabetes mellitus: A subgroup analysis2022

    • Author(s)
      Kaiho Y, Masuda H, Takei M, Hirayama T, Kitta T, Yokoyama M, Kawamorita N, Mitsui T, Nakagawa H, Iwamura M, Arai Y
    • Journal Title

      Int J Urol

      Volume: 29 Issue: 12 Pages: 1498

    • DOI

      10.1111/iju.15025

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mirabegron for overactive bladder in frail patients 80 years or over (HOKUTO study)2022

    • Author(s)
      105.Nakagomi H., Mitsui T, Shimura H, Ihara T, Kira S, Sawada N, Takeda M
    • Journal Title

      BMC Urology

      Volume: 22 Issue: 1 Pages: 40-40

    • DOI

      10.1186/s12894-022-00989-7

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Different effects of GsMTx4 on nocturia associated with the circadian clock and Piezo1 expression in mice2021

    • Author(s)
      Tatsuya Ihara, Takahiko Mitsui, Hiroshi Shimura, SachikoTsuchiya, Mie Kanda, Satoru Kira, Hiroshi Nakagomi, Norifumi Sawada, Manabu Kamiyama, Eiji Shigetomi, Yoichi Shinozaki, Schuichi Koizumi, Masayuki Takeda
    • Journal Title

      Life Sciences

      Volume: 278 Pages: 119555-119555

    • DOI

      10.1016/j.lfs.2021.119555

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The effects of the prenatal environment on cryptorchidism: a narrative review2021

    • Author(s)
      Mitsui T
    • Journal Title

      Int J Urol

      Volume: 28 Issue: 9 Pages: 882-889

    • DOI

      10.1111/iju.14600

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] Type 2 diabetes mellitus mice present an alterd inhibitory control of the forebrain in vuluntary voiding behaviorand an enhanced symtathetic modulation in detrusor relaxation2023

    • Author(s)
      Yoshiyama M, et al
    • Organizer
      ICS 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Diagnosis and treatment in Japanese patients with pediatric neurogenic bladder: 12 months follow-up Data from health insurance database2023

    • Author(s)
      Mitsui T, et al
    • Organizer
      ICS 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Two- photon calcium imaging uncovered individual micturition-related neural activities in the cerebral cortex2023

    • Author(s)
      Shimura H, et al
    • Organizer
      The 17th Pan-Pacific Continence Society Meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 前帯状皮質と一時運動野における排尿関連の神経活動は、場所、細胞タイプ、投射経路によって役割が異なる Micturition-related neural activity in the anterior cingulate cortex and the primary motor cortex depends on the location, cell-type, and projection pathway2023

    • Author(s)
      志村寛史ら
    • Organizer
      第110回日本泌尿器科学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 排尿における大脳皮質の神経活動の解明~個々の神経の種類・機能・経路の固定~2023

    • Author(s)
      志村寛史ら
    • Organizer
      第110回日本泌尿器科学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 山梨大学における骨盤臓器脱に対する腹腔鏡下仙骨膣固定術とロボット支援下仙骨室固定術の臨床的比較 Comparison of perioperative outcome between laparoscopic and robotic sacrocolpopexy for pelvic organ prolapse in University of Yamanashi Hospital2023

    • Author(s)
      葛西義史ら
    • Organizer
      第110回日本泌尿器科学会総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 小児の尿禁制獲得時期に関与する因子:縦断的コホート研究(エコチル調査より)2023

    • Author(s)
      志村寛史ら
    • Organizer
      第32回日本小児泌尿器科学会総会・学術集会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 2型糖尿病マウスは覚醒下自発講堂における変化した前脳排尿制御と排尿筋弛緩における増強した交換神経性調節を呈する2023

    • Author(s)
      芳山充晴ら
    • Organizer
      第30回日本排尿機能学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 山梨大学における難治性過活動膀胱に対するボツリヌス毒素膀胱壁内注入療法の成績2023

    • Author(s)
      澤田智史ら
    • Organizer
      第30回日本排尿機能学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 山梨大学における排尿自立支援の現状について2023

    • Author(s)
      望月孝規ら
    • Organizer
      第30回日本排尿機能学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 排尿における大脳皮質の神経活動の解明:個々の神経の種類・機能・経路の固定2023

    • Author(s)
      志村寛史ら
    • Organizer
      第88回日本泌尿器科学会東部総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Current topics in overactive bladder2021

    • Author(s)
      Mitsui T
    • Organizer
      The 37th Korea-Japan Urological Congress
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Therapeutic potential of cell-type selective optogenetics for a mouse model with urinary frequency.2021

    • Author(s)
      Shimura H, Mitsui T, et al.
    • Organizer
      ICS2021
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Importance of the ACC-PAG pathway in the micturition reflex2021

    • Author(s)
      Mochizuki T, Mitsui T, et al.
    • Organizer
      The 15th Pan-Pacific Continence Society Meeting
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Cine magnetic resonance imaging provides novel predictors of early recovery of continence after radical prostatectomy: Assessment of the dynamics of pelvic floor muscles2021

    • Author(s)
      Shimura H, Mitsui T, et al.
    • Organizer
      The 15th Pan-Pacific Continence Society Meeting
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] 前帯状皮質(ACC)から派生する大脳排尿経路の探索2021

    • Author(s)
      望月孝規、三井貴彦ら
    • Organizer
      第109回日本泌尿器科学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 頻尿モデルマウスへの 光遺伝学的治療の可能性2021

    • Author(s)
      志村寛史、三井貴彦ら
    • Organizer
      第109回日本泌尿器科学会総会
    • Related Report
      2021 Research-status Report
  • [Patent(Industrial Property Rights)] 特許第7031104号2021

    • Inventor(s)
      吉良聡、井原達矢、三井貴彦、武田正之、中込宙史、橋本由佳
    • Industrial Property Rights Holder
      国立大学法人 山梨大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2021
    • Acquisition Date
      2022
    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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