Long‐lasting bladder overactivity and bladder afferent hyperexcitability in rats with chemically‐induced prostatic inflammation

Abstract

Background: Benign prostatic hyperplasia (BPH) is one of the major causes of lower urinary tract symptoms (LUTS), including storage LUTS such as urinary frequency and urgency. Recently, a growing number of clinical studies indicate that prostatic inflammation could be an important pathophysiological mechanism inducing storage LUTS in patients with BPH. Here we aimed to investigate whether nonbacterial prostatic inflammation in a rat model induced by intraprostatic formalin injection can lead to longlasting bladder overactivity and changes in bladder afferent neuron excitability. Methods: Male Sprague-Dawley rats were divided into four groups (n = 12 each): normal control group, 1-week prostatic inflammation group, 4-week inflammation group, and 8-week inflammation group. Prostatic inflammation was induced by formalin (10%; 50 µL per lobe) injection into bilateral ventral lobes of the prostate. Voiding behavior was evaluated in metabolic cages for each group. Ventral lobes of the prostate and the bladder were then removed for hematoxylin and eosin (HE) staining to evaluate inflammation levels. Continuous cystometrograms (CMG) were recorded to measure intercontraction intervals (ICI) and voided volume per micturition. Whole-cell patch clamp recordings were performed on dissociated bladder afferent neurons labeled by fluorogold injected into the bladder wall, to examine the electrophysiological properties.Results: Results of metabolic cage measurements showed that formalin-treated rats exhibited significantly (P < 0.05) increases in micturition episodes/12 hours and decrease in voided volume per micturition at every time point post injection.Continuous CMG illustrated the significant (P < 0.05) higher number of nonvoiding contractions per void and shorter ICI in formalin-treated rats compared with control rats. HE staining showed significant prostatic inflammation, which declined gradually, in prostate tissues of formalin-induced rats. In patch clamp recordings, capsaicinsensitive bladder afferent neurons from rats with prostatic inflammation had significantly (P < 0.05) lower thresholds for spike activation and a "multiple" firing pattern compared with control rats at every time point post injection.

Voiding Dysfunction in Old Male Rats Associated With Enlarged Prostate and Irregular Afferent-Triggered Reflex Responses

“…The present study showed a significantly higher prostate-tobody weight index in aged rats, suggesting that age-related conditions may induce a partial urethral obstruction affecting urination due to complicated voiding patterns in MOR. This observation suggest that it is possible to avoid chemically induced changes in prostate size [16,17]. The immunofluorescence results also revealed an increased presence of neurofilaments in MOR, supporting the possibility that pathological conditions stimulate prostatic innervation and consequently the overgrowth of the gland [18].…”

“…Our results support this hypothesis by showing the coexistence of prostate enlargement, increased prostate innervation, and bladder hyperactivity in MOR. Indeed, in a recent study using a formalin-induced prostatic inflammation model in rats, hyperexcitability of afferent neurons combined with bladder overactivity was observed [ 16 ], supporting the idea of more complex interactions among the prostate, the urinary bladder, and afferent innervation and the possibility that a localized reflex may control both organs.…”

“…Our results support this hypothesis by showing the coexis- tence of prostate enlargement, increased prostate innervation, and bladder hyperactivity in MOR. Indeed, in a recent study using a formalin-induced prostatic inflammation model in rats, hyperexcitability of afferent neurons combined with bladder overactivity was observed [16], supporting the idea of more complex interactions among the prostate, the urinary bladder, One-way analysis of variance showed *P < 0.05, **P < 0.01, and ***P < 0.001 between the MOR and MYR groups; # P < 0.05 and ## P < 0.01 between MOR and MOR+AF-353; and Θ P < 0.05 between MYR and MYR+AF-353. MYR, male young rats; MOR, male old rats; EMG, electromyography.…”

Effects of dutasteride in a rat model of chemically induced prostatic inflammation—Potential role of estrogen receptor β

“…In the present study, rats with formalin‐induced prostatic inflammation exhibited bladder overactivity without inflammatory changes in the bladder, suggesting that there is a mechanism that causes bladder overactivity without direct formalin infiltration into the bladder wall after intraprostatic formalin injection. In this regard, our recent studies showed that localized prostatic inflammation can evoke bladder overactivity and bladder afferent hyperexcitability up to 8 weeks after one‐time intraprostatic formalin injection and that bladder overactivity following prostatic inflammation is induced by prostate‐to‐bladder cross‐talk through activation of the pelvic nerve that contains dichotomized afferents innervating both bladder and prostate 13,14 . Taken together, it is plausible that bladder overactivity after prostatic inflammation was caused by afferent sensitization, rather than the direct local effects of formalin on the bladder in this study.…”

“…There was no significant difference in MVP or RV among three groups (bottom left and right in Figure 1B bladder overactivity following prostatic inflammation is induced by prostate-to-bladder cross-talk through activation of the pelvic nerve that contains dichotomized afferents innervating both bladder and prostate. 13,14 Taken together, it is plausible that bladder overactivity after prostatic inflammation was caused by afferent sensitization, rather than the direct local effects of formalin on the bladder in this study.…”