Number Of Non-voiding Contractions Research Articles

Impaired nitric oxide mechanisms underlying lower urinary tract dysfunction in aging rats.

The study aimed to investigate the bladder and urethral activity and nitric oxide (NO)-related molecular changes in aging rats. Rats were divided into two groups: Group Y (young rats; 12 wk) and Group A (aging rats; 15 mo). A 24-h voiding assay was performed, and the urodynamic parameters were evaluated using awake cystometry (CMG) and urethral perfusion pressure (UPP) recordings under urethane anesthesia. The mRNA expression levels of NO-, ischemia-, and inflammation-related markers in urethra and bladder tissues and cGMP levels in the urethra were assessed. Body weight was significantly higher in Group A than in Group Y. Voiding assay results (24 h) were insignificant. In the CMG, the number of non-voiding contractions per voiding cycle and post-void residual volume were significantly higher in Group A than in Group Y; voiding efficiency was significantly lower in Group A than in Group Y. In the UPP recordings, the urethral pressure reduction and high-frequency oscillation (HFO) amplitude were significantly lower in Group A than in Group Y. The mRNA expression levels of Hif-1α, Vegf-a, and Tgf-β1 in the bladder were significantly higher in Group A than in Group Y. The mRNA expression levels of Nos1 and Prkg1 and the cGMP concentrations in the urethra were significantly lower in Group A than in Group Y. Aging rats can be useful models for studying the natural progression of age-related lower urinary tract dysfunctions, for which impaired NO-mediated transmitter function is likely to be an important mechanism.NEW & NOTEWORTHY Aging rats can be useful models for studying the natural progression of age-related lower urinary tract dysfunctions, for which impaired nitric oxide-mediated transmitter function is likely to be an important mechanism.

Functional and molecular alterations in a rat model of detrusor underactivity induced by bilateral pelvic nerve crush injury

Objective:To investigate the functional and molecular alterations in detrusor underactivity (DU) in a rat model of bilateral pelvic nerve crush injury. Methods:This study included 39 female Sprague-Dawley rats separated into three groups (sham, 2-week DU, and 4-week DU), with 13 rats in each group. A bilateral pelvic nerve crush injury was induced in each group to develop a DU model. Similarly, the sham group was identically prepared but without crushing nerves. Awake continuous cystometry was performed two weeks post-surgery in the sham and 2-week DU groups and four weeks post-surgery in the 4-week DU group (n = 7/each group). In another group of rats (n = 6/each group), the bladders were harvested for western blotting, and the expression of moesin, ezrin, and transthyretin in the bladders was evaluated. Results:On cystometry, voided volume, post-void residual urine volume, bladder capacity, and number of non-voiding contractions were significantly higher in the 2- and 4-week DU groups than in the sham group. Furthermore, voiding efficiency was significantly decreased in the 2- and 4-week DU groups compared to that in the sham group.The expression of moesin in the bladder was significantly higher in the 2-week DU group than that in the sham group. The expression of transthyretin in the bladder was significantly higher in the 2- and 4-week DU groups than that in the sham group. Conclusion:The significant increase in the expression of moesin and transthyretin in the bladder in bilateral pelvic nerve crush injuries may be related to the pathophysiology of DU.

PD23-03 IMPAIRED NITRIC OXIDE MECHANISMS UNDERLYING LOWER URINARY TRACT DYSFUNCTION IN AGING RATS

You have accessJournal of UrologyCME1 Apr 2023PD23-03 IMPAIRED NITRIC OXIDE MECHANISMS UNDERLYING LOWER URINARY TRACT DYSFUNCTION IN AGING RATS Daisuke Gotoh, Kenta Onishi, Yosuke Morizawa, Shunta Hori, Yasushi Nakai, Makito Miyake, Kazumasa Torimoto, Fujimoto Kiyohide, and Naoki Yoshimura Daisuke GotohDaisuke Gotoh More articles by this author , Kenta OnishiKenta Onishi More articles by this author , Yosuke MorizawaYosuke Morizawa More articles by this author , Shunta HoriShunta Hori More articles by this author , Yasushi NakaiYasushi Nakai More articles by this author , Makito MiyakeMakito Miyake More articles by this author , Kazumasa TorimotoKazumasa Torimoto More articles by this author , Fujimoto KiyohideFujimoto Kiyohide More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003296.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Nitric oxide (NO) promotes the intracellular production of cyclic guanosine monophosphate (cGMP) in smooth muscles, reduces the intracellular calcium concentration, and enhances smooth muscle relaxation. However, it remains unknown whether changes in the expression of NO-related molecules are associated with the development of lower urinary tract dysfunction (LUTD) with age. Therefore, we examined changes in bladder and urethral activities, and in NO-related molecule expression using aging rats. METHODS: Fourteen Female Sprague–Dawley rats were divided into two age groups: (A) young rats (12 weeks old, n=8) and (B) aging rats (15 months old, n=6). In both groups, 24 h voiding assay was performed, and the urodynamic parameters were evaluated using cystometry (CMG) and urethral perfusion pressure (UPP) recordings. mRNA expression levels of NO-, ischemia-, and inflammation-related markers in bladder and urethra tissues were assessed, and the cGMP level in the urethra was measured. RESULTS: There was no significant difference in the 24-h voiding assay results between the groups. In CMG, the number of non-voiding contractions (NVCs) per voiding cycle and post-void residual (PVR) were significantly higher, and voiding efficiency (VE) was significantly lower in Group B than in Group A (Figure 1A, B). In the UPP recordings, urethral pressure (UP) reduction and high frequency oscillation (HFO) amplitudes were both significantly lower in Group B than in Group A (Figure 1C, D). In molecular studies, mRNA expression levels of HIF-1α, VEGF, and TGF-β1 in the bladder were significantly higher in Group B than in Group A (Figure 2A). mRNA expression levels of NOS1 and PKG were significantly lower in Group B than in Group A (Figure 2B). In addition, the concentration of cGMP in the urethra was significantly lower in Group B than in Group A (Figure 2C). CONCLUSIONS: Aging rats would be a useful model for the study of the natural progression of age-related LUTD, for which impaired NO-mediated transmitter function is likely to be an important mechanism. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e671 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daisuke Gotoh More articles by this author Kenta Onishi More articles by this author Yosuke Morizawa More articles by this author Shunta Hori More articles by this author Yasushi Nakai More articles by this author Makito Miyake More articles by this author Kazumasa Torimoto More articles by this author Fujimoto Kiyohide More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement PDF downloadLoading ...

Cross-organ sensitization between the prostate and bladder in an experimental rat model of lipopolysaccharide (LPS)-induced chronic pelvic pain syndrome

BackgroundThe aim of the current study was to investigate the effects of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) on bladder function via prostate-to-bladder cross-sensitization in a rat model of lipopolysaccharide (LPS)-induced prostate inflammation.MethodsMale rats were intraprostatically injected with LPS or saline, serving as control. Micturition parameters were examined in a metabolic cage 10 or 14 days later. Subsequently, to evaluate bladder function, cystometry was performed. Micturition cycles were induced by saline infusion and cholinergic and purinergic contractile responses were measured by intravenous injection with methacholine and ATP, respectively. Thereafter, the prostate and bladder were excised and assessed histopathologically for possible inflammatory changes.ResultsMetabolic cage experiments showed increased urinary frequency in rats with LPS-induced CP/CPPS. Cystometry showed a significant increase in the number of non-voiding contractions, longer voiding time and lower compliance in CP/CPPS animals compared to controls. Induction of CP/CPPS led to significantly reduced cholinergic and purinergic bladder contractile responses. Histopathological analysis demonstrated prostatic inflammation in CP/CPPS animals. There were no significant differences between the groups regarding the extent or the grade of bladder inflammation. Prostate weight was not significantly different between the groups.ConclusionsThe present study shows that prostate-to-bladder cross-sensitization can be triggered by an infectious focus in the prostate, giving rise to bladder overactivity and alterations in both afferent and efferent signalling. Future studies are required to fully understand the underlying mechanisms.

Prostate-to-bladder cross-sensitization in a model of zymosan-induced chronic pelvic pain syndrome in rats.

The aim of the present study was to investigate the effects of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) on bladder function and pathophysiology. To create a model for CPPS, rats were intraprostatically injected with zymosan or saline, serving as control. Metabolic cage experiments were performed 7, 14, or 21 days after zymosan injection and after 14 days in the control group. Thereafter, cystometry was performed in which simulated micturition cycles were induced by saline infusion and contractile responses to the cholinergic agonist methacholine and the purinergic agonist ATP were measured. Following cystometry, the prostate and urinary bladder were excised and assessed histopathologically for possible inflammatory changes. Metabolic cage data revealed a significantly increased urinary frequency in zymosan treated rats. Likewise, the volume per micturition was significantly lower in all CPPS groups compared to controls. Cystometry showed a significant increase in the number of nonvoiding contractions, longer voiding time, and a trend towards lower compliance in CPPS rats compared to controls. Induction of CPPS led to significantly reduced cholinergic and purinergic contractile responses. Histopathological analysis demonstrated prostatic inflammation in all CPPS groups, in particular in later stage groups. Both the extent and grade of bladder inflammation were significantly higher in CPPS groups compared to controls. The current findings demonstrate a potential prostate-to-bladder cross-sensitization leading to symptoms of bladder overactivity and signs of bladder inflammation. Future clinical studies are required to verify the outcomes of the current study and enable advancement of patient care.

Silodosin improves functional consequences of lower urinary tract obstruction secondary to benign prostate hypertrophy, a proof of concept study in the spontaneously hypertensive rat supplemented with testosterone

BackgroundThe main purpose of this study is to investigate the effect of silodosin on the urodynamic consequences in a previously established model of lower urinary tract symptoms associated with benign prostate hyperplasia, the spontaneously hypertensive rats (SHR) supplemented with testosterone.MethodsThree groups of animals (8-week-old; n = 10/group) were considered: Wistar Kyoto (control) rats (WKY), SHR supplemented with testosterone at 3 mg/kg/day and treated with either vehicle (SHR-T, n = 10) or silodosin at 0.1 mg/kg/day (SHR-T + silodosin, n = 10) by oral gavage for 6 weeks. Cystometry experiments were performed. The bladder was harvested, weighed and paraffin-embedded for morphometric analysis. The prostate was also harvested and weighed.ResultsThe number of animals included in the analysis were n = 10/10 for WKY and n = 7–8/10 for each SHR rats supplemented with testosterone group. SHR-T displayed a significant decrease in the intercontraction interval, infused volume and mean flow rate whereas the frequency of non-voiding contractions was increased. Silodosin improved the voiding behavior of SHR-T by significantly increasing the intercontraction interval, the infused volume and the mean flow rate and decreasing the number of non-voiding contractions. SHR-T displayed a significant increase in prostate and bladder weights and a 15% increase in the detrusor wall area compared to WKY.ConclusionsChronic silodosin treatment relieved storage symptoms in SHR supplemented with testosterone and decreased the frequency of non-voiding detrusor contractions during the filling phase.

Effect of amniotic fluid stem cell transplantation on the recovery of bladder dysfunction in spinal cord-injured rats

The effects of human amniotic fluid stem cell (hAFSC) transplantation on bladder function and molecular changes in spinal cord-injured (SCI) rats were investigated. Four groups were studied: sham and SCI plus phosphate-buffered saline (SCI + PBS), human embryonic kidney 293 (HEK293) cells, and hAFSCs transplantation. In SCI + PBS rat bladders, cystometry showed increased peak voiding pressure, voiding volume, bladder capacity, residual volume, and number of non-voiding contractions, and the total elastin/collagen amount was increased but collagen concentration was decreased at days 7 and 28. Immunoreactivity and mRNA levels of IGF-1, TGF-β1, and β3-adrenoceptor were increased at days 7 and/or 28. M2 immunoreactivity and M3 mRNA levels of muscarinic receptor were increased at day 7. M2 immunoreactivity was increased, but M2/M3 mRNA and M3 immunoreactivity levels were decreased at day 28. Brain derived-neurotrophic factor mRNA was increased, but immunoreactivity was decreased at day 7. HEK293 cell transplantation caused no difference compared to SCI + PBS group. hAFSCs co-localized with neural cell markers and expressed BDNF, TGF-β1, GFAP, and IL-6. The present results showed that SCI bladders released IGF-1 and TGF-β1 to stimulate elastin and collagen for bladder wall remodelling, and hAFSC transplantation improved these changes, which involved the mechanisms of BDNF, muscarinic receptors, and β3-adrenoceptor expression.

Long-term tadalafil administration can prevent functional and structural changes of the urinary bladder in male rats with partial bladder outlet obstruction.

There have been few reports on whether long-term oral phosphodiesterase 5 inhibitor administration can ameliorate bladder changes due to bladder outlet obstruction (BOO). Therefore, we clarified the chronological changes of the bladder using male BOO rats and evaluated the effects of tadalafil on these changes. Eight-week-old male Sprague-Dawley rats were used. BOO was created by placing a polyethylene catheter around the urethra. Then, the rats were orally treated with a vehicle, or tadalafil 2 or 10 mg/kg until each evaluation period. Cystometric measurements were performed and the degree of fibrosis in the smooth muscle layer was evaluated at 2, 4, and 16 weeks. In BOO rats, a significant increase in the number of non-voiding contractions (NVCs) and a shortened intercontraction interval (ICI) were observed in the earlier phase (2 and 4 weeks) compared to Sham rats. In the chronic phase (16 weeks), markedly increased residual urine volume and an extended ICI were observed accompanied by enhanced smooth muscle fibrosis. These results indicated that the bladder in BOO rats represented the overactive phenotype in the earlier phase and changed into the underactive phenotype in the chronic phase. Even in Sham rats, an increased number of NVCs and enhanced fibrosis were observed with time. Tadalafil administration significantly prevented these bladder changes in both BOO and Sham rats. Long-term oral administration of tadalafil can prevent functional and histological changes in the BOO rat bladder. This agent is also effective for the bladder functional change even in non-obstructed rats.

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

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. 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. 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. 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.

Methylglyoxal, a Reactive Glucose Metabolite, Induces Bladder Overactivity in Addition to Inflammation in Mice.

Diabetic bladder dysfunction (DBD) is one of the most common complication of diabetes. Methylglyoxal (MGO), a highly reactive dicarbonyl compound formed as a by-product of glycolysis, is found at high levels in plasma of diabetic patients. Here, we explored the effects of chronic administration of MGO on micturition pattern (cystometry) and bladder contractility in vitro in healthy male C57/BL6 mice. Methylglyoxal was given at 0.5% in drinking water for 4 weeks. Exposure to MGO led to bladder tissue disorganization, edema of lamina propria, partial loss of urothelium and multiple leukocyte infiltrates. Filling cystometry revealed significant increases of micturition frequency and number of non-voiding contractions (NVCs) in the MGO group, clearly indicating an overactive bladder profile. Bladder contractions induced by electrical-field stimulation (EFS) and carbachol were significantly higher in the MGO group, while the muscarinic M2 and M3 mRNA expressions remained unchanged between groups. Additionally, MGO exposure induced upregulation of TRPA1 and down-regulation of TRPV1 and TRPV4 in bladder tissues. Methylglyoxal did not change the mRNA expression of the advanced glycation end products receptor (RAGE), but markedly increased its downstream NF-κB - iNOS signaling. The mRNA expression of cyclooxygenase-2 (COX-2) and reactive-oxygen species (ROS) levels remained unchanged. Altogether, our data show that 4-week MGO intake in mice produces an overactive bladder phenotype in addition to bladder inflammation and increased NF-kB/iNOS signaling. TRPA1 up-regulation and TRPV1/TRPV4 down-regulation may account for the MGO-induced bladder overactivity. Scavengers of MGO could be an option to ameliorate bladder dysfunction in diabetic conditions.

MP54-08 EFFECTS OF VIBEGRON, A NEW β3-ADRENOCEPTOR AGONIST, ON DETRUSOR OVERACTIVITY AND REMODELING IN A MOUSE MODEL OF SPINAL CORD INJURY (SCI)

INTRODUCTION AND OBJECTIVE: Vibegron is a new β3-adrenoceptor agonist that was approved for the treatment of overreactive bladder (OAB) in Japan in 2018, and could potentially be used to treat patients with neurogenic bladder dysfunction due to SCI. Therefore, we examined the bladder activity and fibrotic and ischemic changes in the bladder of SCI mice with or without vibegron treatment. METHODS: Female C57BL/6N mice were used, and divided into three groups: A group of spinal cord intact mice; B group of SCI mice treated with vehicle; and C group of SCI mice treated with vibegron. SCI mice underwent Th8-9 spinal cord transection followed by oral administration of vehicle or vibegron (30 mg/kg/day) in the morning between 2 to 4 weeks after SCI. The bladder of SCI mice was emptied by abdominal compression once daily after SCI. We evaluated the urodynamic parameters using awake cystometry, the mRNA levels of fibrosis and ischemia-related molecules, and collagen and elastin levels of the bladder 4 weeks after SCI. RESULTS: The number of non-voiding contractions (NVCs) per voiding cycle was significantly lower in the C group than in the B group (Fig. 1A, B). The time required to induce the 1st NVC was significantly longer in the C group than in the B group. In molecular studies, mRNA expression of type 1 collagen, type 3 collagen, transforming growth factor-β1 (TGF-β1), and hypoxia inducible factor-1α (HIF-1α) were significantly higher in the B group than in A and C groups (Fig. 1C). Total collagen and total elastin were significantly higher in the B group than in the A group. CONCLUSIONS: Vibegron, a new β3-adrenoceptor agonist approved for OAB, reduced the number of NVCs, delayed the 1st NVC to appear, and improved the mRNA expression of type 1 collagen, type 3 collagen, TGF-β1 and HIF-1α although the protein level of collagen is not decreased yet at this stage of SCI (4 weeks). Vibegron would be effective for reducing SCI-induced neurogenic detrusor overactivity and tissue remodeling in the bladder.Source of Funding: DOD W81XWH-17-1-0403 KAKENHI for Early-Career Scientists (18K16751)

Altered detrusor contractility and voiding patterns in mice lacking the mechanosensitive TREK-1 channel

BackgroundPreviously published results from our laboratory identified a mechano-gated two-pore domain potassium channel, TREK-1, as a main mechanosensor in the smooth muscle of the human urinary bladder. One of the limitations of in vitro experiments on isolated human detrusor included inability to evaluate in vivo effects of TREK-1 on voiding function, as the channel is also expressed in the nervous system, and may modulate micturition via neural pathways. Therefore, in the present study, we aimed to assess the role of TREK-1 channel in bladder function and voiding patterns in vivo by using TREK-1 knockout (KO) mice.MethodsAdult C57BL/6 J wild-type (WT, N = 32) and TREK-1 KO (N = 33) mice were used in this study. The overall phenotype and bladder function were evaluated by gene and protein expression of TREK-1 channel, in vitro contractile experiments using detrusor strips in response to stretch and pharmacological stimuli, and cystometry in unanesthetized animals.ResultsTREK-1 KO animals had an elevated basal muscle tone and enhanced spontaneous activity in the detrusor without detectable changes in bladder morphology/histology. Stretch applied to isolated detrusor strips increased the amplitude of spontaneous contractions by 109% in the TREK-1 KO group in contrast to a 61% increase in WT mice (p ≤ 0.05 to respective baseline for each group). The detrusor strips from TREK-1 KO mice also generated more contractile force in response to electric field stimulation and high potassium concentration in comparison to WT group (p ≤ 0.05 for both tests). However, cystometric recordings from TREK-1 KO mice revealed a significant increase in the duration of the intermicturition interval, enhanced bladder capacity and increased number of non-voiding contractions in comparison to WT mice.ConclusionsOur results provide evidence that global down-regulation of TREK-1 channels has dual effects on detrusor contractility and micturition patterns in vivo. The observed differences are likely due to expression of TREK-1 channel not only in detrusor myocytes but also in afferent and efferent neural pathways involved in regulation of micturition which may underly the “mixed” voiding phenotype in TREK-1 KO mice.

The preventive effect of a free radical scavenger on oxidative stress after the relief of partial bladder outlet obstruction in a rat model.

AimsTo investigate the effect of a free radical scavenger (tempol) after relief of partial bladder outlet obstruction (pBOO) on bladder function in a rat model.MethodspBOO was induced in 50 eight-week-old female Sprague-Dawley rats and relieved 3 weeks later. The rats were divided randomly into 5 groups: sham-operated, tempol-treated for 1 week (Treat-1w) or 3 weeks (Treat-3w), and no treatment for 1 week (nonTreat-1w) or 3 weeks (nonTreat-3w). Awaken cystometrograms were obtained 1 or 3 weeks after relief according to the grouping. The bladders were isolated and weighed. H&E, Masson’s trichrome and TUNEL staining were used to analyze histological changes. The oxidative stress assessed using malondialdehyde. The expression of beta-3 adrenoreceptor was examined by Western blotting.ResultsThe tempol-treated groups exhibited a significant decrease in the number of non-voiding contractions per voiding cycle (nonTreat-1w vs. Treat-1w, 1.18±0.82 vs. 0.36±0.40, P = 0.010; nonTreat-3w vs. Treat-3w, 1.51±0.69 vs. 0.23±0.25, P = 0.002). The thickness and collagen fiber deposition of the detrusor muscle layer was significantly decreased in the treated groups. Apoptosis detected was mainly observed in the urothelial cell layer, although the rate of apoptosis was significantly decreased in the treated groups (48.9±3.36% vs. 32.7±11.10%, P = 0.024; 25.8±4.67% vs. 15.7±9.83%, P = 0.314). The tempol-treated groups showed significant decreases in the MDA concentrations at both 1 and 3 weeks after relief. The expression of the beta-3 adrenoreceptor was increased in the tempol-treated rats.ConclusionsIschemic reperfusion injury after relief of pBOO caused histological and functional changes in the bladder. Free radical scavenger treatment prevented this oxidative stress.

Effect of TRPV4 activation in a rat model of detrusor underactivity induced by bilateral pelvic nerve crush injury.

To produce an animal model of peripheral neurogenic detrusor underactivity (DU) and to evaluate the effect of TRPV4 receptor activation in this DU model. In female Sprague-Dawley rats, bilateral pelvic nerve crush (PNC) was performed by using sharp forceps. After 10 days, awake cystometrograms (CMG) were recorded in sham and PNC rats. A TRPV4 agonist (GSK 1016790A) with or without a TRPV4 antagonist (RN1734) were administered intravesically and CMG parameters were compared before and after drug administration in each group. The TRPV4 transcript level in the bladder mucosa and histological changes were also evaluated. In CMG, PNC rats showed significant increases in intercontraction intervals (ICI), number of non-voiding contractions (NVCs), baseline pressure, threshold pressure, bladder capacity, voided volumes, and post-void residual (PVR) compared to sham rats. Contraction amplitude and voiding efficiency were significantly decreased in PNC rats. In PNC rats, intravesical application of GSK1016790A (1.5 μM) significantly decreased ICI, bladder capacity, voided volume, and PVR without increasing NVCs, and these effects were blocked by RN1734 (5.0 μM). In contrast, 1.5 μM GSK1016790A had no significant effects on CMG parameters in normal rats. TRPV4 expression within the bladder mucosa of PNC rats was increased in association with urothelial thickening. Rats with bilateral PNC showed characteristics of DU, and this model seems appropriate for further evaluation of peripheral neurogenic mechanisms of DU. Also, TRPV4 receptors, the activation of which reduced bladder capacity and PVR, could be a target for DU treatment.

OAB without an overactive bladder in the acute prostaglandin E2 rat model.

Intravesical prostaglandin E2 (PGE2) was previously used to induce overactive bladder (OAB) symptoms, as it reduces bladder capacity in rats and causes a "strong urgency sensation" in healthy women. However, the mechanism by which this occurs is unclear. To clarify how PGE2 reduces bladder capacity, 100 µM PGE2 was administered intravesically during open, single-fill cystometry with simultaneous measurement of sphincter EMG in the urethane-anesthetized female Wistar rat. PGE2 was also applied to the urethra or bladder selectively by use of a ligature at the bladder neck before (urethra) or during (bladder) closed-outlet, single-fill cystometry. Additional tests of urethral perfusion with PGE2 were made. PGE2 decreased bladder capacity, increased voiding efficiency, and increased sphincter EMG during open cystometry compared with saline controls. The number of nonvoiding contractions did not change with PGE2; however, bladder compliance decreased. During closed-outlet cystometry, PGE2 applied only to the bladder or the urethra did not decrease bladder capacity. Urethral infusion of PGE2 decreased urethral perfusion pressure. Taken together, these results suggest that intravesical PGE2 may decrease bladder capacity by targeting afferents in the proximal urethra. This may occur through urethral relaxation and decreased bladder compliance, both of which may increase activation of proximal urethra afferents from distension of the proximal urethra. This hypothesis stands in contrast to many hypotheses of urgency that focus on bladder dysfunction as the primary cause of OAB symptoms. Targeting the urethra, particularly urethral smooth muscle, may be a promising avenue for the design of drugs and devices to treat OAB.

MP85-03 THE THERAPEUTIC EFFECT OF TRPV4 ACTIVATION IN THE BLADDER ON UNDERACTIVE BLADDER IN RATS WITH PELVIC NERVE CRUSH

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Neurogenic Voiding Dysfunction I1 Apr 2017MP85-03 THE THERAPEUTIC EFFECT OF TRPV4 ACTIVATION IN THE BLADDER ON UNDERACTIVE BLADDER IN RATS WITH PELVIC NERVE CRUSH Ei-ichiro Takaoka, Shun Takai, Takahisa Suzuki, Nobutaka Shimizu, Joonbeom Kwon, Hiroki Okada, Hiroyuki Nishiyama, Naoki Yoshimura, and Christopher J. Chermansky Ei-ichiro TakaokaEi-ichiro Takaoka More articles by this author , Shun TakaiShun Takai More articles by this author , Takahisa SuzukiTakahisa Suzuki More articles by this author , Nobutaka ShimizuNobutaka Shimizu More articles by this author , Joonbeom KwonJoonbeom Kwon More articles by this author , Hiroki OkadaHiroki Okada More articles by this author , Hiroyuki NishiyamaHiroyuki Nishiyama More articles by this author , Naoki YoshimuraNaoki Yoshimura More articles by this author , and Christopher J. ChermanskyChristopher J. Chermansky More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2665AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Incomplete bladder emptying due to detrusor underactivity (DU) is a significant urological problem underlying underactive bladder (UAB). Also, TRPV4 has been reported to be one of the mechanosensitive channels expressed in the bladder. In this study, we sought to produce a consistent rat model of UAB with the modification of our previous model of pelvic nerve crush (PNC) (2016 AUA) and evaluated the therapeutic effect of intravesical application of a TRPV4 agonist on the UAB condition. METHODS In female Sprague-Dawley rats, the visceral branches of bilateral pelvic nerves were identified near the internal iliac vessels and bilateral PNC was made by two times of nerve compression of either side with each 20-seconds duration using sharp forceps. After 10 days, awake cystometrograms (CMG) were recorded in sham control and PNC rats. Then, in both groups, a TRPV4 agonist (GSK1016790A) was continuously administered into the bladder and the CMG parameters were compared before and after intravesical drug administration. RESULTS The bladder weight was significantly increased in PNC rats vs. control rats. In CMG, PNC rats showed significant increases in voided volume, post-void residual urine volume, and residual urine rate compared to control rats. PNC rats also revealed the significant increases in intercontraction intervals (ICI), a number of non-voiding contractions, and threshold pressure while the amplitude during voiding was significantly decreased (table). In the TRPV4 administration study, intravesical application of 1.5µM of GSK 1016790A significantly decreased ICI, voided volume, and post-void residual urine volume in PNC rats while it did not significantly affect any CMG parameters in control rats. CONCLUSIONS Rats with pelvic nerve injury induced by the modified PNC method, which showed the characteristics of DU, seem to be an appropriate model for evaluation of peripheral neurogenic mechanisms of UAB. Also TRPV4 that reduced the bladder capacity and residual urine volume could be a potential target for the treatment of UAB. © 2017FiguresReferencesRelatedDetailsCited byKaplan S (2017) Re: Qualitative Exploration of the Patient Experience of Underactive BladderJournal of Urology, VOL. 199, NO. 3, (588-589), Online publication date: 1-Mar-2018. Volume 197Issue 4SApril 2017Page: e1148-e1149 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Ei-ichiro Takaoka More articles by this author Shun Takai More articles by this author Takahisa Suzuki More articles by this author Nobutaka Shimizu More articles by this author Joonbeom Kwon More articles by this author Hiroki Okada More articles by this author Hiroyuki Nishiyama More articles by this author Naoki Yoshimura More articles by this author Christopher J. Chermansky More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Post-injury bladder management strategy influences lower urinary tract dysfunction in the mouse model of spinal cord injury.

To examine the effects of a different number of daily bladder squeezes on bladder dysfunction in mice with spinal cord injury (SCI). Spinal cord was transected at the Th8/9 in female C57BL/6N mice. Their bladders were manually squeezed to eliminate urine inside every day for 4 weeks. The mice were divided into three groups depending on the number of bladder squeezes; A: once daily, B: twice daily, C: three times daily. Four weeks after transection, single-filling cystometry were performed under an awake condition. NGF in the bladder mucosa and mRNA expression of P2X receptors and TRP channels in L6/S1 dorsal root ganglia (DRG) were measured. Bladder weight in group C was less than that of group A. Bladder capacity, post-void residual, and the number of non-voiding contractions during the storage phase were significantly larger in group A compared to group B or C. The level of NGF in groups C were lower compared to group A or B. The expression of P2X3 and TRPA1 in groups B and C was decreased compared to group A. The expression of P2X2 was decreased in groups B compared to group A. The post-injury bladder management after SCI with an increased number of daily bladder emptying improves the storage and voiding bladder dysfunction associated with the reduction of NGF in the bladder as well as P2X and TRP transcripts in lumbosacral DRG.

Age‐related changes in bladder function with altered angiotensin II receptor mechanisms in rats

To examine alterations in expression of angiotensin II type 1 receptors (AT1R) which induce organ tissue remodeling, angiotensin II type 2 receptors (AT2R) which protect against it, and related molecules in the bladder of matured rats with bladder dysfunction. Female SD rats of three different ages were used: 8 weeks old (8W; n = 5), 9 months old (9M; n = 5), and 15 months old (15M; n = 5). After cystometry, the expression levels of AT1R, connexin43 (Cx43), MAP kinase (MAPK), collagen1, AT2R, PPAR-γ, adiponectin (Adipo), and adiponectin receptor (Adipo-R) were investigated in the bladder. Pressure threshold, post-void residual volume and the number of non-voiding contractions were significantly increased in 15M versus 8W rats (P < 0.01). Maximum voiding pressure was significantly decreased in 15M versus 8W rats (P < 0.05). There was no significant difference in CMG parameters between 8W and 9M rats. In the bladder, the mRNA expression of AT1R, Cx43, MAPK, collagen 1, AT2R, PPAR-γ, Adipo, and Adipo-R were significantly higher in 15M than in 8W rats. The relative expression ratio of AT1R protein against AT2R protein in the mucosa and detrusor was significantly increased in 15M versus 8W rats. These results indicate that matured rats exhibit not only bladder overactivity but also impaired voiding, which are associated with upregulation of AT1R. The upregulation of AT2R also may play a significant role in the suppressing of AT1R induced remodelling. However, because AT1R upregulation is more dominant than AT2R increases, AT2R activation may not be sufficient to suppress AT1R stimulation in matured rats. Neurourol. Urodynam. 35:908-913, 2016. © 2015 Wiley Periodicals, Inc.

Synergic Suppressive Effect of Silodosin and Imidafenacin on Non‐Voiding Bladder Contractions in Male Rats with Subacute Bladder Outlet Obstruction

To investigate single or combined effect of silodosin, an α1A-adrenoceptor antagonist, and imidafenacin, an antimuscarinic agent, on bladder function in a subacute bladder outlet obstruction (BOO) model of male rats. Partial BOO was created in male Wistar rats by ligating the urethra with a steel rod. On day 10 after surgery, when frequent voiding was most remarkable on voiding behavior measurement in a metabolic cage, cystometric investigations in a conscious restrained condition were conducted with cumulative intravenous administration of silodosin alone (0.1, 1, 10, and 100 µg/kg), imidafenacin alone (1, 3, and 10 µg/kg), or a combination of the two drugs. When compared with the Sham rats, the BOO rats showed an increase in bladder capacity, residual volume, mean amplitude and the number of non-voiding contractions (NVCs), accompanied with an increase in bladder weight. In the BOO rats, silodosin alone at 100 µg/kg significantly decreased the number of NVCs, whereas imidafenacin alone at 3 and 10 µg/kg significantly decreased both the number and mean amplitude of NVCs. The combination administration with lower doses (silodosin at 10 µg/kg and imidafenacin at 1 µg/kg) significantly suppressed both the number and mean amplitude of NVCs. The present results indicate a suppressive effect of silodosin or imidafenacin alone and a synergic effect of the combination of these two drugs on NVCs in a subacute BOO model of male rats.

Protein kinase C modulates frequency of micturition and non-voiding contractions in the urinary bladder via neuronal and myogenic mechanisms.

BackgroundProtein Kinase C (PKC) dysfunction is implicated in a variety of smooth muscle disorders including detrusor overactivity associated with frequency and urgency of micturition. In this study, we aimed to evaluate the modulatory effects of endogenous PKC-dependent pathways on bladder storage and emptying function.MethodsWe utilized in vivo cystometry and in vitro organ bath studies using isolated bladder muscle strips (BMS) from rats to measure contractility, intravesical pressure, and voided volume. Both in vitro and in vivo results were statistically analyzed using one-way repeated measures ANOVA between the groups followed by Bonferroni’s post-test, as appropriate (Systat Software Inc., San Jose, CA).ResultsEffects of PKC activators, phorbol-12,13-dibutyrate (PDBu), and phorbol-12,13-myristate (PMA), were concentration-dependent, with high concentrations increasing frequency of micturition, and sensitivity of intramural nerves to electrical field stimulation (EFS), in vitro, while lower concentrations had no effect on BMS sensitivity to EFS. The PKC inhibitors, bisindolylmaleimide1 (Bim-1), (28 nM), and Ro318220 (50 μM) triggered an increase in the number of non-voiding contractions (NVC), and a decrease in the voided volume associated with reduced ability to maintain contractile force upon EFS, but did not affect peak force in vitro. Both low (50 nM) and high PDBu 1 micromolar (1uM) decreased the sensitivity of BMS to carbachol. Application of a low concentration of PDBu inhibited spontaneous contractions, in vitro, and Bim-1-induced NVC, and restored normal voiding frequency during urodynamic recordings in vivo.ConclusionsIn summary, the effects of low PKC stimulation include inhibition of smooth muscle contractile responses, whereas high levels of PKC stimulation increased nerve-mediated contractions in vitro, and micturition contractions in vivo. These results indicate that endogenous PKC signaling displays a concentration-dependent contraction profile in the urinary bladder via both smooth muscle and nerve-mediated pathways.