Conclusions
Because intravesical administration of an EP4 antagonist effectively improved bladder overactivity after prostatic inflammation, EP4 activation, along with increased PGE2 production in the bladder mucosa, seems to be an important contributing factor to bladder overactivity induced by prostatic inflammation. Thus, blockade of EP4 in the bladder could be a therapeutic approach to male lower urinary tract symptoms attributable to benign prostatic hyperplasia with prostatic inflammation.
Methods
Male Sprague-Dawley rats were used. Prostatic inflammation was induced by formalin injection (5%; 50 μL per lobe) into the bilateral ventral lobes of the prostate. At 10 days after induction of prostatic inflammation or vehicle injection, bladder tissues from the deeply anaesthetized rats were harvested and separated into mucosal and detrusor layers. Then, prostaglandin E2 (PGE2) concentrations and protein levels of PGE2 receptors (EP1-4) in the bladder mucosa and detrusor were measured by ELISA and Western blotting, respectively. In separate groups of control and formalin-treated rats, awake cystometry was performed to evaluate the changes in bladder activity after prostatic inflammation. In addition, the effect of intravesical administration of a selective EP4 antagonist (ONO-AE3-208; 30 μm) on bladder activity was evaluated in control rats and rats with prostatic inflammation.
Results
PGE2 concentration and protein levels of EP4, but not other EP receptor subtypes, in the bladder mucosa and detrusor layers were significantly increased in formalin-injected rats vs vehicle-injected control rats. In cystometry, rats with prostatic inflammation exhibited a significant decrease in intercontraction intervals (ICIs) compared with control rats. Intravesical application of ONO-AE3-208 (30 μm), but not vehicle application, significantly increased ICIs in rats with prostatic inflammation, whereas ONO-AE3-208 at this concentration did not significantly affect any cystometric values in control rats. Conclusions: Because intravesical administration of an EP4 antagonist effectively improved bladder overactivity after prostatic inflammation, EP4 activation, along with increased PGE2 production in the bladder mucosa, seems to be an important contributing factor to bladder overactivity induced by prostatic inflammation. Thus, blockade of EP4 in the bladder could be a therapeutic approach to male lower urinary tract symptoms attributable to benign prostatic hyperplasia with prostatic inflammation.