title: Promising Effects of a Novel EP2 and EP3 Receptor Dual Agonist, ONO-8055, on Neurogenic Underactive Bladder in a Rat Lumbar Canal Stenosis Model.
abstract: OBJECTIVE
  We investigated whether the novel EP (prostaglandin E2) receptor agonist ONO-8055 would improve the lower urinary tract dysfunction of neurogenic underactive bladder in a rat lumbar spinal canal stenosis model.
  
  
  METHODS
  First, we studied the agonistic effect of ONO-8055 on EP receptors in EP receptor expressing CHO (Chinese hamster ovary) cells using the increase in the intracellular calcium level and intracellular cAMP (cyclic adenosine monophosphate) production as indicators of receptor activation. The effects of ONO-8055 on bladder and urethral strips from normal rats were then investigated. Finally, the effects of ONO-8055 on bladder and urethral function in rats with lumbar spinal canal stenosis were evaluated by awake cystometry and intraurethral perfusion pressure, respectively. The effects of tamsulosin and distigmine on urethral pressure were also evaluated.
  
  
  RESULTS
  ONO-8055 is a highly potent and selective agonist for EP2 and EP3 receptors on CHO cells. While this compound contracted bladder strips, it relaxed urethral strips. Awake cystometry showed that ONO-8055 significantly decreased bladder capacity, post-void residual urine and voiding pressure. Compared with vehicle, tamsulosin and ONO-8055 significantly decreased urethral pressure.
  
  
  CONCLUSIONS
  ONO-8055 decreased post-void residual urine, probably by decreasing bladder capacity. The decrease in voiding pressure probably resulted from the lowered urethral pressure due to relaxation of the urethra. Thus, the novel EP2 and EP3 receptor dual agonist ONO-8055 has the potential to improve neurogenic underactive bladder.
authors.affiliation: Department of Urology, Toho University Medical Center Ohashi Hospital (NS), Tokyo, Japan; Discovery Research Laboratories VI, Ono Pharmaceutical Co., Ltd., Osaka, Japan. Electronic address: nsekido@med.toho-u.ac.jp.
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Sekido
authors.affiliation: Department of Urology, Toho University Medical Center Ohashi Hospital (NS), Tokyo, Japan; Discovery Research Laboratories VI, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kida
authors.affiliation: Department of Urology, Toho University Medical Center Ohashi Hospital (NS), Tokyo, Japan; Discovery Research Laboratories VI, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Mashimo
authors.affiliation: Department of Urology, Toho University Medical Center Ohashi Hospital (NS), Tokyo, Japan; Discovery Research Laboratories VI, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Wakamatsu
authors.affiliation: Department of Urology, Toho University Medical Center Ohashi Hospital (NS), Tokyo, Japan; Discovery Research Laboratories VI, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Okada
authors.affiliation: Department of Urology, Toho University Medical Center Ohashi Hospital (NS), Tokyo, Japan; Discovery Research Laboratories VI, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Matsuya
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000819:agonists*; D013130:Spinal Stenosis / Q000150:complications*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014521:Urethra / Q000187:drug effects / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D064804:Urological Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; C000625806:ONO-8055; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013844:Thiazoles; D064804:Urological Agents
keywords: constriction, pathological; dinoprostone; spinal canal; urinary bladder, neurogenic; urinary bladder, underactive