Single nucleotide polymorphism (SNP) in COX-2 promoter gene:roles in the prevention of overactive bladder caused by cerebro-vascular accident or bladder outlet obstruction

• Project/Area Number: 18390433
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: University of Fukui
• Principal Investigator: YOKOYAMA Osamu University of Fukui, Faculty of Medical Sciences, Professor (90242552)
• Co-Investigator(Kenkyū-buntansha): AOKI Yoshitaka University of Fukui, Faculty of Medical Sciences, Assistant Professor (30273006) ; YOKOTA Yoshifumi University of Fukui, Faculty of Medical Sciences, Professor (50222386) ; AKINO Hironobu University of Fukui, Faculty of Medical Sciences, Associate Professor (90159335) ; TANASE Kazuya University of Fukui, Hospital, Assistant Professor (00359720) ; KUSUKAWA Naoya University of Fukui, Hospital, Medical doctor (80372499) ; 中井 正治 福井大学, 医学部, 助手 (50372496)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥16,830,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥1,230,000); Fiscal Year 2007: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2006: ¥11,500,000 (Direct Cost: ¥11,500,000)
• Keywords: overactive bladder / COX-2 / single nucleotide polymorphism / prostaglandin / BPH / cerebral infarction / spinalcord injure / urinary incontinence

Research Abstract

It has been reported that a new variant in the COX-2 promoter, a guanine to cytosine substitution at -765 (-765G->C) is located within a putative binding site for the transcription factor Spl. The polymorphism of the COX-2 gene was found to associate with a decreased risk of myocardial infarction and stroke by reduction in PGE2 production. Previously we reported that PGE2 played an important role in neuron-plasticity in the brain and spine, which resulted in the development of OAB. Therefore, in BPH or stroke patients with -765GC genotype or -765CC genotype, development of OAR in believed to be diminished. In the present study, the patients with cerebrovascular accident, spinal lesion, or bladder outlet obstruction (BOO) were classified into two groups ; overactive bladder (OAB) group and non-overactive bladder (non-OAB) group according to the International Prostate symptom Score (IPSS)/OAB symptom score. Blood and urine samples were collected from all patients. Gemonic DNA was prepare d from blood and -765G->C variant was genotyped by restriction endonuclease digestion of the polymerase chain reaction product. Genotypes were determined. The level of prostaglandin E2 (PGE2) in the urine were analyzed with the severity of OAB. The results obtained in 2006 and 2007 were as follows;
1. The urine levels of PGE2 in patients with BOO were significantly higher than that in control.
2. The urine level of PGE2 in patients with cerebrovascular accident was correlated with severity of IPSS. The patients with high score of IPSS reveals high level of urine PGE2.
3. COX inhibitors dose-dependently inhibited detrusor overactivity caused by cerebral infarction in rats. This effect was dependent on suppression of C-fiver afferent nerves in the bladder.
4. Single nucleotide polymorphism (SNP) in COX-2 promoter gene was found in 3 out of 70 patients with OAB. The results will be presented at 2008 NBS annual meeting in Tokyo. We have to accumulate the samples to analyze the correlation between SNP and severity of OAB.
PGE2 excreted from the urothelium in response to bladder distension stimulates C-fiver afferent nerves, subsequently promoting detrusor overactivity. This mechanism seems to be true in patients with BOO. However, the levels of PGE2 were related with the severity of OAB in patients with cerebrovascular accidents. They were not proven to exist BOO. These results suggest that there might exist other underlying mechanisms to explain the role of PGE2 in OAB.

Research Products

• [Journal Article] Effects of antimuscarinics on voiding function after cerebral infarction in a rat model of overactive bladder. (2007)
  • Author(s): Yusup A, Akino H, Miwa Y, Oyama N Aoki Y, Ito H, Tanase K, Matsuta Y, Nakai M, Yokoyama O.
  • Journal Title: Eur J Pharmacol 577 Pages: 143-149
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Improvement of bladder storage function by tamusulosin depends on suppression of C-fiber urethral afferent activity in rats (2007)
  • Author(s): Yokoyama O, Yusup A Oyama Aoki Y, Miwa Y, Akino H.
  • Journal Title: J Urol 177 Pages: 771-775
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Antimuscarinic drug inhibits detrusor overactivity induced by topical application of prostaglandin e(2)to the urethra with a decrease in urethral pressure. (2007)
  • Author(s): Yokoyama O, Miwa Y, Oyama N, Aoki Y. Ito H, Akino H.
  • Journal Title: J Urol 178 Pages: 2208-2212
  • NAID: 120000997268
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Effects of opioid subtypes on detrusor overactivity in rats with cerebral infarction. (2007)
  • Author(s): Nagasaka Y, Yokoyama O, Komatsu K, Ishiura Y, Nakamura Y, Namiki M
  • Journal Title: Int J Urol 14 Pages: 226-231
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Effects of antimuscarinics on voiding function after cerebral infarction in a rat model of overactive bladder (2007)
  • Author(s): Yusup, A., Akino, H., Miwa, Y., Oyama, N., Aoki, Y., Ito, H., Tanase, K., Matsuta, Y., Nakai, M., Yokoyama, O
  • Journal Title: Eur J Pharmacol 577 Pages: 143-149
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Improvement of bladder storage function by tamusulosin depends on suppression of C-fiber urethral afferent activity in rats (2007)
  • Author(s): Yokoyama, O., Yusup, A., Oyama, N., Aoki, Y., Miwa, Y., Akino, H
  • Journal Title: J Urol 177 Pages: 771-775
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antimuscarinic drug inhibits detrusor overactivity induced by topical application of prostaglandin e(2) to the urethra with a decrease in urethral pressure (2007)
  • Author(s): Yokoyama, 0., Miwa, Y., Oyama, N., Aoki, Y., Ito, H., Akino, H
  • Journal Title: J Urol 178 Pages: 2208-2212
  • NAID: 120000997268
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of opioid subtypes on detrusor overactivity in rats with cerebral infarction (2007)
  • Author(s): Nagasaka, Y., Yokoyama, 0., Komatsu, K., Ishiura, Y., Nakamura, Y., Namiki, M
  • Journal Title: Int J Urol 14 Pages: 226-231
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Improvement of bladder storage function by tamusulosin depends on suppression of C-fiber urethral afferent activity in rats. (2007)
  • Author(s): Yokoyama O, Yusup A, Oyama N, Aoki Y, Miwa Y, Akino H
  • Journal Title: J Urol. 177 Pages: 771-775
  • Peer Reviewed
• [Journal Article] Antimuscarinic drug inhibits detrusor overactivity induced by topical application of prostaglandin e(2) to the urethra with a decrease in urethral pressure. (2007)
  • Author(s): Yokoyama O, Miwa Y, Oyama N, Aoki Y, Ito H, Akino H.
  • Journal Title: J Urol. 178 Pages: 2208-2212
  • NAID: 120000997268
  • Peer Reviewed
• [Journal Article] Effects of antimuscarinics on voiding function after cerebral inharction in a rat model of overactive bladder. (2007)
  • Author(s): Yusup A, Akino H, Miwa Y, Oyama N, Aoki Y, Ito H, Tanase K, Matsuta Y, Nakai M, Yokoyama 0.
  • Journal Title: Eur J Pharmacol. 577 Pages: 143-149
  • Peer Reviewed
• [Journal Article] Identification of alpha-1L and alpha-1A adrenoceptors in human prostate by tissue segment binding (2007)
  • Author(s): Morishima S, Tanaka T, Yamamoto H, Suzuki F, Akino H, Yokoyama O, Muramatsu I
  • Journal Title: J Urol 177 Pages: 377-381
  • Peer Reviewed
• [Journal Article] Improvement in bladder storage function by tamsulosin depends on suppression of C-fiber urethral afferent activity in rats. (2007)
  • Author(s): Yokoyama, O., Yusup, A., Oyama, N., Aoki, Y., Miwa, Y., Akino, H.
  • Journal Title: Journal of Urology 177 Pages: 771-775
  • NAID: 120000807688
• [Journal Article] Identification of alpha-1L and alpha-1A adrenoceptors in human prostate by tissue segment binding. (2007)
  • Author(s): Morishima S, Tanaka T, Yamamoto H, Suzuki F, Akino H, Yokoyama O, Muramatsu I
  • Journal Title: Journal of Urology 177 Pages: 377-381
• [Journal Article] Acetylcholinesterase inhibitor acting on the brain improves detrusor overactivity caused by cerebral infarction in rats. (2006)
  • Author(s): Nakai M, Akino H, Kaneda T, Matsuta Y, Shiyama R, Tanas〓 K, Ito H, Aoki Y, Oyama N, Miwa Y, Yokoyama O.
  • Journal Title: Neuroscience 142 Pages: 475-480
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Improvement of bladder storage function by alphal-blocker depends on the suppression of C-fiber afferent activity in rats. (2006)
  • Author(s): Yokoyama O, Yusup A, Oyama N, Aoki Y, Tanase K, Matsuta Y, Miwa Y, Akino H.
  • Journal Title: Neurourol Urodyn 25 Pages: 461-467
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A selective alphalA-adrenoceptor antagonist inhibits detrusor overa ctivityin a rat model of benign prostatic hyperplasia. (2006)
  • Author(s): Tatemichi S, Akiyama K, Kobayashi M, Yamazaki Y, Yokoyama O, Uruno T.
  • Journal Title: J Urol 176 Pages: 1236-1241
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Acetylcholinesterase inhibitor acting on the brain improves detrusor overactivity caused by cerebral infarction in rats (2006)
  • Author(s): Nakai, M., Akino, H., Kaneda, T., Matsuta, Y., Shiyama, R., Tanase, K., Ito, H., Aoki, Y., Oyama, N., Miwa, Y., Yokoyama, 0
  • Journal Title: Neuroscience 142 Pages: 475-480
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Improvement of bladder storage function by alphal-blocker depends on suppression of C-fiber afferent activity in rats (2006)
  • Author(s): Yokoyama, 0., Yusup, A., Oyama, N., Aoki, Y., Tanase, K., Matsuta, Y., Miwa, Y., Akino, H
  • Journal Title: Neurourol Urodyn 25 Pages: 461-467
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A selective alphal A-adrenoceptor antagonist inhibits detrusor overactivityin a rat model of benign prostatic hyperplasia (2006)
  • Author(s): Tatemichi, S., Akiyama, K., Kobayashi, M., Yamazaki, Y., Yokoyama, 0., Uruno, T
  • Journal Title: J Ural 176 Pages: 1236-1241
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Acetylcholinesterase inhibitor acting on the brain improves detrusor overactivity caused by cerebral infarction in rats. (2006)
  • Author(s): Nakai M, Akino H, Kaneda T, Matsuta Y, Shiyama R, Tanase K, Ito H, Aoki Y, Oyama N, Miwa Y, Yokoyama O.
  • Journal Title: Neuroscience 142 Pages: 475-480
• [Journal Article] Symptom assessment tool for overactive bladder syndrome--overactive bladder symptom score. (2006)
  • Author(s): Homma Y, Yoshida M, Seki N, Yokoyama O, Kakizaki H, Gotoh M, Yamanishi T, Yamaguchi O, Takeda M, Nishizawa O.
  • Journal Title: Urology 68 Pages: 318-323
• [Journal Article] A selective alphalA-adrenoceptor antagonist inhibits detrusor overactivity in a rat model of benign prostatic hyperplasia. (2006)
  • Author(s): Tatemichi S, Akiyama K, Kobayashi M, Yamazaki Y, Yokoyama O, Uruno T.
  • Journal Title: Journal of Urology 176 Pages: 1236-1241
• [Presentation] Spontaneous bladder contraction: effect of the KATP potassium channel opener, cromakalim, and the urothelium/suburothelium in a rat model of bladder outlet obstruction. (2008)
  • Author(s): H. Akino, M. Maegawa, K. Tanase, K. Nagase, D. J. Sellers, R. Chess-Williams, C. R. Chapple, N. Mckay, N. Oyama, Y. Miwa, O. Yokoyama
  • Organizer: The 23rd Annual European Association of Urology Congress
  • Place of Presentation: Milano, ITALY
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Spontaneous bladder contraction : effect of the KATP potassium channel opener, cromakalim, and the urothelium/suburothelium in a rat model of bladder outlet obstruction (2008)
  • Author(s): H. Akino, M. Maegawa, K. Tanase, K. Nagase, D.J. Sellers, R. Chess-Williams, C.R. Chapple, N. Mckay, N. Oyama, Y. Miwa, O. Yokoyama
  • Organizer: The 23rd Annual European Association of Urology Congress
  • Place of Presentation: Milano, ITALY
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 脳梗塞ラットの排尿筋過活動に対するFYO-750の作用 (2007)
  • Author(s): 田中一平、秋野裕信、棚瀬和弥、前川正信、長瀬佳子、横山修
  • Organizer: 第14回日本排尿機能学会
  • Place of Presentation: 福島
  • Year and Date: 2007-10-05
• [Presentation] Meratonin enlarges the bladder by the gabaa receptor in htebrain, suggesting its efficaciousness against nocturia (2007)
  • Author(s): Y. Matsuta, A. Yusup, M. Nakai, K. Tanase, Y. Aoki, N. Oyama, Y. Miwa, H. Akino, O. Yokoyama
  • Organizer: Annual Meeting of American Urological Association
  • Place of Presentation: Anaheim, USA.
  • Year and Date: 2007-05-20
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Influences of hormones on lower urinary tract function. (2007)
  • Author(s): O. Yokoyama
  • Organizer: The Second Joint Meeting of American Urological Association(AUA)/Japanese Urological Association(JUA)
  • Place of Presentation: Anaheim, USA.
  • Year and Date: 2007-05-20
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Meratonin enlarges the bladder by the gabaa receptor in hte brain,suggesting its efficaciousness against nocturia (2007)
  • Author(s): Y. Matsuta, A. Yusup, M. Nakai, K. Tanase, Y. Aoki, N. Oyama, Y. Miwa, H. Akino, O. Yokoyama
  • Organizer: 2007 Annual Meeting of American Urological Association
  • Place of Presentation: Anaheim, USA
  • Year and Date: 2007-05-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Influences of hormones on lower urinary tract function (2007)
  • Author(s): O. Yokoyama
  • Organizer: The Second Joint Meeting of American Urological Association (AUA)/Japanese Urological Association (JUA)
  • Place of Presentation: Anaheim, USA
  • Year and Date: 2007-05-20
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The role of the urothelium and suburothelium in spontaneous contractions of pig bladder done strips. (2007)
  • Author(s): H. Akino, Chapple. C. R, McKay. N, Chess-Willams. R, Murakami. S, O. Yokoyama, Sellers. D. J
  • Organizer: 2007 Annual Meeting of International Continence Society
  • Place of Presentation: Rotterdam, NLD
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Effects of corticotropin-releasing factor receptor antagonists on bladder overactivity induced by psychological stress in rats (2007)
  • Author(s): Y. Miwa, T. Kaneda, H. Akino, O. Yokoyama
  • Organizer: 2007 Annual Meeting of International Continence Society
  • Place of Presentation: Rotterdam, NLD
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Antimuscarinic drug compensaters for detrusor dysfunction by decreasing urethrel resistance via an effect on the l-type voltage-operated cancium channel. (2007)
  • Author(s): K. Nagase, H. Akino, Y. Miwa, N. Oyama, Y. Aoki, H. Ito, K. Tanase, M. Maegawa, T. Kaneda, N. Kusukawa, H. Yamauchi, O. Yokoyama
  • Organizer: 2007 Annual Meeting of International Continence Society
  • Place of Presentation: Rotterdam, NLD
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The role of the urothelium and suburothelium in spontaneous contractions of pig bladder done strips (2007)
  • Author(s): H. Akino, Chapple.C.R, MclCay.N, Chess-Willams.R, Murakami.S, 0.Yokoyama, Sellers, D.J
  • Organizer: 2007 Annual Meeting of International Continence Society
  • Place of Presentation: Rotterdam, NLD
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Antimuscarinic drug compensaters for detrusor dysfunction by decreasing urethral resistance via an effect on the 1-type voltage-operated cancium channel (2007)
  • Author(s): K. Nagase, H. Akino, Y. Miwa, N. Oyama, Y. Aoki, H. Ito, K-Tanase, M.Maegawa, T. Kaneda, N. Kusukawa, H.Yamauchi, 0. Yokoyama
  • Organizer: 2007 Annual Meeting of International Continence Society
  • Place of Presentation: Rotterdam, NLD
  • Description: 「研究成果報告書概要(欧文)」より