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Takahira Kuno,1,2 Kenji Tamura,1,3 Nobutaka Shimizu,1 Hideo Fukuhara,1 Satoshi Fukata,1 Shingo Ashida,1 Takashi Karashima,1 Hirofumi Satake,3 Kohji Sawada,4 Ichiro Yamasaki,5 Fumito Komatsu,2 Hajime Kuroiwa,6 Motoaki Saito,7 Keiji Inoue1 1Department of Urology, Kochi Medical School, Kochi University, Nankoku, Japan; 2Department of Urology, Tosa Municipal Hospital, Tosa, Japan; 3Department of Urology, Chikamori Hospital, Kochi, Japan; 4Department of Urology, Kochi Prefectural Hata Kenmin Hospital, Sukumo, Japan; 5Department of Urology, Kubokawa Hospital, Takaoka-gun, Japan; 6Integrated Center for Advanced Medical Technologies (ICAM-Tech), Kochi Medical School, Nankoku, Japan; 7Department of Pharmacology, Kochi Medical School, Kochi University, Nankoku, JapanCorrespondence: Kenji Tamura, Email tamurak@kochi-u.ac.jpObjective: The treatment effects of vibegron have not previously been evaluated in a prospective, non-interventional observational study of elderly Japanese patients, particularly those ≥ 80 years old. In addition, no reports have referred to residual urine volume in switching cases. We therefore grouped patients by condition and investigated the treatment effects of vibegron on Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire Short Form (OAB-q SF), and residual urine volume in each group.Methods: This multicenter, prospective, non-interventional, observational study consecutively enrolled OAB patients with total OABSS score ≥ 3 and OABSS question 3 score ≥ 2. Sixty-three patients from six centers were recruited. Vibegron 50 mg once daily was administered for 12 weeks as first-line monotherapy (first-line group), monotherapy switching from antimuscarinics or mirabegron due to failure of prior therapy (no washout period), or combination therapy with antimuscarinics (second-line group). OABSS, OAB-q SF, and residual urine volume were collected after 4 and 12 weeks. Adverse events were also recorded at each visit.Results: Of the 63 patients registered, 61 were eligible for analysis (first line, n=36; second line, n=25). The OABSS, excluding daytime frequency scores, and OAB-q SF scale showed significant improvement in all conditions. Switching from mirabegron to vibegron significantly reduced residual urine volume. No serious treatment-related adverse events were encountered.Conclusion: Vibegron 50 mg once daily significantly improved OABSS and OAB-q SF even in patients ≥ 80 years old. Notably, switching from mirabegron to vibegron resulted in significant improvements to residual urine volume.Keywords: selective β 3-adrenoreceptor agonist, overactive bladder, residual urine volume, vibegron, mirabegron

To investigate the effects of pretreatment with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate on bladder dysfunction in cyclophosphamide-induced hemorrhagic cystitis in rats.Male Wistar rats (340-460 g) were pretreated with vehicle or with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (100/157 or 300/471 mg/kg/day, po) once daily for 7 days before cystometry. Saline or cyclophosphamide (150 mg/kg, ip) was administered 2 days before cystometry. Cystometry was performed under urethane anesthesia (0.8 g/kg, ip) via a catheter inserted into the bladder. After cystometry, bladder tissues were collected to perform hematoxylin and eosin staining for pathological evaluation (neutrophil infiltration, edema, and bleeding scores), and for enzyme-linked immunosorbent assay and real-time polymerase chain reaction for investigating tissue levels of myeloperoxidase, and mRNA levels of haem oxygenase-1 as a cytoprotective molecule.Compared to controls, cyclophosphamide induced a shorter intercontraction interval, lower bladder compliance, increased number of non-voiding contractions, and increased pathological scores and myeloperoxidase expression in the bladder. Pretreatment with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate (300/471 mg/kg/day) significantly improved cyclophosphamide-induced intercontraction interval shortening and increases in number of non-voiding contractions and neutrophil infiltration/bleeding scores and enhanced haem oxygenase-1 expression in the bladder. In addition, cyclophosphamide-induced decreases in bladder compliance and increases in myeloperoxidase were not detected with 5-aminolevulinic acid hydrochloride combined with sodium ferrous citrate pretreatment.Pretreatment with 5-aminolevulinic acid expects protective effects on bladder dysfunction in cyclophosphamide-induced hemorrhagic cystitis by improving inflammatory changes in bladder tissues perhaps via up-regulation of haem oxygenase-1.

Objective: No reports have evaluated the treatment effects of tadalafil by age group in a positive, noninterventional observational study of Japanese men. The present study aimed to evaluate the treatment effects of tadalafil by age group in a positive, noninterventional observational study of Japanese men. We therefore divided patients into 2 groups about the age of 70 years and investigated the treatment effects of tadalafil regarding voiding and storage functions by age group. Methods: Changes from baseline in each parameter (International Prostate Symptom Score [IPSS], quality of life [QOL] score, Overactive Bladder Symptom Score [OABSS], and residual urine volume) at 4, 12, and 24 weeks after initiating tadalafil for benign prostatic hyperplasia (BPH) patients were compared between groups (50–69 years vs. ≥70 years). In addition, side effects of tadalafil were investigated by age group. Results: In the 50–69 years group, significant improvements from baseline were seen in IPSS total and QOL score for all time points. In addition, significant improvements in IPSS storage subscore from baseline were observed at the 4- and 24-week time points. In the ≥70 years group, significant improvements from baseline were seen in IPSS total, IPSS voiding and storage subscores, and QOL score at each time point. Conclusions: Tadalafil 5 mg once daily appeared effective in clinical settings for elderly BPH patients even over 70 years old.

AIM Brain nitric oxide (NO) have been reported in regulation of the sympatho-adrenomedullary system, which can affect voiding and storage functions. Therefore, we investigated effects of intracerebroventricularly (icv) administered 3-(4-morpholinyl)sydnonimine, hydrochloride (SIN-1) (NO donor) on the micturition reflex, focusing on their dependence on the sympatho-adrenomedullary system and on brain N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in urethane-anesthetized (0.8 g/kg, ip) male Wistar rats. METHODS Plasma noradrenaline and adrenaline were measured just before and 5 minutes after SIN-1 administration. Evaluation of urodynamic parameters was started 1 hour before SIN-1 administration or intracerebroventricular pretreatment with other drugs. RESULTS SIN-1 (100 and 250 µg/animal) elevated plasma adrenaline and reduced intercontraction interval ([ICI] values; 110.5% [SIN-1, 0 µg] and 54.9% [SIN-1, 250 µg] during 15 minutes after SIN-1 administration [P

INTRODUCTION AND OBJECTIVE:Although aging or severe bladder ischemia could be involved in progression of detrusor underactivity (DU), the pathophysiological mechanism of DU is not well clarified. H...

Aims The goal of this study was to test whether central corticotropin-releasing factor (CRF) was involved in angiotensin II (Ang II) and Ang II type 1 (AT1) receptor-mediated facilitation of micturition reflex and to investigate whether peripherally administered telmisartan, AT1 receptor antagonist, suppresses the central Ang II-induced facilitation of micturition reflex in rats. Methods Urethane anesthetized male Wistar rats were placed under continuous cystometry before and after intracerebroventricular administration of each drug. Rats were intracerebroventricularly administered telmisartan (AT1 receptor antagonist), CP154526 (CRF1 receptor antagonist), or K41498 (CRF2 receptor antagonist) 30 minutes before intracerebroventricular administration of Ang II. Some male Wistar rats were perorally pretreated with either vehicle, AT1 receptor antagonist telmisartan or valsartan, once daily for 8 days, then measured blood pressure. Thereafter, Ang II was intracerebroventricularly administered for continuous cystometry. Results Intracerebroventricularly administered telmisartan or CP154526 dose-dependently suppressed the central Ang II-induced intercontraction interval (ICI) reduction. In contrast, intracerebroventricularly administered K41498 did not affect the central Ang II-induced response compared to vehicle pretreatment. Peripherally administered telmisartan but not valsartan suppressed the central Ang II-induced ICI reduction in rats compared to vehicle administration without altering blood pressure. Conclusions Central Ang II induced facilitation of the micturition reflex through AT1 and CRF1 receptors. Peripherally administered telmisartan suppressed central Ang II-induced facilitation of micturition reflex.

Background: Children with spinal cord disorders can present with neurogenic bladder, a condition in which the bladder partly or completely loses its ability to store urine and void at low pressure. A bladder with low compliance may cause urinary incontinence, which negatively impacts quality of life and renal function. Long-term high pressure neurogenic bladder can increase the risk of deterioration in renal function. Antimuscarinic pharmacotherapy with clean intermittent catheterization is currently considered one of the most effective treatments for these patients. However, some patients do not respond to oral medication or have unacceptable adverse events (AEs), which may result in medical withdrawal for these patients. Intravesical oxybutynin is an effective treatment with less AEs compared with oral medication. However, an important issue with this treatment is retention of the solution in the bladder. Moreover, as yet no data are available on the very long-term use and outcome of modified intravesical oxybutynin therapy. In the present study, we report on the efficacy, safety, and side effects of long-term modified intravesical oxybutynin therapy in children with neurogenic bladder. Methods: Modified intravesical oxybutynin (1.25 mg/5 mL, twice a day) was administered to four children (three boys and one girl) with neurogenic bladder (detrusor overactivity and/or low compliance bladder), who were previously unresponsive to or experienced intolerable AEs from oral medications. Results of pretreatment cystometrograms were compared to those from follow-up urodynamic studies. Anticholinergic AEs, occurrence of urinary tract infection, and degree of incontinence during this treatment were also evaluated. Results: After 1 year, bladder compliance improved in three of the four patients. After 3 years, detrusor overactivity was undetectable in all patients. Bladder compliance at 3 years and 10 years after initiation of therapy was similar for three patients, and they are continuing modified intravesical oxybutynin therapy. One patient discontinued therapy at 118 months due to worsening of bladder compliance and upper urinary tract infection. No anticholinergic systemic AEs were observed in any of the patients. Conclusions: These results suggest that modified intravesical oxybutynin is an effective and relatively safe long-term therapeutic option for children with neurogenic bladder. J Clin Med Res. 2019;11(4):256-260 doi: https://doi.org/10.14740/jocmr3752

Benign prostatic hyperplasia/benign prostatic enlargement (BPH/BPE) is a common proliferative disease, and giving rise to associate with lower urinary tract symptoms (LUTS). However, the pathogenesis is not well clarified, and thought to be multifactorial. There are some lines of evidence that impairment in the blood supply of the lower urinary tract causes development of BPH/BPE. Clinical data showed an association between the development of BPH/BPE and atherosclerotic disease such as hypertension, diabetes and hyperlipidemia. The spontaneously hypertensive rat (SHR) has been used as model of genetic hypertension. SHR also shows decreased blood flow and hyperplastic morphological abnormalities in the ventral prostate. Our previous studies demonstrated that chronic treatment with vasodilative drugs nicorandil (ATP sensitive potassium channel opener) and silodosin (alpha1 adrenoceptor antagonist) increased blood flow and suppressed the growth factor and morphological abnormalities in the SHR ventral prostate. These data suggested that prostatic blood flow could be therapeutic targets for BPH/LUTS.

Exposure to psychological/mental stress can affect urinary function, and lead to and exacerbate lower urinary tract dysfunctions. There is increasing evidence showing stress-induced changes not only at phenomenological levels in micturition, but also at multiple levels, lower urinary tract tissues, and peripheral and central nervous systems. The brain plays crucial roles in the regulation of the body's responses to stress; however, it is still unclear how the brain integrates stress-related information to induce changes at these multiple levels, thereby affecting urinary function and lower urinary tract dysfunctions. In this review, we introduce recent urological studies investigating the effects of stress exposure on urinary function and lower urinary tract dysfunctions, and our recent studies exploring "pro-micturition" and "anti-micturition" brain molecules related to stress responses. Based on evidence from these studies, we discuss the future directions of central neurourological research investigating how stress exposure-induced changes at peripheral and central levels affect urinary function and lower urinary tract dysfunctions. Brain molecules that we explored might be entry points into dissecting the stress-mediated process for modulating micturition.

Aims Aging is an obvious risk factor for detrusor underactivity. We investigated the effects of aging on bladder function in spontaneously hypertensive rats. Main methods Male spontaneously hypertensive rats and Wistar Kyoto rats (used as normotensive controls) at the ages of 18, 36, 54, or 72 weeks were used. Bladder weight, blood pressure, bladder blood flow, and urodynamic and renal parameters were measured. Additionally, detrusor thickness and renal histology were evaluated. Key findings In spontaneously hypertensive rats, significant increases were observed in bladder weight/body weight ratio, blood pressure, detrusor thickness, intercontraction interval, urine output, serum creatinine, and renal glomerular and tubular scores, and decreases in bladder blood flow and urine osmolality at 72 weeks as compared to those at 18 weeks. In spontaneously hypertensive rats, significant increases were observed in single voided volume, post voiding residual urine volume, and bladder capacity, with decrease in voiding efficiency were observed at 54 or 72 weeks than at 18 weeks. However, there were no significant differences in blood pressure, urodynamic and renal parameters, detrusor thickness and renal histology among Wistar Kyoto rats of different ages. Significance In spontaneously hypertensive rats, aging induces significant increases in blood pressure, single voided volume, post voiding residual urine volume, intercontraction intervals and urine output, and decreases in voiding efficiency and bladder blood flow indicative of detrusor underactivity. Aging-related severe hypertension could induce voiding dysfunction such as detrusor underactivity via severe bladder ischemia and polyuria. Aged spontaneously hypertensive rats may be useful animal models for detrusor underactivity.

Objectives To investigate whether a response to hydrogen sulfide donors (GYY4137 and sodium hydrosulfide) and the endogenous hydrogen sulfide system (hydrogen sulfide level and expression of cysteine aminotransferase, cystathionine β-synthase, cystathionine γ-lyase, and 3-mercaptopyruvate sulfurtransferase) in the spontaneously hypertensive rat bladder differ with age, we compared the responses of hydrogen sulfide donors to micturition and bladder relaxation, and the endogenous hydrogen sulfide system in the bladder of 18-week versus 12-week-old spontaneously hypertensive rats. Methods GYY4137 was intravesically administered and cystometry was performed in anesthetized rats. The responses of sodium hydrosulfide were evaluated in carbachol-mediated precontracted bladder strips. Bladder hydrogen sulfide levels and expression levels of each enzyme were investigated using the methylene blue method and Western blotting, respectively. Results GYY4137 treatment significantly prolonged intercontraction intervals only in 12-week-old rats. Sodium hydrosulfide-induced bladder relaxation was significantly attenuated in the strips of 18-week-old rats compared with that in 12-week-old rats. In the bladder dome, significant increases in hydrogen sulfide levels and in the expression of cystathionine β-synthase, 3-mercaptopyruvate sulfurtransferase, and cysteine aminotransferase were observed in 18-week-old rats compared with 12-week-old rats. However, cystathionine γ-lyase bands were not detected in bladder tissues of either group. Conclusions Bladder relaxation induced by hydrogen sulfide may be attenuated in spontaneously hypertensive rats in an age-dependent manner.

INTRODUCTION AND OBJECTIVE:In the lower urinary tract, nitric oxide (NO) is well known as a relaxation factor in the urethra. On the other hand, in the central nervous system, NO is reported to hav...

Recently, hydrogen sulfide (H2S) has been recognized as the third gasotransmitter besides nitric oxide and carbon monoxide, and it has been reported that H2S exhibits various physiological functions such as neuromodulation and vasorelaxation. In the lower urinary tract (bladder and prostate), it is reported that donors of H2S induce contraction of the rat detrusor and relaxation of the pig bladder neck. These reports suggest a possibility that H2S may have site-specific effects on the bladder. However, the detailed functions of H2S in each part of the bladder are still unclear. In addition, there is no report showing physiological roles of H2S in the prostate. In this article, we will review the distribution of enzymes related to H2S biosynthesis and physiological roles of H2S in the lower urinary tract based on reports from our and other groups. We will also introduce a possibility that H2S can be a new therapeutic target against lower urinary tract symptoms (LUTS) based on our data from spontaneously hypertensive rats (SHRs), which develop hypertension-mediated LUTS.

INTRODUCTION AND OBJECTIVES:Psychological stress exacerbates bladder dysfunction such as overactive bladder (OAB) and bladder pain syndrome/interstitial cystitis (BPS/IC). We previously reported that bombesin (BB), a stress-related neuropeptide, centrally induces facilitation of the rat micturition reflex. Brain BB is reported to activate hypothalamo-pituitary-adrenal axis and sympathetic nerves, as representative responses to stressful conditions, via brain corticotropin-releasing factor (CRF), another stress-related neuropeptide. Therefore, we examined whether brain CRF is involved in the BB-induced frequent urination in rats.METHODS:(1) In urethane anesthetized (0.8 g/kg, ip) male Sprague-Dawley (SD) rats (300-400 g), a catheter was inserted into the bladder to perform cystometry (CMG, 12 ml/h saline infusion). Astressin (a non-selective CRF receptor antagonist, 1 or 3 nmol/rat) was intracerebroventricularly (icv) pretreated 60 min before BB administration (0.03 nmol/rat, icv). CMG was started 60 min b...

INTRODUCTION AND OBJECTIVES:Psychological stress exacerbates symptoms of bladder dysfunction. We previously reported that epibatidine (EP), a nicotinic acetylcholine receptor (nAChR) agonist, centr...

INTRODUCTION AND OBJECTIVES:Psychological stress is involved in the development of the lower urinary tract symptoms. Our previous reports showed that centrally administered a stress-related neurope...

INTRODUCTION AND OBJECTIVES:Ghrelin, a 28 amino acid growth hormone, is widely distributed throughout the peripheral and central nervous systems. Ghrelin′s many physiological functions include grow...

The aim of this study was to investigate the effects of an anandamide transporter inhibitor that can increase endogenous anandamide concentration on the micturition reflex in urethane-anesthetized rats. Continuous cystometrograms were performed in female Sprague–Dawley rats under urethane anesthesia. After stable micturition cycles were established, VDM11 (1, 3 and 10 mg/kg), an anandamide membrane transporter inhibitor, was administered intravenously to evaluate changes in bladder activity. In experiments examining the effects of cannabinoid (CB) receptor antagonists, VDM11 (10 mg/kg) was injected intravenously when the first bladder contraction was observed after intravenous administration of AM251, a CB1 receptor antagonist (3 mg/kg), or AM630, a CB2 receptor antagonist (3 mg/kg). Intravenous administration of VDM11 increased intercontraction intervals and threshold pressure at doses of 3 mg/kg or higher in dose-dependent fashion. When AM251 was administered one voiding cycle before VDM11 administration, the increases in intercontraction intervals and threshold pressure induced by VDM11 administration alone were not seen. In contrast, when AM630 was administered before VDM11 administration, increases in intercontraction intervals and threshold pressure were observed, as they were after VDM11 alone. These results suggest that anandamide, an endogenous CB ligand, can modulate the micturition reflex and that anandamide transporters play an important role in this modulation. In urethane-anesthetized rats, inhibition of the uptake of anandamide can inhibit the micturition reflex and these inhibitory effects of VDM11 are at least in part mediated by the CB1 receptor.

Testicular torsion is a common urological emergency among adolescent boys and young men. Rotation of the testis and twisting of the spermatic cord rapidly leads to ischemia, resulting in a loss of germ cells. Thus, prompt diagnosis and urgent surgical intervention are required, but the subsequent release of the torsion induces reperfusion injury, which causes further damage to the ischemic testis. Testicular torsion-detorsion (ischemia-reperfusion) injury triggers the generation of reactive oxygen species, pro-inflammatory cytokines, neutrophil recruitment, lipid peroxidation, anoxia and apoptosis, which carry a significant risk of subsequent infertility. Previously, the effects of numerous pharmacological agents and treatments have been evaluated to prevent testicular ischemia-reperfusion injury in animal models. We propose a new treatment, especially postconditioning, to prevent adverse effects of ischemia-reperfusion injury after testicular torsion-detorsion.

Cryptorchidism, a common anomaly of the male genitalia, affects 2-4% of male infants. The post-fertilization effects of unilateral cryptorchidism model in the rat and the effects of antioxidant treatment were investigated. Six-week-old male Wistar rats were randomly separated into four groups. Unilateral cryptorchidism was induced in the right testis of three groups. One group was treated with saline intraperitoneally (i.p.) (Crypto), one group was treated with taurine (500 mg/kg, i.p.; Tau), and another group was treated with sivelestat (15 mg/kg i.p.; Siv). The control group was treated with saline i.p. The treatment was daily for 8 weeks. Five days before sacrifice, mating studies were performed. Body, testicular, and epididymal weights were recorded. Malondialdehyde (MDA) levels in the seminal vesicular fluid (SVF) were measured. Testicular levels of MDA and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were determined bilaterally. TUNEL assay was used to examine DNA fragmentation bilaterally. Histological examination and the Johnsen score were used to evaluate morphological testicular alterations. The Crypto group demonstrated significantly lower right testicular and epididymal weights, significantly increased SVF-MDA levels, testicular MDA and 8-OHdG levels, and the apoptotic score bilaterally compared to the controls. Furthermore, histological evaluation revealed significantly reduced spermatogenesis and mild injury to the cryptorchid testes compared to the control. Treatment with both taurine and sivelestat significantly reduced SVF-MDA levels, testicular MDA, 8-OHdG, and apoptosis bilaterally compared to the Crypto group. Antioxidant treatment was unable to ameliorate spermatogenesis. Newborns delivered by females that mated with Crypto-males had significantly lower body weight compared with the respective animals from the control, Tau and Siv groups. The present study demonstrated that unilateral cryptorchidism-induced testicular damage can significantly affect the contralateral testis as well having further deleterious post-fertilization effect on the development of newborns. Treatment with antioxidants can partially improve the testicular damage bilaterally with beneficial effects for the newborns.

Aims To clarify the roles of hydrogen sulfide (H2 S), an endogenous gasotransmitter, in the rat bladder and prostate, we investigated the distribution of enzymes related to H2 S biosynthesis (cystathionine β-synthase [CBS], cystathionine γ-lyase [CSE], 3-mercaptopyruvate sulfurtransferase [MPST], cysteine aminotransferase [CAT], and D-amino acid oxidase [DAO]) and the content of H2 S. We also investigated the effects of H2 S donors (NaHS and GYY4137) on the contractility of both tissues and on micturition. Methods The distribution of these enzymes was investigated by real-time PCR, Western blot, and immunohistochemistry. Tissue H2 S content was measured by the methylene blue method. The effects of NaHS (1 × 10-9 to 3 × 10-4 M) were evaluated on carbachol (10-5 M)-induced pre-contracted bladder strips, and on noradrenaline (10-5 M)-induced pre-contracted prostate strips, which were pretreated with propranolol (10-6 M). In addition, in urethane-anesthetized male Wistar rats, the effects of intravesically instilled GYY4137 (10-8 , 10-7 , and 10-6 M) on micturition were evaluated by cystometry. Results MPST and CAT were detected in the bladder and prostate, CBS was only detected in the prostate, while CSE and DAO were not detected in both tissues. Immunoreactivity of these enzymes was mainly detected in the urothelium and smooth muscle layer of the bladder and in the prostate glandular epithelium. H2 S was detected in both tissues. NaHS dose-dependently induced relaxation of pre-contracted bladder and prostate strips. Intravesically instilled GYY4137 significantly prolonged intercontraction intervals. Conclusions It is possible that H2 S can function as an endogenous relaxation factor in the rat bladder and prostate.

BACKGROUND Rho kinase (ROCK) pathway is associated with various cellular functions, such as smooth muscle contraction, inflammatory response, and cell proliferation. The spontaneously hypertensive rat (SHR) is commonly used genetically hypertensive rat model which develops hyperplastic morphological abnormalities in the ventral prostate. We investigated whether administration of hydroxyfasudil, a ROCK inhibitor, could reduce the levels of growth factors, inflammatory markers, and morphological abnormalities in the ventral prostate of the SHR. METHODS Twelve-week-old SHRs were treated with hydroxyfasudil (1 mg/kg/day, i.p.) or vehicle once daily for another 6 weeks. Wistar Kyoto (WKY) rats treated with vehicle were used as normotensive controls. At 18 weeks of age, blood pressure and heart rate were measured by the tail cuff method. Then the rats were sacrificed, and the ventral prostates were removed. The levels of ROCK activity, growth factors (TGF-β1 and bFGF), a smooth muscle differentiation marker (α-SMA) and an inflammatory cytokine (IL-6) in the ventral prostate were measured by ELISA and western blot. A histological evaluation in each group was also performed. RESULTS There were significant increases in blood pressure, prostate weight, prostate body weight ratio, and tissue levels of ROCK activity, TGF-β1, bFGF, α-SMA, and IL-6 in the SHR compared to the WKY rat. Histological examination of the ventral prostate showed morphological abnormalities such as a higher degree of proliferation in the glandular epithelial and stromal area in the SHR compared to the WKY rat. Treatment with hydroxyfasudil reduced the elevated ROCK activity, TGF-β1, bFGF, α-SMA, and IL-6 found in the ventral prostate of the SHR. Moreover, treatment with hydroxyfasudil decreased the morphological abnormalies in the SHR ventral prostate. CONCLUSIONS Treatment with hydroxyfasudil decreased the growth factors, an inflammatory cytokine, and morphological abnormalies in the SHR ventral prostate. These results suggest that chronic treatment with hydroxyfasudil may inhibit the progression of prostatic hyperplasia in the SHR. Prostate 75:1774–1782, 2015. © 2015 Wiley Periodicals, Inc.

Although the pathogenesis of lower urinary tract symptoms, benign prostatic hyperplasia/benign prostatic enlargement and erectile dysfunction is poorly understood and thought to be multifactorial, it has been traditionally recognized that these conditions increase with age. There is increasing evidence that there is an association between cardiovascular disease and lower urinary tract symptoms as well as benign prostatic hyperplasia/benign prostatic enlargement and erectile dysfunction in elderly patients. Age might activate systemic vascular risk factors, resulting in disturbed blood flow. Hypertension, diabetes, hyperlipidemia and atherosclerosis are also linked to the etiology of lower urinary tract symptoms, benign prostatic hyperplasia/benign prostatic enlargement and erectile dysfunction. In the present review, we discuss the relationship between decreased pelvic blood flow and lower urinary tract symptoms, benign prostatic hyperplasia/benign prostatic enlargement and erectile dysfunction. Furthermore, we suggest possible common mechanisms underlining these urological conditions.

To investigate the effects of activation of sensory neuron-specific receptors (SNSRs) on cyclophosphamide (CYP) bladder overactivity in rats. Female Sprague–Dawley rats (235–258 g) were used. Rats were injected with either CYP (200 mg/kg, intraperitoneally) or saline (control). Continuous cystometrograms (0.04 ml/min) were recorded 48 h after CYP or saline injection under urethane anesthesia. After stable micturition cycles were established, a selective rat SNSR1 agonist, bovine adrenal medulla 8-22 (BAM8-22), was administered intravenously or intrathecally. Cyclophosphamide treatment-induced higher baseline pressure and shorter intercontraction intervals compared with the control group. Intravenous administration of BAM8-22 at 10, 30 and 100 μg/kg significantly increased intercontraction intervals in the CYP-treated group. Intrathecal administration of BAM8-22 at 0.03, 0.1 and 0.3 μg also significantly increased intercontraction intervals in the CYP-treated group. Intravenous or intrathecal administration of BAM8-22 did not change baseline pressure or maximum voiding pressure in the CYP-treated group. These findings indicate that activation of SNSRs can suppress CYP-induced bladder overactivity, probably due to suppression of bladder afferent activity.

Objective In order to characterize the significance of immune system function in patients with advanced renal cell carcinoma (RCC), we investigated the interactive relationships among the following parameters: metastatic characteristics, expression of Fas ligand (FasL) in nephrectomized specimens, immunological parameters, and patient's prognosis. Materials and methods Thirty-five patients with advanced RCC were stratified into 3 groups according to the characteristics of metastasis timing, at first presentation (mFP), within 5 years of nephrectomy (early-recurrence), after 5 years (late-recurrence). Immunological parameters [hemoglobin, lymphocyte count, neutrophil/lymphocyte ratio (NLR), serum albumin, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and Charlson Comorbidity Index], FasL expression in RCC, and patient prognosis from occurrence of metastasis were compared among the groups. Thirty-five patients were also stratified into 2 groups according to FasL positivity and individual parameters. Patient's prognosis and the remaining immunological parameters were compared between groups. Results The NLRs of the late-recurrence group were significantly lower than those of the mFP (P = 0.0004) and early-recurrence (P = 0.013) groups. The FasL mRNA positivity of the late-recurrence group was significantly lower than those of the mFP (P = 0.001) and early-recurrence (P = 0.0277) groups. The prognosis of the late-recurrence group was significantly better than that of the early-recurrence group (P = 0.0255). NLRs were significantly lower in the FasL-negative group than in the -positive group (P = 0.0182). The cause-specific survival rates of the ECOG PS 0 group were significantly higher than that of the ECOG PS > 0 group (P Conclusions Our results suggest the associations of the prognosis in advanced RCC with peripheral blood NLR and FasL expression in nephrectomized tumor. The characteristics of lower values of NLR and FasL expression positivity in late-recurrence compared with other metastatic timings suggest strong host immune activity, and may imply relatively long survival. On the other hand, elucidation of the patient's general condition obtained not only by chemical data but also by ECOG PS is crucial in the management of patients with advanced RCC.

Purpose As hypertension (HT) is one of the risk factors for lower urinary tract symptoms, we investigated the effect of an angiotensin II type I receptor blocker, olmesartan, on bladder dysfunction in the spontaneously hypertensive rat (SHR). Materials and Methods Twelve-week-old male SHRs were administered perorally with olmesartan (0, 1, or 3 mg/kg/day) or nifedipine (30 mg/kg/day) for 6 weeks. Wistar rats were used as normotensive controls. The effects of olmesartan or nifedipine on blood pressure (BP), bladder blood flow (BBF), urodynamic parameters, tissue levels of malondialdehyde (MDA), nuclear factor erythroid 2-related factor 2 (Nrf2), and nerve growth factor (NGF) were measured in the bladder. Localization of 4-hydroxy-2-nonenal (4-HNE), Nrf2, and NGF in the bladder was shown by immunohistochemistry. Results The SHRs showed significant increase in BP, micturition frequency, and expression of MDA, 4-HNE, Nrf2, and NGF when compared to the control Wistar rats. Conversely, there was a decrease in BBF and single voided volume in SHRs when compared to Wistar rats. Treatment with olmesartan and nifedipine significantly improved BP. However, only olmesartan significantly ameliorated urodynamic parameters and oxidative damage compared to the non-treated SHR. The immunoreactivities of 4-HNE, Nrf2, and NGF in SHR urothelium and blood vessels were increased compared to the control. Treatment with a high dose of olmesartan decreased the expressions of 4-HNE, Nrf2, and NGF in the bladder. Conclusion Our data suggest that BP, BBF, and oxidative stress may be responsible for the functional changes in HT-related bladder dysfunction. Olmesartan significantly ameliorated this bladder dysfunction. Neurourol. Urodynam. 33:350–357, 2014. © 2013 Wiley Periodicals, Inc.

Objectives The present study investigated prognostic indicators, including clinicopathological and preoperative hematological factors, and developed a prognostic factor-based risk stratification model in bladder cancer patients treated with radical cystectomy. Methods Data were collected from 249 consecutive bladder cancer patients treated with radical cystectomy without neoadjuvant therapy. Prognostic values of the preoperative hematological parameters, along with the patients' clinicopathological parameters were evaluated. A risk stratification model was developed to predict disease-specific survival after radical cystectomy using the regression coefficients of multivariate analysis. Results In the multivariate analysis, preoperative hemoglobin and C-reactive protein levels, as well as the pathological factors of T stage, positive surgical margin and lymph node metastasis, were independently predictive of disease-specific survival. Low hemoglobin ( 0.5 mg/dL), extravesical T stage (≥pT3a) and positive surgical margin were independent predictors of poor disease-specific survival. The risk stratification model showed significant differences in disease-specific survival between the three subgroups. Conclusions This is the first report to show the significance of combining preoperative hemoglobin with the pathology of radical cystectomy specimens as an independent predictor for disease-specific survival, and it also represents the largest contemporary series to date demonstrating that two types of preoperative hematological disorders, assessed by hemoglobin and C-reactive protein, are independent predictors in bladder cancer patients treated with radical cystectomy. Our risk stratification model could provide physicians with useful prognostic information for identifying patients who might be candidates for multimodal treatments.