Effects of the selective prostacyclin receptor antagonist RO3244019 on the micturition reflex in rats.
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.
Cefalu
Joseph S
JS
Roche Palo Alto, Palo Alto, California 94304, USA. joseph.cefalu@roche.com
Zhu
Quan Ming
QM
Eggers
Anne-Christin
AC
Kaan
Timothy K Y
TK
Ho
Meghan J
MJ
Jett
Mary-Frances
MF
Cockayne
Debra A
DA
Ford
Anthony P D W
AP
Nunn
Philip A
PA
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
D044006:Receptors, Epoprostenol; D002211:Capsaicin; D007213:Indomethacin