The activated complement pathway in the fibrous process of benign prostatic hyperplasia.

BACKGROUND: To elucidate the changes in activated complement pathway in the fibrous process of benign prostatic hyperplasia (BPH), we analyzed the correlation between complement component expression and histological types of fibrosis using human BPH tissue. METHODS: Fifty-six histological BPH patients who underwent prostate needle biopsy at our institution (mean age 68.6 ± 6.5 years), divided into two histological groups, fibromuscular and fibrous, were compared. Inflammatory cell infiltration in BPH tissue was evaluated by immunohistochemical staining using CD45, with complement expression analysis performed using C3, factor B, and C5b-9 antibody, and the occupancy ratio of the stained region was calculated. Further, correlation between the histological types of fibrous components in BPH tissue and lower urinary tract symptoms questionnaires was analyzed. RESULTS: Twenty-seven (48.2%) and 29 (51.8%) cases were classified in the fibromuscular and fibrous groups, respectively. The proportion of CD45-positive cells in BPH tissue was significantly higher in the fibromuscular group. In complement component analysis, factor B did not significantly differ between groups, while C3 (fibromuscular group; 10.7 ± 8.2%, fibrous group; 16.4 ± 12.7%) and C5b-9 (fibromuscular group; 15.9 ± 6.2%, fibrous group; 17.6 ± 9.2%) were significantly higher in the fibrous group (p = 0.04, p = 0.04, respectively). International Prostate Symptom Score Q5 subscore, indicating slow stream, was significantly higher in the fibrous group (p = 0.04). CONCLUSIONS: In fibrous BPH with abundant fibrosis, the late complement pathway in addition to alternative pathway was activated compared to fibromuscular BPH. These results suggested that the alternative and late complement pathways were involved in the histological fibrous process of BPH.

Effects of oral administration of nonselective Trk inhibitor on bladder overactivity in rodent models of prostatic inflammation.

BACKGROUND: Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI). METHODS: Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin. RESULTS: The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity. CONCLUSIONS: The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity.

Improvement of lower urinary tract dysfunction by a monoacylglycerol lipase inhibitor in mice with spinal cord injury.

AIMS: Activation of the endocannabinoid system by monoacylglycerol lipase (MAGL) blockade may affect the lower urinary tract function. We investigated the effect of an MAGL inhibitor, MJN110, on neurogenic lower urinary tract dysfunction (LUTD) in the mouse model of spinal cord injury (SCI). METHODS: Female C57BL/6 mice that underwent spinal cord transection at T8-10 level were divided into three groups consisting of (1) vehicle-treated SCI mice, (2) 5 mg/kg, or (3) 10 mg/kg of MJN110-treated SCI mice. MJN110 and vehicle were administered intraperitoneally for 7 days from 4 weeks after spinal cord transection. We then conducted awake cystometrograms and compared urodynamic parameters between three groups. The expression of cannabinoid (CB) receptors, TRP receptors, and inflammatory cytokines in L6-S1 dorsal root ganglia (DRG) or the bladder mucosa were evaluated and compared among three groups. Changes in the level of serum 2-arachidonoylglycerol (2-AG) and bladder MAGL were also evaluated. RESULTS: In the cystometrogram, detrusor overactivity (DO) parameters, such as the number of nonvoiding contraction (NVC), a ratio of time to the 1st NVC to intercontraction interval (ICI), and NVC integrals were improved by MJN110 treatment, and some effects were dose dependent. Although MJN110 did not improve voiding efficiency, it decreased bladder capacity, ICI, and residual urine volume compared to vehicle injection. MJN110 treatment groups had lower CB2, TRPV1, TRPA1, and inflammatory cytokines mRNA levels in DRG and bladder mucosa. Serum 2-AG was increased, and bladder MAGL was decreased after MAGL inhibitor treatment. CONCLUSIONS: MAGL inhibition improved LUTD including attenuation of DO after SCI. Thus, MAGL can be a therapeutic target for neurogenic LUTD after SCI.

Prognosis of lower urinary tract symptoms and function after robot-assisted radical prostatectomy in patients with preoperative low bladder contractility: A prospective, observational study.

OBJECTIVES: To examine the prognosis of lower urinary tract symptoms and function after robot-assisted radical prostatectomy (RARP) in patients with low preoperative bladder contractility. METHODS: A total of 115 patients who underwent RARP were enrolled and divided into two groups by preoperative urodynamic findings: normal (patients with bladder contractility index [BCI] ≥ 100; n = 70) and low contractility (patients with BCI < 100; n = 45) groups. Lower urinary tract symptoms and function parameters were prospectively evaluated at 1, 3, 6, 9, and 12 months after RARP in both groups. RESULTS: International Prostatic Symptom Score voiding scores 1, 3, 6, 9, and 12 months after RARP were significantly higher (p < 0.05), and the maximum flow rate (Qmax) values before and 1, 3, 9, and 12 months after RARP were significantly lower in the low contractility group (p < 0.05). Comparing preoperative and postoperative parameters, IPSS voiding scores in the normal contractility group were significantly improved from 6 months after RARP, whereas those in the low contractility group were almost unchanged. Qmax and the 1-h pad test in both groups temporarily deteriorated 1 month after RARP, whereas voided volume and postvoiding residual volume significantly decreased from 1 to 12 months after RARP. CONCLUSIONS: This observational study showed that patients with low preoperative bladder contractility might have a weak improvement in voiding symptoms and function after RARP.

Association between nocturnal polyuria and 24-h blood pressure fluctuations in males with lower urinary tract symptoms: A multicenter prospective study.

OBJECTIVES: Nocturnal polyuria (NP) is one of the causes of nocturia that impairs quality of life. It is necessary to consider that NP is latent when the initial treatment for nocturia is unsatisfactory. Therefore, it is important to establish a treatment for NP based on the pathophysiology. We have previously reported the relationship between NP and fluctuation in blood pressure. The present study aimed to investigate the association between NP and 24-h blood pressure fluctuations in a multicenter prospective study. METHODS: This study included male patients with lower urinary tract symptoms. We categorized the patients into the nonnocturnal polyuria (non-NP) group (≤0.33) and the NP group (>0.33) based on the nocturnal polyuria index from the frequency volume chart. We measured the 24-h diurnal blood pressure and compared the two groups. RESULTS: Among 90 patients, 46 in the non-NP group and 44 in the NP group were included. There was no significant difference in the systolic and diastolic blood pressure during waking time between the two groups; however, the degree of systolic blood pressure reduction during sleep time in the NP group was significantly less than that in the non-NP group (p = 0.039). In the multivariate analysis, systolic BP during sleep was significantly associated with NP (OR 0.970, p = 0.028). CONCLUSION: NP is associated with inadequate nocturnal blood pressure reduction in males, suggesting that reduction in nocturnal blood pressure may lead to improvement in nocturia.

Unilateral adrenalectomy for a drug-resistant bilateral primary aldosteronism with heart failure: pathophysiology and surgical indication.

BACKGROUND: Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to refractory hypertension has not been established. In this report, we present a case with bilateral PA who presented with persistent hypertension, despite treatment with 6 drugs, and left-dominant heart failure, which was improved after unilateral adrenalectomy. CASE PRESENTATION: A 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. His heart rhythm was atrial fibrillation and the left ventricle was diffusely hypertrophic and hypokinetic. Coronary arteries were normal on coronary arteriogram. Primary aldosteronism was suspected based on severe hypokalemia (2.5 mEq/L) and plasma aldosterone concentration (PAC; 1,410 pg/mL). Although computed tomography (CT) showed a single left cortical nodule, adrenal vein sampling (AVS) indicated bilateral PA. Early in the case, heart failure and hyperkalemia in this patient were improved by treatment with a combination of 6 antihypertensive drugs (spironolactone 25 mg/day, eplerenone 100 mg/day, azosemide 60 mg/day, tolvaptan 7.5 mg/day, enalapril 5 mg/day, and bisoprolol fumarate 10 mg/day); however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient's heart failure. In order to reduce aldosterone secretory tissue, a laparoscopic adrenalectomy was performed for the left adrenal gland, given the higher level of aldosterone from the left gland compared to the right. Following surgery, the patient's heart failure was successfully controlled despite the persistence of high PAC. Treatment with anti-hypertensive medications was reduced to two drugs (eplerenone 100 mg/day and bisoprolol fumarate 10 mg/day). In order to elucidate the mechanism of drug resistance, immunohistochemistry (IHC) and real time-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue. IHC and RT-PCR demonstrated that the expression of SF-1 in this patient (at both the protein and mRNA levels) was higher than that observed in unilateral PA cases that showed good responsivity to drug treatment. CONCLUSIONS: Unilateral adrenalectomy to reduce aldosterone secretory tissue may be useful for patients with drug-refractory, bilateral PA. Elevated expression of SF-1 may be involved in drug resistance in PA.

Mechanism of Androgen-Independent Stromal Proliferation in Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a chronic proliferative disease showing stromal-dominant proliferation. However, the detailed proliferation mechanism has remained unclear. Although aging and androgen have been reported as definitive risk factors for BPH, recent studies have focused on the involvement of androgen-independent factors. Androgen-independent factors include ischemia, oxidative stress, metabolic syndrome, infection, autoimmune reactions, and inflammation, with inflammation in BPH tissues playing a central role in the BPH proliferative process. Inflammation in BPH tissues by various factors finally leads to tissue remodeling and stromal proliferation through the wound healing process of the prostate. To elucidate the proliferative mechanism of BPH, a study using whole-genome gene expression analysis in a stromal-dominant BPH rat model was performed and showed that immune response-related pathways and complement classical pathways are activated. Furthermore, expression analysis using this BPH rat model showed that the autoimmune reaction triggered complement pathway activation in the proliferative process of BPH. BPH is a multifactorial disease, and understanding the role of androgen-independent factors including immune responses contributes to elucidating the pathogenesis of BPH. Androgen-independent factors may lead to new therapeutic targets for BPH, and further development of this research is expected.

Involvement of Mast-Cell-Tryptase- and Protease-Activated Receptor 2-Mediated Signaling and Urothelial Barrier Dysfunction with Reduced Uroplakin II Expression in Bladder Hyperactivity Induced by Chronic Bladder Ischemia in the Rat.

We aimed to investigate the relationship between mast cell (MC) infiltration into the bladder with urothelial barrier dysfunction and bladder hyperactivity in a chronic bladder ischemia (CBI) rat model. We compared CBI rats (CBI group; n = 10) with normal rats (control group; n = 10). We measured the expression of mast cell tryptase (MCT) and protease-activated receptor 2 (PAR2), which are correlated with C fiber activation via MCT, and Uroplakins (UP Ia, Ib, II and III), which are critical to urothelial barrier function, via Western blotting. The effects of FSLLRY-NH2, a PAR2 antagonist, administered intravenously, on the bladder function of CBI rats were evaluated with a cystometrogram. In the CBI group, the MC number in the bladder was significantly greater (p = 0.03), and the expression of MCT (p = 0.02) and PAR2 (p = 0.02) was significantly increased compared to that of the control group. The 10 µg/kg FSLLRY-NH2 injection significantly increased the micturition interval of CBI rats (p = 0.03). The percentage of UP-II-positive cells on the urothelium with immunohistochemical staining was significantly lower in the CBI group than in the control group (p < 0.01). Chronic ischemia induces urothelial barrier dysfunction via impairing UP II, consequently inducing MC infiltration into the bladder wall and increased PAR2 expression. PAR2 activation by MCT may contribute to bladder hyperactivity.

Insights into the development of a new index, vesical adaptation response to diuresis, for understanding lower urinary tract dysfunction.

OBJECTIVES: To clarify how vesical adaptation response, the homeostatic system that constantly changes voided volume to adapt to diuresis, is involved in male lower urinary tract symptoms and bladder storage function. METHODS: We included male patients older than 65 years with lower urinary tract symptoms. Vesical adaptation response to diuresis was defined as a positive correlation between urine output rate and voided volume on 3-day sensory-related frequency volume charts. Patients were divided into two groups according to the presence or absence of vesical adaptation response to diuresis, and characteristics were compared between groups. RESULTS: Ninety-four male patients were finally analyzed. Vesical adaptation response to diuresis was found in 48 patients (51%) and was lacking in 46 patients (49%). Patients without vesical adaptation response to diuresis were significantly more often diagnosed with overactive bladder (P = 0.04). After adjusting for confounders, absence of vesical adaptation response to diuresis was significantly associated with overactive bladder (adjusted odds ratio 3.76, 95% confidence interval 1.34-10.55; P = 0.01) and benign prostatic enlargement (adjusted odds ratio 1.04, 95% confidence interval 1.01-1.07; P = 0.02). CONCLUSIONS: The absence of vesical adaptation response to diuresis, characterized by decreased voided volume during a diuretic phase, can be interpreted as a form of bladder storage dysfunction. Assessment of vesical adaptation response to diuresis may provide a new index of bladder storage function and contribute to a better understanding of the pathophysiology underlying bladder storage dysfunction in patients with lower urinary tract symptoms.

Upregulation of glucocorticoid receptor-mediated glucose transporter 4 in enzalutamide-resistant prostate cancer.

Enzalutamide (Enz) is a second-generation androgen receptor (AR) antagonist for castration-resistant prostate cancer (CRPC) therapy, and it prolongs survival time in these patients. However, during Enz treatment, CRPC patients usually acquire resistance to Enz and often show cross-resistance to other AR signaling inhibitors. Although glucocorticoid receptor (GR) is involved in this resistance, the role of GR has not yet been clarified. Here, we report that chronic Enz treatment induced GR-mediated glucose transporter 4 (GLUT4) upregulation, and that upregulation was associated with resistance to Enz and other AR signaling inhibitors. Additionally, inhibition of GLUT4 suppressed cell proliferation in Enz-resistant prostate cancer cells, which recovered from Enz resistance and cross-resistance without changes in GR expression. Thus, a combination of Enz and a GLUT4 inhibitor could be useful in Enz-resistant CRPC patients.

The effect of ß3-adrenoceptor gene polymorphisms on lower urinary tract function in males.

PURPOSE: To clarify the role of Trp64Arg polymorphisms of the gene encoding the ß3-adrenoceptor for lower urinary tract function in males, the present study investigated the association between the Trp64Arg polymorphisms and lower urinary tract symptoms (LUTS) and function. METHODS: This prospective observational study included patients who underwent robot-assisted radical prostatectomy. Before surgery, blood samples were collected, and analyses of ß3-adrenoceptor gene polymorphism were performed using the real-time polymerase chain reaction. The present cohort was divided into patients with wild type (Trp64Trp) and with variant type (Trp64Arg + Arg64Arg), and LUTS and lower urinary tract function before surgery were compared between them. RESULTS: Wild type was found in 247 patients, with variant type in 129. There were no significant differences in LUTS between the two groups. Residual urine volume (PVR) (wild type: variant type = 47 ± 53 mL: 58 ± 77 mL, P = 0.04) and voiding time on uroflowmetry (wild type: variant type = 29 ± 15 s: 33 ± 17 s, P = 0.04) were significantly increased in the variant type. CONCLUSION: The Trp64Arg variant of the ß3-adrenoceptor gene significantly increased PVR and voiding time in men. However, it was not significantly associated with the emergence of LUTS. Thus, since the effect of ß3-adrenoceptor gene polymorphisms on the genitourinary organs might be weak, whether men possess the Trp64Arg variant of the ß3-adrenoceptor gene might not critically affect urinary quality of life, but modestly affect the lower urinary tract function.

Prevalence and predictors of postoperative detrusor underactivity after robot-assisted radical prostatectomy: A prospective observational study.

OBJECTIVES: To identify the prevalence and predictors of postoperative detrusor underactivity during the early postoperative period after robot-assisted radical prostatectomy. METHODS: We carried out a prospective observational study of 64 patients scheduled for robot-assisted radical prostatectomy using urodynamic study before and 1 month after robot-assisted radical prostatectomy. Detrusor underactivity was defined as maximum flow rate ≤15 mL/s and detrusor pressure at maximum flow rate ≤25 cmH2 O during voiding. Incidences of pre- and postoperative detrusor underactivity were assessed, and predictors of postoperative detrusor underactivity were determined using uni- and multivariate logistic regression analyses. Factors comprised patient characteristics (age, prostate weight etc.), operative factors (surgical duration, nerve sparing etc.) and preoperative urodynamic study parameters (maximum flow rate, bladder contractile index etc.). RESULTS: Pre- and postoperative detrusor underactivity at 1 month after robot-assisted radical prostatectomy were detected in one patient (1.6%) and 24 patients (37.5%), respectively. Univariate analysis selected preoperative maximum flow rate (P = 0.02), detrusor pressure at maximum flow rate (P = 0.04) and bladder contractile index (P < 0.01) as predictors of postoperative detrusor underactivity (odds ratio 0.83, 0.97 and 0.94, respectively). On multivariate analyses, only preoperative bladder contractile index was associated with postoperative detrusor underactivity (P < 0.01; odds ratio 0.94). A cut-off of 102.8 offered optimal accuracy in receiver operating characteristic analysis. Patient characteristics and operative factors were not significantly associated with postoperative detrusor underactivity. CONCLUSIONS: A comparatively high prevalence of postoperative detrusor underactivity is observed in patients at 1 month after robot-assisted radical prostatectomy. Patients with preoperative low bladder contractile index have a higher probability of developing early postoperative detrusor underactivity after robot-assisted radical prostatectomy.

Perioperative Detection of Circulating Tumor Cells in Radical or Partial Nephrectomy for Renal Cell Carcinoma.

BACKGROUND: The current study was conducted to clarify the frequency of systemic circulating tumor cells (CTCs) appearing after surgery for renal cell carcinoma and to evaluate the differences in postoperative CTCs between different surgical procedures. METHODS: This prospective, cohort study included 60 consecutive patients who underwent laparoscopic radical nephrectomy (RN) (n = 22), laparoscopic partial nephrectomy (PN) (n = 19), open RN (n = 8), or open PN (n = 11). In this study CTCs were measured by the FISHMAN-R system, and CTCs drawn from a peripheral artery were collected just before and immediately after surgery. The number of pre- and postoperative CTCs and the perioperative changes in CTCs were measured for each surgical method. RESULTS: Six patients were excluded from the current analyses. Preoperative CTCs did not differ significantly by surgical approach (laparoscopic RN: 3.4 ± 4.2; laparoscopic PN: 3.4 ± 4.1; open RN: 7.7 ± 6.8; open PN: 6.0 ± 7.6; P = 0.19). Open RN resulted in a significantly greater number of postoperative CTCs (laparoscopic RN: 4.8 ± 3.7; laparoscopic PN: 7.9 ± 9.1; open RN: 22.5 ± 26.3; open PN: 6.4 ± 6.3; P < 0.001) and perioperative changes in CTCs (laparoscopic RN: 1.3 ± 5.3; laparoscopic PN: 4.5 ± 9.6; open RN: 14.7 ± 25.0; open PN: 0.4 ± 6.3; P < 0.001). No significant differences in these were observed among the three groups except in the open RN group. In the multivariate analysis, the surgical approach was significantly correlated with the number of postoperative CTCs (P = 0.016) and the perioperative change in CTCs (P = 0.01). CONCLUSIONS: This proof-of-concept study indicated that after surgery, more cancer cells can be expelled into the bloodstream, especially after open RN. Sufficient and careful follow-up assessment for the emergence of distant metastases is needed for patients undergoing open RN.

Morphological change and characteristics of myofibroblasts during the growth process of benign prostatic hyperplasia.

OBJECTIVES: To clarify the morphological change and characteristics of myofibroblast during the growth process of benign prostatic hyperplasia. METHODS: This study examined the characteristics of myofibroblasts during the growth process of the prostate in the stromal component-dominant benign prostatic hyperplasia rat model. Transforming growth factor-ß1 and insulin-like growth factor-binding protein 3 expression were evaluated by western blotting (n = 6). We used double immunohistochemical staining to evaluate the number of myofibroblasts positive for α-smooth muscle actin and vimentin in benign prostatic hyperplasia tissues. Expression and histological analyses of the benign prostatic hyperplasia were also carried out in rats at 2, 3 and 8 weeks after urogenital sinus implantation (n = 6). To evaluate the fine morphological characteristics of myofibroblasts in human benign prostatic hyperplasia tissues, electron microscopy analysis was additionally carried out. RESULTS: There was a significant upregulation of the transforming growth factor-ß1 and insulin-like growth factor-binding protein 3 expression in benign prostatic hyperplasia (P < 0.05). There was a significant increase in the number of myofibroblasts in benign prostatic hyperplasia (P < 0.05) compared with normal prostate, with these abundantly located in the stromal area. The transforming growth factor-ß1 and insulin-like growth factor-binding protein 3 expression and number of myofibroblasts showed a time-dependent increase (P < 0.05), with growth factor expressions preceding the myofibroblast increase. Electron microscopy confirmed that the myofibroblast progenitor cells, which possess abundant stress fibers, were predominantly located around fibrous areas in human benign prostatic hyperplasia. CONCLUSIONS: Differentiation into myofibroblasts induced by transforming growth factor-ß1 and insulin-like growth factor-binding protein 3 actively occurs during the growth process of benign prostatic hyperplasia. Myofibroblast progenitor cells seem to be associated with prostatic fibrosis in human benign prostatic hyperplasia.

Usefulness of a novel classification based on perioperative changes of membranous urethral length using hierarchical cluster analysis of urinary incontinence and overactive bladder symptoms after robot-assisted radical prostatectomy: A prospective observational study.

AIMS: The aim of the present study was to construct a novel classification based on perioperative changes of membranous urethral length (MUL) using hierarchical cluster analysis to predict urinary incontinence (UI) and overactive bladder (OAB) symptoms after robot-assisted radical prostatectomy (RARP). METHODS: A total of 299 patients who underwent RARP with complete pre and postoperative MUL data were included in the present study. Hierarchical cluster analysis was performed to identify the groups with similar perioperative MUL and prostate size. UI and OAB symptoms after RARP were evaluated in each cluster for 12 months after RARP. RESULTS: Four groups were identified by the cluster analysis of these factors: preservation of MUL type (cluster 1, n = 92); standard type (cluster 2, n = 137); large prostate type (cluster 3, n = 23); and loss of MUL type (cluster 4, n = 47). Although there was significantly more UI in clusters 3 and 4 than in clusters 1 and 2 up to 3 months after RARP, UI improvement was the most delayed in cluster 3. Improvement of OAB symptoms was also most delayed in cluster 3. Urinary quality of life (QOL) was significantly worse in cluster 4 than in clusters 1 and 2. CONCLUSIONS: Cluster analysis successfully classified patients after RARP into four characteristic groups based on perioperative MUL. Recovery from UI and OAB symptoms and urinary QOL after RARP were significantly different among these groups. This classification based on cluster analysis might be useful to predict recovery from UI and OAB symptoms when following QOL after RARP.

Atherosclerosis as a predictor of transient exacerbation of overactive bladder symptoms after robot-assisted laparoscopic radical prostatectomy.

OBJECTIVES: To assess whether atherosclerosis is involved in the development of overactive bladder and the function of lower urinary tract after robot-assisted radical prostatectomy. METHODS: The present cohort consisted of 80 consecutive participants. The preoperative cardio-ankle vascular index was used to evaluate the presence of atherosclerosis. The present cohort was split into two groups, the atherosclerotic group, whose cardio-ankle vascular index was ≥9.0, and the control group, whose index was <9.0. The overactive bladder symptom score and lower urinary tract function were compared for 12 months after surgery. RESULTS: The total score of the questionnaire was significantly higher at 6 and 9 months after surgery in the atherosclerosis group (P = 0.04, P = 0.03, respectively). Both the urgency and urgency incontinence subscores of the questionnaire showed a parallel tendency to that of the total score after surgery. At 3 months after surgery, there was a significant increase in the prevalence of de novo overactive bladder in the atherosclerosis group (P = 0.04). At 9 and 12 months after surgery, there was a significant decrease of voided volume in the atherosclerotic group (P < 0.01, P = 0.04, respectively). CONCLUSIONS: Atherosclerosis delays the improvement in both overactive bladder symptoms and storage function postoperatively, and it is involved in the transient increase in the prevalence of de novo overactive bladder. Atherosclerosis might be a predictor of the development of overactive bladder after robot-assisted radical prostatectomy.

The association between local atherosclerosis of the prostatic artery and benign prostatic enlargement in humans: Putative mechanism of chronic ischemia for prostatic enlargement.

BACKGROUND: To investigate the possible pathogenesis of the benign prostatic enlargement (BPE) induced by local atherosclerosis, the association between local atherosclerosis and prostatic enlargement was investigated, and molecular biological analyses were performed using human prostatectomy specimens. METHODS: A total of 69 consecutive patients who underwent robot-assisted radical prostatectomy (RARP) participated in this prospective study. To evaluate actual local atherosclerosis, prostatic arteries were removed during RARP. Microscopic assessment of local atherosclerosis was classified as one of three degrees of narrowing (minimal, moderate, and severe) according to the degree of obstruction of the inner cavity of the prostatic artery. The expressions of several mediators related to chronic ischemia and cell proliferation of the prostate were investigated by immunohistochemistry. RESULTS: The median age of the present cohort was 68 (range: 55-75) years. Although there was no relationship between local atherosclerosis and lower urinary symptoms evaluated by questionnaires, local atherosclerosis was significantly more severe in patients who had a history of treatment for benign prostatic hyperplasia (P = 0.02). Prostate size was significantly larger in the severe local atherosclerosis group than in the minimal and moderate local atherosclerosis groups (P < 0.001 and P = 0.03, respectively). Thepositive expression rates of hypoxia-inducible factor (HIF)-1α, malondialdehyde (MDA), transforming growth factor (TGF)-ß1 , and basic fibroblast growth factor (bFGF) in the prostate were significantly higher in patients with local atherosclerosis than in patients without local atherosclerosis (all P < 0.01, respectively). CONCLUSIONS: In human surgical specimens, there is evidence that local atherosclerosis of the prostatic artery is significantly associated with prostate size. Given the molecular evidence provided in this study, the putative mechanism for this relationship is that chronic ischemia induced upregulation of oxidative stress pathways, leading to BPE.

The impact of nerve-sparing robot-assisted radical prostatectomy on lower urinary tract function: Prospective assessment of patient-reported outcomes and frequency volume charts.

AIMS: To elucidate the effects of a nerve-sparing (NS) procedure on lower urinary tract symptoms (LUTS) and urinary function after robot-assisted radical prostatectomy (RARP), the associations between the NS procedure and LUTS and urinary function were investigated. METHODS: The participants in this study were 200 consecutive patients who underwent RARP. These patients were categorized into unilateral and bilateral NS groups and the non-NS group. The International Prostate Symptom Score (IPSS), quality of life (QOL) index, frequency-volume chart, uroflowmetry, 1-h pad test, and the 5-item International Index of Erectile Function (IIEF-5) questionnaire were evaluated before and after RARP. RESULTS: The total IPSS score was significantly lower in the unilateral (P = 0.03) and bilateral NS groups (P = 0.03) than in the non-NS group after RARP. Diurnal maximum voided volume (MVV) values were significantly greater in the bilateral NS group than in the non-NS group after RARP (P = 0.002). Nocturnal frequency was significantly decreased in the unilateral NS group than in the non-NS group after RARP (3 months P = 0.01, 12 months P = 0.01). Erectile function was significantly better in both the unilateral NS group (P < 0.0001) and the bilateral NS group (P = 0.02) than in the non-NS group 12 months after RARP. CONCLUSIONS: The NS procedure in RARP has the possibility to improve not only erectile function, but also LUTS, owing to both the increase of MVV and the decrease of nocturia. Therefore, the NS procedure is also recommended from the viewpoint of early improvement of LUTS and lower urinary tract dysfunction after RARP.

Case of possible multiple system atrophy with a characteristic imaging finding of open bladder neck during storage phase as an initial sign.

Multiple system atrophy is a neurodegenerative disease that affects autonomic and motor systems. Patients with multiple system atrophy usually experience lower urinary tract symptoms, which sometimes appear as an initial symptom before the emergence of the generalized symptoms. An open bladder neck during the filling phase on video urodynamic study is one characteristic imaging finding after the diagnosis of multiple system atrophy, but has not previously been reported at an early phase of the disease. We report a case in which an open bladder neck was observed on several imaging modalities before generalized symptoms emerged. Because occult neurogenic bladder might exist in patients whose lower urinary tract symptoms are resistant to pharmacotherapy, we report this case to raise awareness of the importance of sufficient imaging evaluations. An open bladder neck might be an important imaging finding for diagnosing multiple system atrophy, irrespective of the presence of generalized symptoms. This finding could help avoid false diagnosis and unnecessary treatment.

Pathophysiology of Overactive Bladder and Pharmacologic Treatments Including ß3-Adrenoceptor Agonists -Basic Research Perspectives.

Overactive bladder (OAB) is a symptom-based syndrome defined by urinary urgency, frequency, and nocturia with or without urge incontinence. The causative pathology is diverse; including bladder outlet obstruction (BOO), bladder ischemia, aging, metabolic syndrome, psychological stress, affective disorder, urinary microbiome, localized and systemic inflammatory responses, etc. Several hypotheses have been suggested as mechanisms of OAB generation; among them, neurogenic, myogenic, and urothelial mechanisms are well-known hypotheses. Also, a series of local signals called autonomous myogenic contraction, micromotion, or afferent noises, which can occur during bladder filling, may be induced by the leak of acetylcholine (ACh) or urothelial release of adenosine triphosphate (ATP). They can be transmitted to the central nervous system through afferent fibers to trigger coordinated urgency-related detrusor contractions. Antimuscarinics, commonly known to induce smooth muscle relaxation by competitive blockage of muscarinic receptors in the parasympathetic postganglionic nerve, have a minimal effect on detrusor contraction within therapeutic doses. In fact, they have a predominant role in preventing signals in the afferent nerve transmission process. ß3-adrenergic receptor (AR) agonists inhibit afferent signals by predominant inhibition of mechanosensitive Aδ-fibers in the normal bladder. However, in pathologic conditions such as spinal cord injury, it seems to inhibit capsaicin-sensitive C-fibers. Particularly, mirabegron, a ß3-agonist, prevents ACh release in the BOO-induced detrusor overactivity model by parasympathetic prejunctional mechanisms. A recent study also revealed that vibegron may have 2 mechanisms of action: inhibition of ACh from cholinergic efferent nerves in the detrusor and afferent inhibition via urothelial ß3-AR.