Transient receptor potential ankyrin 1 channels in the bladder mediate low temperature elicited bladder overactivity in rats.

AIMS: This study aimed to investigate whether pathways involving transient receptor potential ankyrin 1 (TRPA1) channels in the urinary bladder mediate the bladder overactivity elicited by exposure to a low temperature in rats. METHODS: At postnatal week 10, female Sprague-Dawley (SD) rats were intraperitoneally injected with the TRPA1 channel antagonist, HC030031, at room temperature (RT) and subsequently exposed to low temperature (LT). Bladder specimens treated with HC030031 were evaluated for contractions through cumulative addition of the TRPA1 channel agonist trans-cinnamaldehyde. Two days before cystometric investigation, small interfering RNA (siRNA) targeting TRPA1 was transfected into urinary bladders. Then, cystometric investigations were performed on rats subjected to TRPA1 siRNA transfection at both RT and LT. Expression of TRPA1 channels in the urinary bladder was assessed through immunohistochemistry and real-time reverse transcription-polymerase chain reaction. RESULTS: At RT, micturition patterns were unaffected by HC030031 treatment. However, upon exposure to LT, rats treated with HC030031 exhibited a reduction of LT-elicited bladder overactivity, as evidenced by inhibited decreases in voiding interval, micturition volume, and bladder capacity. Additionally, HC030031 inhibited trans-cinnamaldehyde-induced contractions. Immunohistochemical analysis showed the presence of TRPA1 channels in the urinary bladder. Notably, rats with TRPA1 siRNA-transfected bladders could partially inhibit bladder overactivity during LT exposure. CONCLUSIONS: These findings indicate that pathways involving TRPA1 channels expressed in the urinary bladder could mediate the LT-elicited bladder overactivity.

Molecular Mechanisms of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury.

This article provides a synopsis of current progress made in fundamental studies of lower urinary tract dysfunction (LUTD) after spinal cord injury (SCI) above the sacral level. Animal models of SCI allowed us to examine the effects of SCI on the micturition control and the underlying neurophysiological processes of SCI-induced LUTD. Urine storage and elimination are the two primary functions of the LUT, which are governed by complicated regulatory mechanisms in the central and peripheral nervous systems. These neural systems control the action of two functional units in the LUT: the urinary bladder and an outlet consisting of the bladder neck, urethral sphincters, and pelvic-floor striated muscles. During the storage phase, the outlet is closed, and the bladder is inactive to maintain a low intravenous pressure and continence. In contrast, during the voiding phase, the outlet relaxes, and the bladder contracts to facilitate adequate urine flow and bladder emptying. SCI disrupts the normal reflex circuits that regulate co-ordinated bladder and urethral sphincter function, leading to involuntary and inefficient voiding. Following SCI, a spinal micturition reflex pathway develops to induce an overactive bladder condition following the initial areflexic phase. In addition, without proper bladder-urethral-sphincter coordination after SCI, the bladder is not emptied as effectively as in the normal condition. Previous studies using animal models of SCI have shown that hyperexcitability of C-fiber bladder afferent pathways is a fundamental pathophysiological mechanism, inducing neurogenic LUTD, especially detrusor overactivity during the storage phase. SCI also induces neurogenic LUTD during the voiding phase, known as detrusor sphincter dyssynergia, likely due to hyperexcitability of Aδ-fiber bladder afferent pathways rather than C-fiber afferents. The molecular mechanisms underlying SCI-induced LUTD are multifactorial; previous studies have identified significant changes in the expression of various molecules in the peripheral organs and afferent nerves projecting to the spinal cord, including growth factors, ion channels, receptors and neurotransmitters. These findings in animal models of SCI and neurogenic LUTD should increase our understanding of pathophysiological mechanisms of LUTD after SCI for the future development of novel therapies for SCI patients with LUTD.

Therapeutic effects of a soluble guanylate cyclase activator, BAY 60-2770, on lower urinary tract dysfunction in mice with spinal cord injury.

We aimed to evaluate the effects of a soluble guanylate cyclase (sGC) activator, BAY 60-2770, on neurogenic lower urinary tract dysfunction in mice with spinal cord injury (SCI). Mice were divided into the following three groups: spinal cord intact (group A), SCI + vehicle (group B), and SCI + BAY 60-2770 (group C). SCI mice underwent Th8-Th9 spinal cord transection and treatment with BAY 60-2770 (10 mg/kg/day) once daily for 2-4 wk after SCI. We evaluated urodynamic parameters using awake cystometry and external urethral sphincter electromyograms (EMG); mRNA levels of mechanosensory channels, nitric oxide (NO)-, ischemia-, and inflammation-related markers in L6-S1 dorsal root ganglia, the urethra, and bladder tissues; and protein levels of cGMP in the urethra at 4 wk after SCI. With awake cystometry, nonvoiding contractions, postvoid residual, and bladder capacity were significantly larger in group B than in group C. Voiding efficiency (VE) was significantly higher in group C than in group B. In external urethral sphincter EMGs, the duration of notch-like reductions in intravesical pressure and reduced EMG activity time were significantly longer in group C than in group B. mRNA expression levels of transient receptor potential ankyrin 1, transient receptor potential vanilloid 1, acid-sensing ion channel (ASIC)1, ASIC2, ASIC3, and Piezo2 in the dorsal root ganglia, and hypoxia-inducible factor-1α, VEGF, and transforming growth factor-ß1 in the bladder were significantly higher in group B than in groups A and C. mRNA levels of neuronal NO synthase, endothelial NO synthase, and sGCα1 and protein levels of cGMP in the urethra were significantly lower in group B than in groups A and C. sGC modulation might be useful for the treatment of SCI-related neurogenic lower urinary tract dysfunction.NEW & NOTEWORTHY This is the first report to evaluate the effects of a soluble guanylate cyclase activator, BAY 60-2770, on neurogenic lower urinary tract dysfunction in mice with spinal cord injury.

Functional and histologic imaging of urinary bladder wall after exposure to psychological stress and protamine sulfate.

To quantify the urinary bladder wall T1 relaxation time (T1) before and after the instillation contrast mixture in rats previously subjected to water avoidance stress (WAS) and/or acute exposure to protamine sulfate (PS). Female Wistar rats were randomized to receive either sham (control) or 1 h of WAS for ten consecutive days before the evaluation of nocturnal urination pattern in metabolic cages. T1 mapping of urinary bladder wall at 9.4 T was performed pre- and post- instillation of 4 mM Gadobutrol in a mixture with 5 mM Ferumoxytol. Subsequently, either T1 mapping was repeated after brief intravesical PS exposure or the animals were sacrificed for histology and analyzing the mucosal levels of mRNA. Compared to the control group, WAS exposure decreased the single void urine volume and shortened the post-contrast T1 relaxation time of mucosa- used to compute relatively higher ingress of instilled Gadobutrol. Compromised permeability in WAS group was corroborated by the urothelial denudation, edema and ZO-1 downregulation. PS exposure doubled the baseline ingress of Gadobutrol in both groups. These findings confirm that psychological stress compromises the paracellular permeability of bladder mucosa and its non-invasive assay with MRI was validated by PS exposure.

Therapeutic effects of nerve growth factor-targeting therapy on bladder overactivity in rats with prostatic inflammation.

BACKGROUND: The present study examined the effect of liposomes conjugated with antisense oligonucleotide of nerve growth factor (NGF-OND) on local overexpression of NGF and bladder overactivity using rats with prostatic inflammation (PI). METHODS: Male Sprague-Dawley rats were divided into three groups: (1) Control group; intact rats, (2) PI-NS group; rats with PI and intravesical instillation of normal saline (NS), (3) PI-OND group; rats with PI and intravesical instillation of NGF-OND. On Day 0, PI was induced by intraprostatic 5%-formalin injection. On Day 14, NGF-OND or NS was instilled directly into the bladder after laparotomy. On Day 28, therapeutic effects of NGF-OND were evaluated by awake cystometry and histological analysis as well as reverse-transcription polymerase chain reaction measurements of messenger RNA (mRNA) levels of NGF in the bladder and prostate, inflammatory markers in the prostate, C-fiber afferent markers, and an A-type K+ channel α-subunit (Kv 1.4) in L6-S1 dorsal root ganglia (DRG). RESULTS: Intravesical NFG-OND treatment reduced PI-induced overexpression of NGF in both bladder and prostate, and reduced PI-induced bladder overactivity evident as longer intercontraction intervals in association with reductions of TRPV1 and TRPA1 mRNA expression levels in DRG. mRNA expression of Kv1.4 in DRG was reduced after PI, but improved in the PI-OND group. CONCLUSIONS: These results indicate that NGF locally expressed in the bladder is an important mediator inducing bladder overactivity with upregulation of C-fiber afferent markers and downregulation of an A-type K+ channel subunit in DRG following PI, and that liposome-based, local NGF-targeting therapy could be effective for not only bladder overactivity and afferent sensitization, but also PI. Thus, local blockade of NGF in the bladder could be a therapeutic modality for male LUTS due to BPH with PI.

Effects of low-dose insulin or a soluble guanylate cyclase activator on lower urinary tract dysfunction in streptozotocin-induced diabetic rats.

AIMS: To examine the effects of low-dose insulin or a soluble guanylate cyclase activator (sGC) on lower urinary tract dysfunction (LUTD) in rats with diabetes mellitus (DM). MAIN METHODS: Female Sprague-Dawley rats were divided into non-DM control (N), DM induced by streptozotocin (65 mg/kg), with low-dose insulin (DI), DM with vehicle (D), and DM with sGC (GC) groups. In GC group, BAY 60-2770 (1 mg/kg/day) was orally administered in 6-8 weeks after DM. Voiding assay at 2, 4, and 8 weeks after DM, cystometry, and urethral pressure recordings at 8 weeks of DM were performed. mRNA levels of NO-related markers and cGMP protein levels in the urethra, and ischemia and inflammation markers in the bladder were evaluated by RT-PCR. KEY FINDINGS: Moderate levels of high blood glucose were maintained in Group DI versus Group D. The 24-h voided volume was significantly higher in Group D versus Groups N and DI. Non-voiding contractions were significantly greater, and voiding efficiency and urethral pressure reduction were significantly lower in Group D versus Groups N, DI, and GC. Urethral cGMP levels were significantly lower in Group D versus Groups N and GC. mRNA levels of PDE5 in the urethra and ischemia and inflammation markers in the bladder increased in Group D versus Group N or DI was reduced after sGC treatment. SIGNIFICANCE: DI rats with a lesser degree of bladder and urethral dysfunction might be useful as a slow-progressive DM model. sGC activation could be an effective treatment of LUTD in DM.

Efficacy of vibegron, a novel ß3-adrenoreceptor agonist, for lower urinary tract dysfunction in mice with spinal cord injury.

OBJECTIVES: To investigate the effect of vibegron, a new clinically approved ß3-adrenoceptor agonist in lower urinary tract dysfunction in mice with spinal cord injury. METHODS: Investigators performed cystometry under awake conditions in 4-week spinal cord injury female mice. Two weeks after spinal cord injury, saline or vibegron (30 mg/kg) was orally administered for 2 weeks prior to the urodynamic study. Investigators removed L6-S1 dorsal root ganglia from the saline- or vibegron-treated spinal cord injury mice as well as from saline-treated normal (spinal intact) mice to evaluate the levels of transient receptor potential cation channel subfamily V member 1, transient receptor potential cation channel subfamily A member 1, activating transcription factor 3, and inducible nitric oxide synthase transcripts using real-time polymerase chain reaction. RESULTS: In vibegron-treated spinal cord injury mice, nonvoiding contractions during bladder filling, which were increased in spinal cord injury compared to spinal intact mice, were significantly decreased. Micturition pressure or voiding efficiency was not significantly increased in comparison to measurements in saline-treated spinal cord injury mice. The expression of transient receptor potential cation channel subfamily V member 1, transient receptor potential cation channel subfamily A member 1, activating transcription factor 3, and inducible nitric oxide synthase messenger RNA was increased in spinal cord injury mice compared to spinal intact mice, but significantly decreased after vibegron treatment. CONCLUSIONS: Vibegron improves spinal cord injury-induced detrusor overactivity in addition to significantly reducing C-fiber afferent receptors such as transient receptor potential cation channel subfamily V member 1, transient receptor potential cation channel subfamily A member 1, and inflammatory cytokines/markers, such as activating transcription factor 3 and inducible nitric oxide synthase, in spinal cord injury mice. Thus, vibegron might be effective in the treatment of storage lower urinary tract dysfunction induced by C-fiber afferent activation after spinal cord injury.

Effect of oxybutynin patch versus mirabegron on nocturia-related quality of life in female overactive bladder patients: A multicenter randomized trial.

OBJECTIVES: To investigate the effect of oxybutynin patch versus ß3-adrenoceptor agonist mirabegron on nocturia-related quality of life in female overactive bladder patients. METHODS: In the present study, female overactive bladder patients were enrolled. The patients were randomly allocated into two groups: the oxybutynin patch group and the mirabegron group. Each of the drugs was given for 8 weeks. The changes in the total Nocturia Quality of Life Questionnaire score were evaluated. Parameters on a frequency volume chart were also evaluated. RESULTS: In total, 100 patients (51 oxybutynin patch, 49 mirabegron) were treated with oxybutynin patch or mirabegron. The changes in the Nocturia Quality of Life Questionnaire score 4 weeks after administration were 3.8 ± 18.6 and 8.7 ± 13.1 with the oxybutynin patch group and the mirabegron group, respectively, which were significantly higher than those at the baseline. Furthermore, the changes in the Nocturia Quality of Life Questionnaire score 8 weeks after administration were 4.3 ± 16.5 and 7.7 ± 12.3, respectively. A statistical difference was seen only in the mirabegron group. Regarding the Nocturia Quality of Life Questionnaire subscores, oxybutynin patch and mirabegron significantly improved the Nocturia Quality of Life Questionnaire bother/concern subscore 4 and 8 weeks after administration, whereas the Nocturia Quality of Life Questionnaire sleep/energy subscore was not significantly improved in each period. Eight weeks after administration, 24-h frequency, 24-h urinary urgency and mean voided urine volume were improved in both groups statistically. CONCLUSIONS: The oxybutynin patch improves quality of life, focusing mainly on nocturia by improving the bother/concern subscores of the Nocturia Quality of Life Questionnaire in the short term.

Time-dependent progression of neurogenic lower urinary tract dysfunction after spinal cord injury in the mouse model.

This study evaluated the time-course changes in bladder and external urinary sphincter (EUS) activity and the expression of mechanosensitive channels in lumbosacral dorsal root ganglia (DRG) after spinal cord injury (SCI). Female C57BL/6N mice in the SCI group underwent transection of the Th8/9 spinal cord. Spinal intact mice and SCI mice at 2, 4, and 6 wk post-SCI were evaluated by single-filling cystometry and EUS-electromyography (EMG). In another set of mice, the bladder and L6-S1 DRG were harvested for protein and mRNA analyses. In SCI mice, nonvoiding contractions were confirmed at 2 wk post-SCI and did not increase over time to 6 wk. In 2-wk SCI mice, EUS-EMG measurements revealed detrusor sphincter dyssynergia, but periodic EMG reductions during bladder contraction were hardly observed. At 4 wk, SCI mice showed increases of EMG activity reduction time with increased voiding efficiency. At 6 wk, SCI mice exhibited a further increase in EMG reduction time. RT-PCR of L6-S1 DRG showed increased mRNA levels of transient receptor potential vanilloid 1 and acid-sensing ion channels (ASIC1-ASIC3) in SCI mice with a decrease of ASIC2 and ASIC3 at 6 wk compared with 4 wk, whereas Piezo2 showed a slow increase at 6 wk. Protein assay showed SCI-induced overexpression of bladder brain-derived neurotrophic factor with a time-dependent decrease post-SCI. These results indicate that detrusor overactivity is established in the early phase, whereas detrusor sphincter dyssynergia is completed later at 4 wk with an improvement at 6 wk post-SCI, and that mechanosensitive channels may be involved in the time-dependent changes.NEW & NOTEWORTHY This is the first paper to evaluate the time-course changes of bladder dysfunction associated with mechanosensitive channels in a mouse model.

Effects of a new ß3-adrenoceptor agonist, vibegron, on neurogenic bladder dysfunction and remodeling in mice with spinal cord injury.

AIMS: To examine vibegron effects on lower urinary tract dysfunction (LUTD) in mice with spinal cord injury (SCI). METHODS: Female mice underwent Th8-9 spinal cord transection and were orally administered vehicle or vibegron after SCI. We evaluated urodynamic parameters at 4 weeks after SCI with or without vibegron. Fibrosis- and ischemia-related messenger RNA (mRNA) and protein levels of collagen and elastin were measured in bladders of vehicle- and vibegron-treated SCI mice, and spinal intact mice. RESULTS: Non-voiding contractions (NVCs) were significantly fewer (15.3 ± 8.9 vs 29.7 ± 11.4 contractions; P < .05) and the time to the first NVC was significantly longer (1488.0 ± 409.5 vs 782.7 ± 399.7 seconds; P < .01) in vibegron-treated SCI mice vs vehicle-treated SCI mice. mRNAs levels of collagen types 1 and 3, transforming growth factor-ß1 (TGF-ß1), and hypoxia-inducible factor-1α (HIF-1α) were significantly upregulated in vehicle-treated SCI mice compared with spinal intact and vibegron-treated SCI mice (Col 1: 3.5 vs 1.0 and 2.0-fold; P < .01 and P < .05, Col 3: 2.1 vs 1.0 and 1.2-fold; P < .01 and P < .05, TGF-ß1: 1.2 vs 1.0 and 0.9-fold; P < .05 and P < .05, HIF-1α: 1.4 vs 1.0 and 1.0-fold; P < .05 and P < .01). Total collagen and elastin protein levels in vehicle- and vibegron-treated SCI mice did not differ. CONCLUSIONS: Vibegron reduced NVCs, delayed the first NVC, and improved collagen types 1 and 3, TGF-ß1, and HIF-1α mRNA expression in SCI mice. Vibegron might be effective for SCI-induced LUTD.

The early, long-term inhibition of brain-derived neurotrophic factor improves voiding, and storage dysfunctions in mice with spinal cord injury.

AIMS: We examined the time course of urodynamic changes and the effect of the short or long-term inhibition of brain-derived neurotrophic factor (BDNF) from the early phase after spinal cord injury (SCI) in mice. METHODS: The spinal cord of female C57BL/6N mice was completely transected. We examined filling cystometry and bladder BDNF levels at 10, 20, and 30 days after SCI, with an additional day-5 measurement of BDNF. In a separate group of mice, anti-BDNF antibody (Ab) (10 µg/kg/h) was subcutaneously administered using osmotic pumps from day 3 after SCI, and single-filling cystometry was performed at 10 and 30 days (7 and 27 days of treatment, respectively) after SCI. RESULTS: Compared to spinal intact mice, bladder mucosal BDNF was increased at each time point after SCI with the maximal level at day 5 after SCI. Voiding efficiency was lower at each time point after SCI than that of spinal intact mice. The number of non-voiding contractions (NVC) during bladder filling was gradually increased with time. In both 10- and 30-day SCI groups treated with anti-BDNF Ab, voiding efficiency was improved, and the duration of notch-like intravesical pressure reductions during voiding bladder contractions was prolonged. The number of NVC was significantly decreased only in 30-day SCI mice with 27-day anti-BDNF treatment. CONCLUSIONS: Overexpression of BDNF is associated with the deterioration of voiding efficiency after SCI. The early-started, long-term inhibition of BDNF improved voiding dysfunction and was also effective to reduce the later-phase development of detrusor overactivity after SCI.

Therapeutic effects of Choreito, a traditional Japanese (Kampo) medicine, on detrusor overactivity induced by acetic acid in rats.

Choreito (CRT), a traditional Japanese (Kampo) medicine, is widely used for the treatment of overactive bladder (OAB) and other lower urinary tract symptoms in Japan. This study aimed to identify the effects and therapeutic mechanism of CRT on the improvement of detrusor overactivity (DO) using an experimental rat model. Forty-five female Sprague-Dawley rats were equally divided into three groups: intravesical saline instillation with normal food (normal group), intravesical acetic acid (AA) instillation with normal food (AA group), and intravesical AA instillation with CRT (AA with CRT group). To induce a decrease in bladder capacity, instillation of 0.2% AA was used based on prior studies. Cystometric investigation was employed to clarify the effects of AA and CRT. Microcirculation was performed using a laser blood flowmeter, and the localization of hypoxia-inducible factor 1α (HIF1α) was assessed by immunohistochemistry. The bladder capacities of the normal, AA, and AA with CRT groups were 1.2 ± 0.3 mL, 0.4 ± 0.1 mL, and 0.8 ± 0.1 mL, respectively. CRT significantly attenuated AA irritation of the urinary bladder and exerted protective effects on basal pressure, micturition pressure, micturition interval, and micturition volume. Furthermore, CRT could prevent the excess blood flow and edematous change under the urothelium induced by intravesical AA instillation. No obvious changes in immunohistochemical HIF1α staining were observed among the groups. CRT attenuated DO induced by intravesical AA instillation in a rat experimental model. CRT might impart therapeutic effects on OAB via the mitigation of urothelial damage and regulation of excess blood flow.

Urethral dysfunction in a rat model of chemically induced prostatic inflammation: potential involvement of the MRP5 pump.

Prostate inflammation (PI) is a clinical condition associated with infection and/or inflammation of the prostate. It is a common disease frequently associated to lower urinary tract (LUT) symptoms. The urethra is an understudied structure in the LUT and plays a fundamental role in the urinary cycle. Here, we proposed to evaluate the effect of PI on the urethra tissue. Male Sprague-Dawley rats were used, and PI was induced by formalin injection into the ventral lobes of the prostate. The pelvic urethra at the prostatic level was harvested for histological analysis, contraction (electrical field stimulation and phenylephrine), and relaxation (sodium nitroprusside/MK-571) experiments. Various gene targets [cytochrome c oxidase subunit 2, transforming growth factor-ß1, interleukin-1ß, hypoxia-inducible factor-1α, α1A-adrenoceptor, inositol 1,4,5-trisphosphate receptor type 1, voltage-gated Ca2+ channel subunit-α1D, neuronal nitric oxide synthase, soluble guanylyl cyclase, phosphodiesterase 5A, protein kinase CGMP-dependent 1, and multidrug resistance-associated protein 5 (MRP5; ATP-binding cassette subfamily C member 5)] were quantified, and cGMP levels were measured. No histological changes were detected, and functional assays revealed decreased contraction and increased relaxation of urethras from the PI group. The addition of MK-571 to functional assays increased urethral relaxation. Genes associated with inflammation were upregulated in urethras from the PI group, such as cytochrome oxidase c subunit 2, transforming growth factor-ß1, interleukin-1ß, and hypoxia-inducible factor-1α. We also found increased expression of L-type Ca2+ channels and the neuronal nitric oxide synthase enzyme and decreased expression of the MRP5 pump. Finally, cGMP production was enhanced in urethral tissue of PI animals. The results indicate that PI is associated with proinflammatory gene expression in the urethra without histologically evident inflammation and that PI produces a dysfunctional urethra and MRP5 pump downregulation, which results in cGMP accumulation inside the cell. These findings would help to better understand LUT dysfunctions associated with PI and the role of MRP pumps in the control of LUT function.

Morphological and clinical evaluation of prostatic urethra using modified sonourethrography with retrograde jelly injection.

OBJECTIVE: Using modified sonourethrography (mSUG) with retrograde jelly injection to precisely measure the morphological characteristics of the prostatic urethra, we assessed prostatic urethral morphology associated with clinical parameters of benign prostatic hyperplasia (BPH). METHODS: BPH patients (n = 43) and control patients with localized prostate cancer (PC; n = 57) were imaged by mSUG before surgery. Using the seminal colliculus as a landmark, prostatic urethral angulation (PUA), sagittal urethral diameter, and anterior or posterior prostatic urethral length were measured. The International Prostatic Symptoms Score (IPSS) was also evaluated in all patients. The Bladder Outlet Obstruction Index (BOOI) was measured in BPH patients that could void in a pressure-flow study. Parameters were compared between BPH and PC patients, and correlations among morphological and clinical parameters were evaluated. RESULTS: Prostatic urethras were clearly observed in all patients by mSUG. PUA, sagittal urethral diameter, and posterior urethral length were all greater in BPH than PC patients (P < .05). Among all parameters examined, PUA had the strongest correlation with IPSS (r = 0.56). Longitudinal urethral diameter showed the strongest correlation with BOOI, whereas PUA was not correlated with BOOI. CONCLUSIONS: Prostatic urethral morphology can be imaged precisely by mSUG. Morphometric measurements showed that increased PUA was strongly correlated with problematic urinary symptoms, and a flattened shape of the posterior urethra, such as extension of the sagittal urethral diameter, was correlated with urinary tract obstruction by BPH.

Combined treatment with a ß3 -adrenergic receptor agonist and a muscarinic receptor antagonist inhibits detrusor overactivity induced by cold stress in spontaneously hypertensive rats.

AIMS: This study determined if combined treatment with the muscarinic receptor (MR) antagonist solifenacin and the ß3 -adrenergic receptor (AR) agonist mirabegron could inhibit detrusor overactivity induced by cold stress in spontaneously hypertensive rats (SHRs). METHODS: Thirty-two female 10-week-old SHRs were fed an 8% NaCl-supplemented diet for 4 weeks. Cystometric measurements of the unanesthetized, unrestricted rats were performed at room temperature (RT, 27 ± 2°C) for 20 min. The rats were then intravenously administered vehicle, 0.1 mg/kg solifenacin alone, 0.1 mg/kg mirabegron alone, or the combination of 0.1 mg/kg mirabegron and 0.1 mg/kg solifenacin (n = 8 each group). Five minutes later, the treated rats were exposed to low temperature (LT, 4 ± 2°C) for 40 min. Finally, the rats were returned to RT. After the cystometric investigations, the ß3 -ARs and M3 -MRs expressed within the urinary bladders were analyzed. RESULTS: Just after transfer from RT to LT, vehicle-, solifenacin-, and mirabegron-treated SHRs exhibited detrusor overactivity that significantly decreased voiding interval and bladder capacity. However, treatment with the combination of solifenacin and mirabegron partially inhibited the cold stress-induced detrusor overactivity patterns. The decreases of voiding interval and bladder capacity in the combination-treated rats were significantly inhibited compared to other groups. Within the urinary bladders, there were no differences between expression levels of M3 -MR and ß3 -AR mRNA. The tissue distribution of M3 -MRs was similar to that of the ß3 -ARs. CONCLUSIONS: This study suggested that the combination of solifenacin and mirabegron act synergistically to inhibit the cold stress-induced detrusor overactivity in SHRs. Neurourol. Urodynam. 36:1026-1033, 2017. © 2016 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.

[Bilateral Testicular Tumor after Bilateral Orchiopexy : A Case Report].

We report a case of bilateral testicular tumor after bilateral orchiopexy. A 42-year-old man who underwent bilateral orchiopexy in early childhood consulted our hospital due to right testicular enlargement in February 2012. Blood tests revealed elevation of human chorionic gonadotropin ß, and a right testicular tumor was suspected. No metastasis was found on contrast-enhanced computed tomography. Although there was no swelling in the left testis, a heterogeneous hypoechoic mass was detected on left scrotal ultrasonography, and bilateral testicular tumors were supected. Left testis biopsy was performed and an intraoperative rapid diagnosis of a testicular tumor was made. Bilateral high orchiectomy was performed. No recurrence has been found over follow-up for 36 months after surgery.

[A case of advanced prostate fibrosarcoma that reacted well to chemotherapy].

Prostate fibrosarcoma is an extremely rare tumor for which complete excision has been the mainstay of treatment. Although chemotherapy has been attempted in cases with positive surgical margins and/or advanced stage disease, the effectiveness of this therapy has not been established. Herein, we report a case of advanced prostate fibrosarcoma that reacted well to chemotherapy. A 40-year-old man was referred for treatment of a large prostatic tumor with multiple lung, liver, and bone metastases. Needle biopsy of the prostate revealed that the tumor was a high-grade undifferentiated sarcoma. Chemotherapy with doxorubicin and ifosfamide was administered. After five courses of chemotherapy, the primary prostate tumor decreased markedly, and the lung and liver metastases almost disappeared. Radical cystoprostatectomy and ileal conduit formation were performed. Pathological diagnosis was fibrosarcoma. Another three courses of doxorubicin and ifosfamide therapy were performed, and doxorubicin was replaced by etoposide because the maximum dose of doxorubicin was reached. However, the effectiveness of the second-line therapy was poor, and the tumor progressed again. The patient died of lung metastasis 15 months later.

[Two cases of lower abdominal tumors difficult to differentiate from urachal tumors].

CASE 1: A 28-year-old woman visited a local medical doctor, complaining of abdominal pain, urinary frequency and a sense of residual urine. Magnetic resonance imaging revealed a lower abdominal extraperitoneal tumor, approximately 5 cm in diameter, adjacent to the bladder dome. It was thought to be a urachal tumor, and she was referred to our hospital. A hard hen's egg-sized mass was palpable in the lower abdomen. Urinary analysis was normal. Cytological examination was also negative. Cystoscopy revealed redness in the bladder dome mucosa. Although the preoperative diagnosis was a urachal cancer, the pathological diagnosis on surgery was desmoids, and tumor excision was performed. No recurrence has been seen for 7 years postoperatively. CASE 2: A 71-year-old man complaining of swelling of the lower abdomen was referred to our department because he was suspected to have a urachal tumor, of about 15 cm in diameter, on computed tomography. A hard infant head-sized mass was palpable in the lower abdomen. Urinary analysis was normal. Cystoscopical examination showed a markedly compressed bladder dome, however, no abnormal findings were seen in the mucosa. Although the preoperative diagnosis was a urachal tumor, the intraoperative pathological diagnosis revealed no malignancy. The mass was connected to the bladder dome, and partial cystectomy was conducted. The final pathological diagnosis was a solitary fibrous tumor. No recurrence has been seen for 5 years postoperatively. Because a urachal tumor is highly malignant, radical cystectomy and urinary diversion might be planned preoperatively. However, care should be taken not to be too invasive, considering the possibility of a benign tumor.

[A case of alpha-fetoprotein-producing female urethral adenocarcinoma].

We report a rare case of alpha-fetoprotein (AFP)-producing female urethral adenocarcinoma. A 52- year-old woman had urinary frequency. Ultrasonography showed a mass near the bladder. Therefore, she was referred to our hospital. Magnetic resonance imaging showed an approximately 4 cm mass at the urethra. Computed tomography did not show any lymphnode metastasis or distant metastasis. High serum levels of AFP were revealed. Carcinoembryonic antigen (CEA) and prostate specific antigen (PSA) were within the normal range. A transvaginal needle biopsy suggested adenocarcinoma. Radical cystourethrectomy and ileal conduit formation were performed. Histopathological diagnosis was adenocarcinoma. Immunohistochemical staining was positive for AFP and CEA, and negative for PSA. Serum AFP normalized immediately postoperatively. Adjuvant chemotherapy or radiotherapy was not performed. Eleven years postoperatively, the patient showed no evidence of tumor recurrence. To our knowledge, this is the first reported case of AFP producing female urethral adenocarcinoma.