There is increasing evidence indicating the positive correlation between prostatic inflammation and lower urinary tract symptoms (LUTS) in male with benign prostatic hyperplasia (BPH) [1] although the underlying mechanism is still unclear. Therefore, in the present study using a rat model of non-bacterial prostatic inflammation, we evaluated the expression profiles of E series prostaglandin receptor subtypes, which are reportedly implicated in development of OAB [2], in the bladder, and investigated the effect of EP4 receptor blockade on bladder overactivity after prostatic inflammation.

Male Spraque-Dewley rats were used. Prostatic inflammation was induced by formalin (5%; 50 µl per lobe) injection into bilateral ventral lobes of the prostate.  Rats with intraprostatic vehicle injection were used as controls.  At 10 days after induction of prostatic inflammation or vehicle injection, bladder tissues were harvested and separated into mucosal and detrusor layers. Then, prostaglandin E2 (PGE2) concentrations in bladder mucosa were measured by ELISA, and protein levels of PGE2 receptors (EP1 to 4) were evaluated by Western blot. In separate groups of control and formalin-treated rats, bladder function was evaluated using awake cystometry to evaluate the changes in bladder activity after prostatic inflammation. Also, the effect of intravesical administration of a selective EP4 receptor antagonist (ONO-AE3-208; 30μM) on bladder activity was evaluated in control rats and rats with prostatic inflammation.  The cystometric parameters evaluated included intercontraction intervals (ICI), baseline pressure (BP), pressure threshold (PT), bladder contraction amplitude, post-void residual volume (RV), bladder capacity and non-voiding contraction (NVC) (Table.1).

Compared to vehicle-injected rats, PGE2 concentration and protein levels of EP4 receptors, but not EP1, EP2 or EP3, in bladder mucosa were significantly (p<0.05) increased in formalin-treated rats.  In cystometry, rats with formalin-induced prostatic inflammation exhibited a significant (p<0.05) decrease in ICI compared to vehicle-treated rats. In rats with prostatic inflammation, intravesical application of ONO-AE3-208 (30μM), but not vehicle treatment, significantly increased ICI and bladder capacity (Fig.1 & Table 1) whereas ONO-AE3-208 at this concentration did not significantly affect any CMG parameters in control rats.

Rats with formalin-induced prostatic inflammation showed bladder overactivity evident as shorter ICI in association with increased PGE2 production and elevated EP4 receptor expression in bladder mucosa whereas other EP receptors did not change after prostatic inflammation. Furthermore, intravesical administration of ONO-AE3-208, a selective EP4 receptor antagonist, ameliorated bladder overactivity as evidenced by increased ICI and bladder capacity without affecting other cystometric parameters including bladder contraction amplitude.  These results suggest that the PGE2-EP4 receptor mechanism in bladder mucosa are enhanced to induce bladder overactivity after prostatic inflammation, and that EP4 receptor activation in bladder mucosa is possibly to be implicated in modulation of afferent inputs from the bladder during the storage phase, rather than efferent nerves or bladder contractility that affect voiding function.

Because intravesical administration of an EP4 receptor antagonist effectively improved bladder overactivity after prostatic inflammation, EP4 receptor activation along with increased PGE2 production in bladder mucosa seems to be an important contributing factor to bladder overactivity induced by prostatic inflammation. Thus, blockade of EP4 receptors in the bladder could be a therapeutic modality for male LUTS due to BPH with prostatic inflammation.

Nickel, J.C., et al., The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol, 2008. 54(6): p. 1379-84
Jiang Y, Araki I, Kobayashi H et al. The expression of prostaglandin E2 receptors (EP1, 2, 3 and 4) in the human urinary bladder epithelium of normal and bladder outlet obstruction- a novel mechanism in the afferent hyperactivity of bladder. 2008 AUA Meeting (Abstract 1318). J Urol 2008; 179: 472