Are ATP, PG and NGF released from the urethral epithelium key mediator to develop overactive bladder?

• Project/Area Number: 21659371
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Urology
• Research Institution: University of Fukui
• Principal Investigator: TANASE Kazuya 福井大学, 医学部・附属病院, 助教 (00359720)
• Co-Investigator(Kenkyū-buntansha): AKINO Hironobu 福井大学, 医学部, 准教授 (90159335) ; YOKOYAMA Osamu 福井大学, 医学部, 教授 (90242552) ; KUSUKAWA Naoya 福井大学, 医学部, 助教 (80372499) ; WATANABE Nozomu 福井大学, 医学部附属病院, 医員 (80572429) ; 松田 陽介 福井大学, 医学部, 助教 (90345687)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥3,180,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥180,000); Fiscal Year 2011: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2010: ¥600,000 (Direct Cost: ¥600,000); Fiscal Year 2009: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: 前立腺肥大症 / 混合性尿失禁 / 尿道上皮 / ATP / Prostaglandin / α_1遮断薬 / COX inhibitor / EP遮断薬 / 過活動膀胱 / 尿道 / 上皮細胞 / 知覚神経 / prostaglandin / 下部尿路 / mediator

Research Abstract

Stretch-induced release of some mediators from the urethral epithelium may play an important role in the induction of detrusor overactivity in patients with mixed incontinence or bladder outlet obstruction. In the present study, we evaluated whether the urethral epithelium was capable of synthesizing and releasing mediators in response to urethral distension. The ATP releases elicited by urethral distension for three minutes increased significantly, reaching13 times as much as those at baseline. The PGE_2 release also increased significantly, 7 times as much as those at baseline. The nonselective COX inhibitor ketoprofen significantly suppressed ATP release by 64% and PGE_2 release by 51%. Therefore, there is a possibility that mediators released from the urethra participate in the development of detrusor overactivity. PGE_2 release was not influented by both of EP1 antagonist ONO-8711 or EP3 antagonist ONO-AE5-599. However they significantly suppressed ATP release. Intraurethral or in travenous administration of a1-blocker tamsulosin did not suppress ATP or PGE_2 release from the urethra.
In BOO rats ; the ATP release elicited by urethral distension increased reaching 2 times as much as those at baseline. The PGE_2 release also increased reaching 6 times as much as those at baseline. As compared with the normal rats, the ATP release of BOO rats were decreased significantly. A similar trend was observed for the PGE_2 release, but not significantly. As compared with the normal rats, the ATP release of BOO rats were significantly decreased. A similar trend was observed for the PGE_2 release, but without significance. Intraurethral administration of tamsulosin did not suppress the increase in ATP or PGE_2 release from the urethral epithelium.
Although a1-blocker has been reported to suppress detrusor overactivity via inhibition of urethral afferent nerves, the underlying mechanism did not depend on mediators from the urethral urothelium. COX inhibitors decreased ATP release from the urethelium, suggesting that there was an interaction between ATP and PGE_2. COX inhibitors may become a new therapeutic strategy for patients with OAB caused by the incompetent urethra.

Research Products

• [Journal Article] Metabolic syndrome and nocturia (2012)
  • Author(s): Aoki Y, Yokoyama O
  • Journal Title: LUTS Volume: 4 Issue: s1 Pages: 11-15
  • DOI: 10.1111/j.1757-5672.2011.00118.x
  • Peer Reviewed
• [Journal Article] IPSS is lower in hypertensive patients treated with angiotensin-II receptor blocker : posthoc analyses of a lower urinary tract symptoms population (2012)
  • Author(s): Ito H, Taga M, Tsuchiyama K, Akino H, Yokoyama O
  • Journal Title: Neurourol Urodyn Volume: (in press)
  • Peer Reviewed
• [Journal Article] Male LUTS : hypertension as a risk factor for storage symptoms, but not voiding symptoms (2012)
  • Author(s): Ito H, Yoshiyasu T, Yamaguchi O, Yokoyama O.
  • Journal Title: LUTS Volume: (in press) Issue: 2 Pages: 68-72
  • DOI: 10.1111/j.1757-5672.2011.00115.x
  • Peer Reviewed
• [Journal Article] Co-administration of anα(1)-blocker improves the efficacy and safety of antimuscarinic agents in rats with detrusor overactivity (2011)
  • Author(s): Nagase K, Ito H, Aoki Y, Tanase K, Akino H, Yokoyama O
  • Journal Title: Int J Urol Volume: 836-843 Issue: 12 Pages: 18-18
  • DOI: 10.1111/j.1442-2042.2011.02868.x
  • Peer Reviewed
• [Journal Article] Responsiveness and minimal clinically important change in overactive bladder symptom score (2011)
  • Author(s): Gotoh M, Homma Y, Yokoyama O, Nishizawa O
  • Journal Title: Urology Volume: 78 Issue: 4 Pages: 768-773
  • DOI: 10.1016/j.urology.2011.06.020
  • Peer Reviewed
• [Journal Article] Outline of JUA clinical guidelines for benign prostatic hyperplasia (2011)
  • Author(s): Homma Y, Gotoh M, Yokoyama O, Masumori N, Kawauchi A, Yamanishi T, Ishizuka O, Seki N, Kamoto T, Nagai A, Ozono S
  • Journal Title: Int J Urol Volume: 18 Pages: 741-756
  • NAID: 10031164869
  • Peer Reviewed
• [Journal Article] Efficacy of solifenacin on nocturia in Japanese patients with overactive bladder : impact on sleep evaluated by bladder diary (2011)
  • Author(s): Yokoyama O, Yamaguchi O, Kakizaki H, Itoh N, Yokota T, Okada H, Ishizuka O, Ozono S, Gotoh M, Sugiyama T, Seki N, Yoshida M, Yamada S
  • Journal Title: J Urol Volume: 186 Issue: 1 Pages: 170-174
  • DOI: 10.1016/j.juro.2011.02.2700
  • Peer Reviewed
• [Journal Article] ASSIST Study Group. Solifenacin as Add-on Therapy for Overactive Bladder Symptoms in Men Treated for Lower Urinary Tract Symptoms-ASSIST (2011)
  • Author(s): Yamaguchi O, Kakizaki H, Homma Y, Takeda M, Nishizawa O, Gotoh M, Yokoyama O, Seki N, Yoshida M
  • Journal Title: Randomized Controlled Study. Urology Volume: 78 Issue: 1 Pages: 126-133
  • DOI: 10.1016/j.urology.2011.02.055
  • Peer Reviewed
• [Journal Article] Antimuscarinics suppress adenosine triphosphate and prostaglandin E2 release from urothelium with potential improvement in detrusor overactivity in rats with cerebral infarction (2011)
  • Author(s): Yokoyama O, Tanaka I, Kusukawa N, Yamauchi H, Ito H, Aoki Y, Oyama N, Miwa Y, Akino H
  • Journal Title: J Urol Volume: 185 Issue: 6 Pages: 2392-2397
  • DOI: 10.1016/j.juro.2011.02.048
  • Peer Reviewed
• [Journal Article] alpha(1)-Adrenoceptor blocker naftopidil improves sleep disturbance with reduction in nocturnal urine volume (2011)
  • Author(s): Yokoyama O, Aoki Y, Tsujimura A, Takao T, Namiki M, Okuyama
  • Journal Title: World J Urol Volume: 29 Issue: 2 Pages: 233-238
  • DOI: 10.1007/s00345-010-0544-4
  • Peer Reviewed
• [Journal Article] Modulation of Stretch-evoked Adenosine Triphosphate Release from the Bladder Epithelium by Prostaglandin E_2 (2011)
  • Author(s): Tanaka I, Nagase K, Tanase K, Aoki Y, Akino H, Yokoyama O
  • Journal Title: J Urol Volume: 185 Issue: 1 Pages: 341-341
  • DOI: 10.1016/j.juro.2010.09.042
  • Peer Reviewed
• [Journal Article] Propiverine hydrochloride in Japanese patients with overactive bladder : a randomized, double-blind, placebo-controlled trial (2011)
  • Author(s): Gotoh M, Yokoyama O, Nishizawa O
  • Journal Title: Int J Urol Volume: 18 Issue: 5 Pages: 365-373
  • DOI: 10.1111/j.1442-2042.2011.02732.x
  • NAID: 10030822672
  • Peer Reviewed
• [Journal Article] Modulation of stretch evoked ATP release from bladder epithelium by prostaglandin E2. (2011)
  • Author(s): Tanaka I, Nagase K, Tanase K, Aoki Y, Akino H, Yokoyama O
  • Journal Title: J Urol Volume: 185 Pages: 341-346
  • Peer Reviewed
• [Journal Article] Propiverine hydrochloride in Japanese patients with overactive bladder : a randomized, double-blind, placebo-controlled trial. (2011)
  • Author(s): Gotoh M, Yokoyama O, Nishizawa O
  • Journal Title: Int J Urol Volume: (In press)
  • NAID: 10030822672
  • Peer Reviewed
• [Journal Article] Efficacy of solifenacin on nocturia in Japanese patients with overactive bladder : impact on sleep evaluated by bladder diary (2011)
  • Author(s): Yokoyama O, Yamaguchi O, Kakizaki H, Itoh N, Yokota T, Okada H, Ishizuka O, Ozono S, Gotoh M, Sugiyama T, Seki N, Yoshida M, Yamada S.
  • Journal Title: J Urol Volume: (In press)
  • Peer Reviewed
• [Journal Article] Pharmacologic and Genetic Analysis of Mechanisms Underlying Detrusor overactivity in rats (2010)
  • Author(s): Yokoyama O
  • Journal Title: Neurourol Urodyn Volume: 29 Issue: 1 Pages: 107-111
  • DOI: 10.1002/nau.20746
  • Peer Reviewed
• [Journal Article] Influence of Urethral Sphincter Incompetence on Bladder Shape and Function in Myelodysplastic Children (2010)
  • Author(s): Yokoyama O, Ito H, Namiki M
  • Journal Title: LUTS Volume: 2 Issue: 1 Pages: 27-30
  • DOI: 10.1111/j.1757-5672.2010.00056.x
  • Peer Reviewed
• [Journal Article] Selectiveα1A-blocker improves bladder storage function in rats via suppression of C-fiber afferent activity (2010)
  • Author(s): Yokoyama O, Ito H, Aoki Y, Oyama N, Miwa Y, Akino H
  • Journal Title: World J Urol Volume: 28 Issue: 5 Pages: 609-14
  • DOI: 10.1007/s00345-009-0481-2
  • Peer Reviewed
• [Journal Article] Zolpidem increases bladder capacity and decreases urine excretion in rats (2010)
  • Author(s): Yokoyama O, Matsuta Y, Yanai-Inamura H, Watanabe M, Ohtake A, , Suzuki M, Sasamata M
  • Journal Title: Neurourol Urodyn Volume: 29 Issue: 4 Pages: 107-111
  • DOI: 10.1002/nau.20797
  • Peer Reviewed
• [Journal Article] Urinary Prostaglandin E(2) was increased in patients with suprapontine brain diseases, and associated with overactive bladder syndrome (2010)
  • Author(s): Yamauchi H, Akino H, Ito H, Aoki Y, Nomura T, Yokoyama O
  • Journal Title: Urology Volume: 76(5) Issue: 5 Pages: 1267-1267
  • DOI: 10.1016/j.urology.2010.06.012
  • Peer Reviewed
• [Journal Article] Melatonin increases bladder capacity via GABAergic system and decreases urine volume in rats (2010)
  • Author(s): Matsuta Y, Yusup A, Tanase K, Ishida H, Akino H, Yokoyama O
  • Journal Title: J Urol Volume: 184 Issue: 1 Pages: 386-91
  • DOI: 10.1016/j.juro.2010.03.002
  • Peer Reviewed
• [Journal Article] Improvement of non-inflamatory detrusor overactivity through supressionof peripheral C-fiber by cyclooxygenase inhibitors (2010)
  • Author(s): Tanaka I, Nagase K, Tanase K, Aoki Y, Akino H, Yokoyama O
  • Journal Title: J Urol Volume: 183 Issue: 2 Pages: 786-792
  • DOI: 10.1016/j.juro.2009.09.071
  • Peer Reviewed
• [Journal Article] A. alpha(1)-Adrenoceptor blocker naftopidil improves sleep disturbance with reduction in nocturnal urine volume. (2010)
  • Author(s): Yokoyama O, Aoki Y, Tsujimura A, Takao T, Namiki M, Okuyama
  • Journal Title: World J Urol Volume: 29 Pages: 233-238
  • Peer Reviewed
• [Journal Article] Improvement of non-inflammatory detrusor overactivity through suppression of peripheral C-fiber by cyclooxygenase inhibitors (2010)
  • Author(s): Tanaka I, Nagase K, Tanase K, Aoki Y, Akino H, Yokoyama O.
  • Journal Title: J Urol 183 Pages: 786-792
  • Peer Reviewed
• [Journal Article] Animal model with detrusor overactivity caused by cerebral infarction as a useful tool for pharmacological therapeutic approaches (2009)
  • Author(s): Yokoyama O, Ishiura Y, Nakamura Y
  • Journal Title: LUTS Volume: 1 Issue: s1
  • DOI: 10.1111/j.1757-5672.2009.00042.x
  • Peer Reviewed
• [Journal Article] Neurogenic Bladder Society Clinical guidelines for overactive bladder (2009)
  • Author(s): Yamaguchi O, Nishizawa O, Takeda M, Yokoyama O, Homma Y, Kakizaki H, Obara K, Gotoh M, Igawa Y, Seki N, Yoshida M
  • Journal Title: Int J Urol Volume: 16 Issue: 2 Pages: 126-42
  • DOI: 10.1111/j.1442-2042.2008.02177.x
  • Peer Reviewed
• [Journal Article] Clinical guideline for male lower urinary tract symptoms (2009)
  • Author(s): Homma Y, Araki I, Igawa Y, Ozono S, Gotoh M, Yamanishi T, Yokoyama O, Yoshida M
  • Journal Title: Int J Urol Volume: 16(10) Issue: 10 Pages: 775-790
  • DOI: 10.1111/j.1442-2042.2009.02369.x
  • NAID: 10025617982
  • Peer Reviewed
• [Journal Article] 前立腺生検前の3T-MRI診断の有用性に関する検討 (2009)
  • Author(s): 大山伸幸, 棚瀬和弥, 黒川哲之, 多賀峰克, 横川竜生, 楠川直也, 金田大生, 前川正信, 伊藤秀明, 青木芳隆, 三輪吉司, 秋野裕信, 横山修
  • Journal Title: 泌尿器外科 22 Pages: 1067-1068
• [Presentation] Effects of alphal-blocker on the release of ATP and prostaglandin E2 from the urethral epithelium in BOO rats (2011)
  • Author(s): Nagase K, Tanaka I, Zha X, Kusukawa, N, Ito H, Aoki Y, Oyama N, Miwa Y, Akino H, Yokoyama O
  • Organizer: 41st Annual Meeting of the International Continence Society
  • Place of Presentation: Glasgow, UK(招待講演)
  • Year and Date: 2011-09-01
• [Presentation] Treatment satisfaction with antimuscarinics in male patients with overactive bladder (2011)
  • Author(s): Yokoyama O
  • Organizer: 6^<th> Japan-Asean Conference on Men's Health and Aging
  • Place of Presentation: Kamakura, Japan
  • Year and Date: 2011-07-01
• [Presentation] Epidemiology in men's health (2010)
  • Author(s): Yokoyama O
  • Organizer: 5^<th> Japan-Asean Conference on Men's Health and Aging
  • Place of Presentation: Kota Kinabalu, Malaysia
  • Year and Date: 2010-07-09
• [Presentation] Epidemiology for men' s health (2010)
  • Author(s): Yokoyama O
  • Organizer: 2010APSSAM
  • Place of Presentation: Kota Kinabaru, Malaysia
  • Year and Date: 2010-07-09
• [Presentation] Understanding the Science (2009)
  • Author(s): Yokoyama O
  • Organizer: 30th Congress of the Societe Internationale d' Urologie, Counting the Cost of OAB and Its Burden on Society
  • Place of Presentation: Shanghai(CHN)
  • Year and Date: 2009-11-03
• [Presentation] Relationship between nocturia and metabolic syndrome (2009)
  • Author(s): Aoki Y, Kusukawa N, Matsuta Y, Maegawa M, Tanase K, Ito H, Oyama N, Miwa Y, Akino H, Yokoyama O
  • Organizer: International Continence Society 39th Annual Meeting
  • Place of Presentation: San Francisco(USA)
  • Year and Date: 2009-10-03
• [Presentation] 下部尿路症状とメタボリック症候群との関連について (2009)
  • Author(s): 横山修
  • Organizer: 第16回日本排尿機能学会,ランチョンセミナー1
  • Place of Presentation: 福岡
  • Year and Date: 2009-10-03
• [Presentation] The effect of atropine on spontaneous contractions in bladder strips from rats ; effect of the mucosa and bladder and outlet obstruction (2009)
  • Author(s): H.Akino, I.Tanaka, M.Maegawa, N.Watanabe, N.Oyama, Y.Miwa, O.Yokoyama
  • Organizer: International Continence Society 39th Annual Meeting
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2009-10-01
• [Presentation] Mwchanical distension of the urethra induces a release of ATP/PGE2 from the epithelium (2009)
  • Author(s): K.Nagase, I.Tanaka, Zha.X, N.Kusukawa, H.Ito, Y.Aoki, N.Oyama, Y.Miwa, H.Akino, O.Yokoyama
  • Organizer: International Continence Society 39th Annual Meeting
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2009-10-01
• [Presentation] Serotonin the spine is associated with bladder hypersensitivity caused by estrogen deficiency in rats (2009)
  • Author(s): K.Tanase, K.Nagase, Zha.X, I.Tanaka, M.Maegawa, R.Yokogawa, Y.Aoki, N.Oyama, Y.Miwa, H.Akino, O.Yokoyama
  • Organizer: International Continence Society 39th Annual Meeting
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2009-10-01
• [Presentation] Suppression of the strech-evoked ATP and PGE2 release from the bladder urothelium by cyclooxygenase inhibitors (2009)
  • Author(s): I.Tanaka, K.Nagase, M.Maegawa, Y.Aoki, H.Akino, O.Yokoyama
  • Organizer: International Continence Society 39th Annual Meeting
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2009-10-01
• [Presentation] Erectile dysfunction and lower urinary tract symptoms : possible pathophysiological relation to vascular function (2009)
  • Author(s): Yokoyama O
  • Organizer: 4th Japan and Korea Satellite Symposium
  • Place of Presentation: Toyama
  • Year and Date: 2009-07-02
• [Presentation] Is female nocturia associated with metabolic syndrome? (2009)
  • Author(s): Aoki Y, Takahara N, Tanase K, Ito H, Oyama N, Miwa Y, Akino H, Yokoyama O
  • Organizer: 2009 Annual Meeting of American Urological Association
  • Place of Presentation: Chicago(USA)
  • Year and Date: 2009-04-28
• [Presentation] What is the most valuable mediator secreted from the urothelium of the urinary bladder in patients with neurogenic overactive bladder? (2009)
  • Author(s): Yamauchi H, Ito H, Aoki Y, Akino H, Yokoyama O, Nomura T
  • Organizer: 2009 Annual Meeting of American Urological Association
  • Place of Presentation: Chicago(USA)
  • Year and Date: 2009-04-07