title: Effects of the selective prostacyclin receptor antagonist RO3244019 on the micturition reflex in rats.
abstract: OBJECTIVE
  We investigated the role of prostacyclin on afferent modulation of the micturition reflex using the novel selective prostacyclin receptor antagonist RO3244019 in rat models of bladder function.
  
  
  METHODS
  The effects of RO3244019 on urodynamic parameters were evaluated in 3 rat models. In the anesthetized isovolumetric bladder contraction and the volume induced micturition reflex (Refill) models the effects of RO3244019 and chronic capsaicin desensitization were compared. In the citric acid induced detrusor overactivity model the effects of RO3244019 and the cyclooxygenase inhibitor indomethacin were evaluated.
  
  
  RESULTS
  In the isovolumetric bladder contraction model RO3244019 dose dependently decreased bladder contraction frequency with a mean +/- SEM maximum decrease of 72.2% +/- 4.3% at 3.16 mg/kg. RO3244019 also dose dependently increased the micturition threshold in the Refill model with a maximum increase of 86.9% +/- 19.1% at 3.0 mg/kg. In animals that were chronically treated with capsaicin bladder contraction frequency was decreased by 88.9% in the isovolumetric bladder contraction model and micturition threshold was increased by 68.1% in the Refill model relative to sham treated rats. RO3244019 (3.0 mg/kg) further increased the micturition threshold in capsaicin treated animals by 53.7% +/- 18.1% from baseline. In the citric acid induced detrusor overactivity model citric acid decreased the voiding interval to 28.5% of baseline. This effect was reversed by RO3244019 (73.0% +/- 6.4%) and indomethacin (97.7% +/- 5.5%) at 3.0 mg/kg compared to vehicle (55.0% +/- 4.1%).
  
  
  CONCLUSIONS
  The prostacyclin receptor antagonist RO3244019 decreased bladder contraction frequency and increased micturition threshold in the anesthetized isovolumetric bladder contraction and Refill models, respectively, and increased the micturition voiding interval in the conscious citric acid induced detrusor overactivity model. Additionally, RO3244019 remained effective for increasing the micturition threshold in the Refill model even following chronic capsaicin desensitization. Taken together these data suggest that prostacyclin may have a facilitory role in the micturition reflex by modulating the threshold for activation of capsaicin sensitive and insensitive bladder sensory afferents.
authors.affiliation: Roche Palo Alto, Palo Alto, California 94304, USA. joseph.cefalu@roche.com
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Cefalu
authors.forename: Quan Ming
authors.initials: QM
authors.lastname: Zhu
authors.forename: Anne-Christin
authors.initials: AC
authors.lastname: Eggers
authors.forename: Timothy K Y
authors.initials: TK
authors.lastname: Kaan
authors.forename: Meghan J
authors.initials: MJ
authors.lastname: Ho
authors.forename: Mary-Frances
authors.initials: MF
authors.lastname: Jett
authors.forename: Debra A
authors.initials: DA
authors.lastname: Cockayne
authors.forename: Anthony P D W
authors.initials: AP
authors.lastname: Ford
authors.forename: Philip A
authors.initials: PA
authors.lastname: Nunn
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol / Q000037:antagonists & inhibitors*; D012016:Reference Values; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D012680:Sensitivity and Specificity; D014554:Urination / Q000187:drug effects* / Q000502:physiology; D014563:Urodynamics / Q000187:drug effects* / Q000502:physiology
chemical_list: D044006:Receptors, Epoprostenol; D002211:Capsaicin; D007213:Indomethacin