One-year results with selective bladder denervation in women with refractory overactive bladder.

AIMS: To report 1-year results with selective bladder denervation (SBD) of the trigone in women with refractory overactive bladder (OAB). METHODS: In this prospective, international, multicenter case series, women with refractory OAB underwent a single SBD treatment of the bladder subtrigone region using temperature-controlled radiofrequency. Patients were followed for 1 year and evaluated for changes in OAB symptoms and adverse events. RESULTS: Among 35 women, 29 (83%) returned for 1-year follow up. Median symptom reductions based on 3-day bladder diaries were 68% for urgency urinary incontinence ( P < .001), 67% for urinary incontinence ( P < .001), 43% for urgency episodes ( P < .001), 5% for urinary frequency ( P = .19), and 33% for the total urgency and frequency score ( P < .001), with the majority of treatment benefit realized in the first month. Treatment benefit was reported in 72% of patients, the clinical success rate (≥50% reduction in urgency urinary incontinence) was 69%, and the dry rate was 10%. Statistically significant improvements occurred on Symptom Bother and Health-related Quality of Life scales on the Overactive Bladder questionnaire, and on 6 of 9 King's Health Questionnaire domains. Patients with less severe baseline symptoms had similar quality of life improvements as those with more severe baseline symptoms. Device- or procedure-related adverse events were reported in 6 (17%) patients. CONCLUSIONS: A single treatment with selective bladder denervation is durable for 1-year in a significant proportion of women with refractory overactive bladder.

Urethral diverticulum: A systematic review.

Objective: To present a review of the current literature regarding the presentation, diagnosis, and treatment of female urethral diverticula (UD). Methods: A systematic search of the PubMed database was performed to identify studies evaluating female UD. Article titles, abstracts and full-text manuscripts were screened to identify relevant studies, which then underwent data extraction and analysis. Results: In all, 50 studies evaluating the presentation, diagnosis and treatment of female UD were deemed relevant for inclusion. Almost all studies were retrospective single-arm case series. Female UD are outpouchings of the urethral lumen into the surrounding connective tissue. The presentation of female UD is diverse and can range from incidental findings to lower urinary tract symptoms, frequent urinary tract infections, dyspareunia, urinary incontinence (UI), or malignancy. Repair of UD begins with an accurate assessment and diagnosis, which should include adequate radiographic imaging, usually including magnetic resonance imaging. Once the diagnosis is confirmed, the usual treatment is surgical excision and reconstruction, most often through a transvaginal approach. The principles of transvaginal urethral diverticulectomy include: removal of the entire urethral diverticulum wall, watertight closure of the urethra, multi-layered and non-overlapping closure of surrounding tissue with absorbable suture, and preservation or creation of continence. Results of surgical repair are usually excellent, although long-term recurrence of these lesions may occur. Complications of urethral diverticulectomy include urethrovaginal fistula, UI, and rarely urethral stricture. Conclusion: Whilst urethral diverticulectomy excision and reconstruction is a challenging procedure, it is ultimately satisfying for the patient and the surgeon when relief of bothersome symptoms is achieved. Adherence to principles of reconstructive surgery is important to ensure a satisfactory result. Abbreviations: PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; UD: urethral diverticulum/diverticula; UI: urinary incontinence; US: ultrasonography; VCUG: voiding cystourethrogram.

Surgery for urinary incontinence in women: Report from the 6th international consultation on incontinence.

Urinary incontinence is a prevalent condition worldwide and causes a tremendous impact on a woman's quality of life. While conservative and non-surgical therapies are options for treatment, surgery for stress urinary incontinence (SUI) is common. Options include colposuspension, slings (pubovaginal and midurethral), and periurethral bulking. While evidence supports each of these options in the treatment of SUI, each is associated with various rates of success and unique adverse event profiles. Urgency urinary incontinence (UUI) is initially treated with behavioral modification and pharmacologic means, with surgery reserved for those with refractory symptoms or significant complications from medication use. At present, intravesical onabotulinumtoxinA injections, percutaneous tibial nerve stimulation, and sacral neurostimulation are all viable options for refractory UUI/overactive bladder. As with surgical interventions for SUI, each of these is, likewise, associated with unique outcomes and adverse event profiles. Herein, we summarize the findings and conclusions from the 6th International Consultation on Incontinence (ICI) regarding surgical treatment of urinary incontinence in women.

Nongenomic modulation of the large conductance voltage- and Ca2+-activated K+ channels by estrogen: A novel regulatory mechanism in human detrusor smooth muscle.

Estrogens have an important role in regulating detrusor smooth muscle (DSM) function. However, the underlying molecular and cellular mechanisms by which estrogens control human DSM excitability and contractility are not well known. Here, we used human DSM specimens from open bladder surgeries on 27 patients to elucidate the mechanism by which 17ß-estradiol regulates large conductance voltage- and Ca2+-activated K+ (BK) channels, the most prominent K+ channels in human DSM We employed single BK channel recordings on inside-out excised membrane patches, perforated whole-cell patch-clamp on freshly isolated DSM cells, and isometric tension recordings on DSM-isolated strips to investigate the mechanism by which 17ß-estradiol activates BK channels. 17ß-Estradiol (100 nmol/L) rapidly increased depolarization-induced whole-cell K+ currents in DSM cells. The 17ß-estradiol stimulatory effects on whole-cell BK currents were completely abolished by the selective BK channel inhibitor paxilline (1 µmol/L), clearly indicating that 17ß-estradiol specifically activates BK channels. 17ß-Estradiol also increased the frequency of ryanodine receptor-mediated transient BK currents. Single BK channel recordings showed that 17ß-estradiol (100 nmol/L) significantly increased the BK channel open probability of inside-out excised membrane patches, revealing that 17ß-estradiol activates BK channels directly. 17ß-Estradiol reduced spontaneous phasic contractions of human DSM-isolated strips in a concentration-dependent manner (100 nmol/L-1 µmol/L), and this effect was blocked by paxilline (1 µmol/L). 17ß-Estradiol (100 nmol/L) also reduced nerve-evoked contractions of human DSM-isolated strips. Collectively, our results reveal that 17ß-estradiol plays a critical role in regulating human DSM function through a direct nongenomic activation of BK channels.

Analysis of Complications of Pelvic Mesh Excision Surgery Using the Clavien-Dindo Classification System.

PURPOSE: We describe and categorize complications using the Clavien-Dindo classification system in patients who underwent vaginal mesh excision surgery. MATERIALS AND METHODS: With institutional review board approval we retrospectively reviewed the records of 277 patients who underwent vaginal mesh extraction between 2007 and 2015 at a single institution. Surgical complications were stratified using the Clavien-Dindo classification system. Complications were perioperative (prior to discharge) or postoperative (within 90 days). Indications for initial mesh placement, mesh revision procedure, time to resolution and medical comorbidities were assessed. RESULTS: Of the 277 patients 47.3% had at least 1 surgical complication, including multiple complications in 7.2%. A total of 155 complications were identified, which were grade II in 49.0% of cases, grade I in 25.8%, grade IIIb in 18.7%, grade IIIa in 5.2% and grade IVa in 1.3%. No grade IVb or V complications were identified. The indication for initial mesh placement did not significantly affect complication frequency. Patients who underwent combined stress urinary incontinence and pelvic organ prolapse mesh revision surgeries had an increased frequency of complications compared to those treated with mesh revision surgery for pelvic organ prolapse or stress urinary incontinence alone (p = 0.045). Most complications occurred postoperatively and resolved by 90 days. Age, body mass index, smoking status and diabetes were not associated with increased complications. CONCLUSIONS: Despite the complexity of mesh revision surgery most complications are minor. Serious complications may develop, emphasizing the need for proper patient counseling and surgical experience when performing these procedures.

Dimethyl sulfoxide (DMSO) as intravesical therapy for interstitial cystitis/bladder pain syndrome: A review.

AIMS: The purpose of this review is to update the current understanding of dimethyl sulfoxide (DMSO) and its role in the treatment of interstitial cystitis (IC). METHODS: A systematic review was conducted using the PRIMSA checklist to identify published articles involving intravesical DMSO for the treatment of IC. RESULTS: Thirteen cohort studies and three randomized-controlled trials were identified. Response rates relying on subjective measurement scores range from 61 to 95%. No increased efficacy was found with "cocktail" DMSO therapy. Great variation existed in diagnostic criteria, DMSO instillation protocols and response measurements. CONCLUSIONS: The current evidence backing DMSO is a constellation of cohort studies and a single randomized-controlled trial versus placebo. The optimal dose, dwell time, type of IC most likely to respond to DMSO, definitions of success/failure and the number of treatments are not universally agreed upon. Improvements in study design, phenotyping patients based on symptoms, as well as the emergence of reliable biomarkers of the disease may better guide the use of DMSO in the future.

Stress urinary incontinence surgery trends in academic female pelvic medicine and reconstructive surgery urology practice in the setting of the food and drug administration public health notifications.

AIMS: To investigate the possible effects of the Food and Drug Administration (FDA) Public Health Notifications in 2008 and 2011 regarding surgical trends in transvaginal mesh (TVM) placement for stress urinary incontinence (SUI) and related mesh revision surgery in Female Pelvic Medicine & Reconstructive Surgery (FPMRS) practice in tertiary care academic medical centers in the United States. METHODS: Surgical volume for procedures performed primarily by FPMRS surgeons at eight academic institutions across the US was collected using Current Procedural Terminology (CPT) codes for stress urinary incontinence repair and revision surgeries from 2007 to 2013. SAS statistical software was used to assess for trends in the data. RESULTS: There was a decrease in the use of synthetic mesh sling for the treatment of SUI at academic tertiary care centers over the past 7 years; however, this was not statistically significant. While the total number of surgical interventions for SUI remained stable, there was an increase in the utilization of autologous fascia pubovaginal slings (AFPVS). The number of mesh sling revision surgeries, including urethrolysis and removal or revision of slings, increased almost three-fold at these centers. CONCLUSIONS: These observed trends suggest a possible effect of the FDA Public Health Notifications regarding TVM on surgical practice for SUI in academic centers, even though they did not specifically warn against the use of synthetic mesh for this indication. Indications for surgery, complications, and outcomes were not evaluated during this retrospective study. However, such data may provide alternative insights into reasons for the observed trends. Neurourol. Urodynam. 36:1155-1160, 2017. © 2016 Wiley Periodicals, Inc.

Female Urethral Diverticula in the Contemporary Era: Is the Classic Triad of the "3Ds" Still Relevant?

OBJECTIVE: To evaluate the correlation between signs and symptoms of urethral diverticulum (UD), especially the classic triad of 3Ds including dysuria, dyspareunia, and postvoid dribbling, before and after transvaginal urethral diverticulectomy, in relation to anatomic configuration on imaging. MATERIALS AND METHODS: After IRB approval, records of 54 females who underwent transvaginal urethral diverticulectomy were retrospectively reviewed. Urinary symptoms before and after the procedure were correlated with the anatomical configuration of the UD on magnetic resonance imaging. RESULTS: The median age of the patients was 52 years (range 29-77). Common presenting symptoms were stress urinary incontinence (60%), dyspareunia (60%), and recurrent urinary tract infections (70%). The classic 3Ds were present collectively in only 5% of patients. Dyspareunia was the most common of the 3 "Ds." Twenty-seven percent of patients had none of the classic 3Ds. On physical examination, the most common finding was a tender anterior vaginal wall mass (52%). Presenting signs and symptoms did not correlate with anatomic configuration in terms of radial urethral involvement, size, or length of urethral involvement on preoperative magnetic resonance imaging. After median 14 months of follow-up, no patient reported the classic 3Ds after surgery. CONCLUSION: Recurrent urinary tract infections, stress urinary incontinence, dyspareunia, and vaginal mass are the most common presentations of UD. The classic triad "3Ds" is rarely seen in the individual patient. Preoperative anatomic configuration on imaging is not correlated with the severity or nature of presenting symptoms.

BK channel regulation by phosphodiesterase type 1: a novel signaling pathway controlling human detrusor smooth muscle function.

Large-conductance Ca(2+)-activated K(+) (BK) channels are critical regulators of detrusor smooth muscle (DSM) function. We aimed to investigate phosphodiesterase type 1 (PDE1) interactions with BK channels in human DSM to determine the mechanism by which PDE1 regulates human urinary bladder physiology. A combined electrophysiological, functional, and pharmacological approach was applied using human DSM specimens obtained from open bladder surgeries. The perforated whole cell patch-clamp technique was used to record transient BK currents (TBKCs) and the cell membrane potential in freshly isolated human DSM cells in combination with the selective PDE1 inhibitor, 8-methoxymethyl-3-isobutyl-1-methylxanthine (8MM-IBMX). Isometric DSM tension recordings were used to measure spontaneous phasic and electrical field stimulation-induced contractions in human DSM isolated strips. Selective pharmacological inhibition of PDE1 with 8MM-IBMX (10 µM) increased TBKC activity in human DSM cells, which was abolished by subsequent inhibition of protein kinase A (PKA) with H-89 (10 µM). The stimulatory effect of 8MM-IBMX on TBKCs was reversed upon activation of muscarinic acetylcholine receptors with carbachol (1 µM). 8MM-IBMX (10 µM) hyperpolarized the DSM cell membrane potential, an effect blocked by PKA inhibition. 8MM-IBMX significantly decreased spontaneous phasic and nerve-evoked contractions of human DSM isolated strips. The results reveal a novel mechanism that pharmacological inhibition of PDE1 attenuates human DSM excitability and contractility by activating BK channels via a PKA-dependent mechanism. The data also suggest interactions between PDE1 and muscarinic signaling pathways in human DSM. Inhibition of PDE1 can be a novel therapeutic approach for the treatment of overactive bladder associated with detrusor overactivity.

Removal of Polypropylene Sling Mesh From the Urethra: An Anatomic Technique.

OBJECTIVE: To describe a technique for removal of intraurethral mesh with minimal disruption of the periurethral anatomy. MATERIALS AND METHODS: Through a midline transvaginal approach the sling is located lateral to the urethra and divided. The medial portion of the divided sling is carefully dissected back to its entrance laterally into the urethral lumen. A stay suture is placed on the dissected sling. The sling is located on the contralateral side and likewise divided and dissected back to the urethral lumen. The completely dissected sling is pulled through such that the holding stitch is through and through the urethral lumen, allowing easy localization of the urethral defect on lateral walls of the urethra. These defects are closed with an absorbable suture and the vaginal incision is closed. RESULTS: Three patients have undergone a transvaginal removal of their intraurethral mesh using the described technique. At a mean follow-up of 6.0 months, there were no intraoperative or postoperative complications. All patients were obstructed preoperatively and all developed stress urinary incontinence postoperatively requiring 0-1 pads per day. CONCLUSION: Current approaches to the surgical repair of chronic intraurethral mesh have significant limitations that are minimized by the described technique. This anatomic removal of mesh from the urethra has several advantages including no disruption of the ventral wall of the urethra, complete removal of foreign body from the urethra, and simplified localization of the urethral wall defect to allow for anatomic closure.

Functional link between muscarinic receptors and large-conductance Ca2+ -activated K+ channels in freshly isolated human detrusor smooth muscle cells.

Activation of muscarinic acetylcholine receptors (mAChRs) constitutes the primary mechanism for enhancing excitability and contractility of human detrusor smooth muscle (DSM). Since the large-conductance Ca(2+)-activated K(+) (KCa1.1) channels are key regulators of human DSM function, we investigated whether mAChR activation increases human DSM excitability by inhibiting KCa1.1 channels. We used the mAChR agonist, carbachol, to determine the changes in KCa1.1 channel activity upon mAChR activation in freshly isolated human DSM cells obtained from open bladder surgeries using the perforated whole cell and single KCa1.1 channel patch-clamp recordings. Human DSM cells were collected from 29 patients (23 males and 6 females, average age of 65.9 ± 1.5 years). Carbachol inhibited the amplitude and frequency of KCa1.1 channel-mediated spontaneous transient outward currents and spontaneous transient hyperpolarizations, which are triggered by the release of Ca(2+) from ryanodine receptors. Carbachol also caused membrane potential depolarization, which was not observed in the presence of iberiotoxin, a KCa1.1 channel inhibitor, indicating the critical role of the KCa1.1 channels. The potential direct carbachol effects on KCa1.1 channels were examined under conditions of removing the major cellular Ca(2+) sources for KCa1.1 channel activation with pharmacological inhibitors (thapsigargin, ryanodine, and nifedipine). In the presence of these inhibitors, carbachol did not affect the single KCa1.1 channel open probability and mean KCa1.1 channel conductance (cell-attached configuration) or depolarization-induced whole cell steady-state KCa1.1 currents. The data support the concept that mAChR activation triggers indirect functional KCa1.1 channel inhibition mediated by intracellular Ca(2+), thus increasing the excitability in human DSM cells.

Patient perception of transvaginal mesh and the media.

OBJECTIVE: To assess the penetration of media-based information on transvaginal mesh (TVM) in our patient population and to determine whether exposure affects patient opinion. Since the 2011 Federal Drug Administration communication on TVM, many advertisements from legal practices have been directed toward patients. MATERIALS AND METHODS: An 18-item survey was administered to female patients at 2 sites from August 2012 to April 2013. Patients presenting with new diagnoses of pelvic organ prolapse or stress urinary incontinence or patients who reported prior mesh surgery were excluded. RESULTS: Ninety-nine questionnaires were completed. Sixty-six of the patients (67%) were aware of TVM; and of these, 38 (58%) cited advertisements as the initial source of information. Only 12% were aware of the Food and Drug Administration's communication. Regarding opinion of TVM, 9% chose "it is a safe product," 9% "safety depends on factors related to patient," 4.5% "not a safe product," 1.5% "safety depends on the doctor," 68% "I don't know," and 4.5% marked 2 selections. Only 12% indicated knowing the difference in the use of TVM for pelvic organ prolapse vs stress urinary incontinence. When asked what influenced their opinion of TVM the most; responses were as follows: advertisement (33.3%), medical professional (22.7%), friends or family who underwent TVM procedure (12.1%), media article (6.1%), and "not sure" (25.8%). CONCLUSION: Advertisements of TVM lawsuits had a high penetration into our patient population but did not produce an overtly negative response in our sample. Clinicians should be aware of the impact of these advertisements on patient opinion and counsel patients accordingly with unbiased and scientifically accurate information.

Management of failed stress urinary incontinence surgery.

With the increasing volume of surgery being performed for the treatment of female stress urinary incontinence (SUI), especially with the widespread use of midurethral slings (MUS), recurrent urinary incontinence is becoming an increasingly common condition. Various preoperative and intraoperative factors have been associated with failed SUI surgery. Treatment options for failed SUI surgery include conservative management and/or surgical management, which include pubovaginal sling, MUS, retropubic suspension, periurethral bulking agents, and artificial sphincters. The choice of treatment option will depend on the etiology of the patient's failure, patient comorbidities, and patient preference.

Neurogenic detrusor overactivity is associated with decreased expression and function of the large conductance voltage- and Ca(2+)-activated K(+) channels.

Patients suffering from a variety of neurological diseases such as spinal cord injury, Parkinson's disease, and multiple sclerosis often develop neurogenic detrusor overactivity (NDO), which currently lacks a universally effective therapy. Here, we tested the hypothesis that NDO is associated with changes in detrusor smooth muscle (DSM) large conductance Ca(2+)-activated K(+) (BK) channel expression and function. DSM tissue samples from 33 patients were obtained during open bladder surgeries. NDO patients were clinically characterized preoperatively with pressure-flow urodynamics demonstrating detrusor overactivity, in the setting of a clinically relevant neurological condition. Control patients did not have overactive bladder and did not have a clinically relevant neurological disease. We conducted quantitative polymerase chain reactions (qPCR), perforated patch-clamp electrophysiology on freshly-isolated DSM cells, and functional studies on DSM contractility. qPCR experiments revealed that DSM samples from NDO patients showed decreased BK channel mRNA expression in comparison to controls. Patch-clamp experiments demonstrated reduced whole cell and transient BK currents (TBKCs) in freshly-isolated DSM cells from NDO patients. Functional studies on DSM contractility showed that spontaneous phasic contractions had a decreased sensitivity to iberiotoxin, a selective BK channel inhibitor, in DSM strips isolated from NDO patients. These results reveal the novel finding that NDO is associated with decreased DSM BK channel expression and function leading to increased DSM excitability and contractility. BK channel openers or BK channel gene transfer could be an alternative strategy to control NDO. Future clinical trials are needed to evaluate the value of BK channel opening drugs or gene therapies for NDO treatment and to identify any possible adverse effects.

BRL37344, a ß3-adrenergic receptor agonist, decreases nerve-evoked contractions in human detrusor smooth muscle isolated strips: role of BK channels.

OBJECTIVE: To investigate the mechanism by which BRL37344, a ß3-adrenergic receptor (ß3-ARs) agonist, facilitates the inhibition of nerve-evoked contractions in human detrusor smooth muscle (DSM) isolated strips and to identify the role of large-conductance Ca(2+)-activated K(+) (BK) channels in this process. METHODS: Human DSM specimens were obtained from open bladder surgeries on patients without preoperative history of overactive bladder symptoms. Isometric DSM tension recordings were conducted using force-displacement transducers and thermostatically controlled tissue baths. Nerve-evoked contractions were generated by electrical field stimulation (EFS). RESULTS: BRL37344, a ß3-AR agonist, significantly decreased the amplitude, muscle force, and duration of the DSM contractions induced by 20 Hz EFS, in a concentration-dependent manner. This BRL37344-mediated inhibition of the amplitude and muscle force of the nerve-evoked DSM contraction was significantly reduced by iberiotoxin, a highly selective inhibitor of the BK channel, revealing a role for BK channels in the ß3-AR-induced inhibition of human DSM nerve-evoked contractions. We further used atropine, α,ß-methylene-ATP, and suramin to separate the cholinergic and purinergic components of human DSM nerve-evoked contractions. We found that the ß3-AR agonist, BRL37344, inhibited both components of the EFS-induced (0.5-50 Hz) DSM contractions. CONCLUSION: This study supports the concept that ß3-AR agonists inhibit nerve-evoked contractions in human DSM. We have further revealed that BK channels play a critical role in BRL37344-mediated relaxation of nerve-evoked contractions in human DSM. The study suggests that in addition to ß3-ARs, BK channels may also represent promising pharmacologic targets in the treatment of urinary bladder dysfunction.

Selective inhibition of phosphodiesterase 1 relaxes urinary bladder smooth muscle: role for ryanodine receptor-mediated BK channel activation.

The large conductance voltage- and Ca(2+)-activated K(+) (BK) channel is a major regulator of detrusor smooth muscle (DSM) excitability and contractility. Recently, we showed that nonselective phosphodiesterase (PDE) inhibition reduces guinea pig DSM excitability and contractility by increasing BK channel activity. Here, we investigated how DSM excitability and contractility changes upon selective inhibition of PDE type 1 (PDE1) and the underlying cellular mechanism involving ryanodine receptors (RyRs) and BK channels. PDE1 inhibition with 8-methoxymethyl-3-isobutyl-1-methylxanthine (8MM-IBMX; 10 µM) increased the cAMP levels in guinea pig DSM cells. Patch-clamp experiments on freshly isolated DSM cells showed that 8MM-IBMX increased transient BK currents and the spontaneous transient hyperpolarization (STH) frequency by ∼2.5- and ∼1.8-fold, respectively. 8MM-IBMX hyperpolarized guinea pig and human DSM cell membrane potential and significantly decreased the intracellular Ca(2+) levels in guinea pig DSM cells. Blocking BK channels with 1 µM paxilline or inhibiting RyRs with 30 µM ryanodine abolished the STHs and the 8MM-IBMX inhibitory effects on the DSM cell membrane potential. Isometric DSM tension recordings showed that 8MM-IBMX significantly reduced the spontaneous phasic contraction amplitude, muscle force integral, duration, frequency, and tone of DSM isolated strips. The electrical field stimulation-induced DSM contraction amplitude, muscle force integral, and duration were also attenuated by 10 µM 8MM-IBMX. Blocking BK channels with paxilline abolished the 8MM-IBMX effects on DSM contractions. Our data provide evidence that PDE1 inhibition relaxes DSM by raising cellular cAMP levels and subsequently stimulates RyRs, which leads to BK channel activation, membrane potential hyperpolarization, and decrease in intracellular Ca(2+) levels.

Expression and function of K(V)2-containing channels in human urinary bladder smooth muscle.

The functional role of the voltage-gated K(+) (K(V)) channels in human detrusor smooth muscle (DSM) is largely unexplored. Here, we provide molecular, electrophysiological, and functional evidence for the expression of K(V)2.1, K(V)2.2, and the electrically silent K(V)9.3 subunits in human DSM. Stromatoxin-1 (ScTx1), a selective inhibitor of K(V)2.1, K(V)2.2, and K(V)4.2 homotetrameric channels and of K(V)2.1/9.3 heterotetrameric channels, was used to examine the role of these channels in human DSM function. Human DSM tissues were obtained during open bladder surgeries from patients without a history of overactive bladder. Freshly isolated human DSM cells were studied using RT-PCR, immunocytochemistry, live-cell Ca(2+) imaging, and the perforated whole cell patch-clamp technique. Isometric DSM tension recordings of human DSM isolated strips were conducted using tissue baths. RT-PCR experiments showed mRNA expression of K(V)2.1, K(V)2.2, and K(V)9.3 (but not K(V)4.2) channel subunits in human isolated DSM cells. K(V)2.1 and K(V)2.2 protein expression was confirmed by Western blot analysis and immunocytochemistry. Perforated whole cell patch-clamp experiments revealed that ScTx1 (100 nM) inhibited the amplitude of the voltage step-induced K(V) current in freshly isolated human DSM cells. ScTx1 (100 nM) significantly increased the intracellular Ca(2+) level in DSM cells. In human DSM isolated strips, ScTx1 (100 nM) increased the spontaneous phasic contraction amplitude and muscle force, and enhanced the amplitude of the electrical field stimulation-induced contractions within the range of 3.5-30 Hz stimulation frequencies. These findings reveal that ScTx1-sensitive K(V)2-containing channels are key regulators of human DSM excitability and contractility and may represent new targets for pharmacological or genetic intervention for bladder dysfunction.

Suppression of human detrusor smooth muscle excitability and contractility via pharmacological activation of large conductance Ca2+-activated K+ channels.

Overactive bladder syndrome is frequently associated with increased detrusor smooth muscle (DSM) contractility. We tested the hypothesis that pharmacological activation of the large-conductance voltage- and Ca(2+)-activated K(+) (BK) channel with NS-1619, a selective BK channel opener, reduces the excitability and contractility of human DSM. We used the amphotericin-perforated whole cell patch-clamp technique on freshly isolated human DSM cells, live-cell Ca(2+) imaging, and isometric DSM tension recordings of human DSM strips obtained from open bladder surgeries. NS-1619 (30 µM) significantly increased the amplitude of the voltage step-induced whole cell BK currents, and this effect was abolished by pretreatment with 200 nM iberiotoxin (IBTX), a selective BK channel inhibitor. In current-clamp mode, NS-1619 (30 µM) significantly hyperpolarized the resting membrane potential, and the hyperpolarization was reversed by IBTX (200 nM). NS-1619 (30 µM) significantly decreased the intracellular Ca(2+) level in isolated human DSM cells. BK channel activation with NS-1619 (30 µM) significantly inhibited the amplitude, muscle force, frequency, duration, and tone of the spontaneous phasic and pharmacologically induced DSM contractions from human DSM isolated strips. IBTX (200 nM) suppressed the inhibitory effects of NS-1619 on spontaneous contractions. The amplitude of electrical field stimulation (0.5-50 Hz)-induced contractions was significantly reduced by NS-1619 (30 µM). Our data suggest that pharmacological activation of BK channels could represent a novel treatment option to control bladder dysfunction in humans.

Sling location in women with recurrent stress urinary incontinence following midurethral sling.

OBJECTIVE: Persistent or recurrent stress urinary incontinence (SUI) after a midurethral sling (MUS) may result from incorrect location of the sling relative to the midurethra. This study's objective was to evaluate the incidence of bladder neck (BN) or more proximal MUS in women undergoing reoperation for SUI after synthetic MUS. MATERIAL AND METHODS: A retrospective review was performed of patients referred and treated for isolated recurrent SUI after synthetic MUS (transobturator or retropubic approach). Patients undergoing sling excision for other indications (eg, outlet obstruction, urinary tract erosion) were excluded. Preoperative video urodynamic (VUDS) parameters were examined. Operative reports at re-exploration provided the anatomic location of the sling. RESULTS: Fifteen women with SUI after MUS underwent VUDS and subsequent reoperation. The MUS was found proximal to or at the BN in 8 (53%) women and suburethral in 7 (47%). Women with BN or proximal sling location were equally likely to have an open (4/8 patients) or closed BN (4/8 patients) at rest on filling cystography. VUDS parameters, including the radiographic finding of an open BN preoperatively, were not predictive of BN or more proximal sling location intraoperatively. MUSs found at the BN or proximal were more likely to be retropubic slings (7/8 patients). Rates of concomitant anterior prolapse repair did not differ according to sling location. CONCLUSION: Recurrent SUI as a result of proximal MUS location cannot be predicted on preoperative VUDS parameters. Surgical exploration is the primary method for identifying this phenomenon as the etiology of failure in these patients.