Suburothelial Space Research Articles

Therapeutic Effect of Botulinum Toxin A on Sensory Bladder Disorders-From Bench to Bedside.

Bladder oversensitivity arises from several different conditions involving the bladder, bladder outlet, systemic or central nervous system diseases. Increase of the bladder sensation results from activation of the sensory receptors in the urothelial cells or suburothelial tissues. Medical treatment targeting the overactive bladder (OAB) or interstitial cystitis (IC) might relieve oversensitive bladder symptoms (frequency, urgency and pain) in a portion of patients, but a certain percentage of patients still need active management. Botulinum toxin A (BoNT-A) has been demonstrated to have anti-inflammatory and antinociceptive effects in bladder sensory disorders and has been shown effective in the reduction of bladder oversensitivity and the increase of functional bladder capacity. For patients with OAB, urgency and urinary incontinence improved, while in patients with IC, bladder pain could be relieved in association with reduction of bladder oversensitivity after BoNT-A intravesical injection. Histological evidence has confirmed the therapeutic mechanism and clinical efficacy of intravesical BoNT-A injection on patients with OAB or IC. Bladder oversensitivity can also be relieved with the instillation of liposome encapsulated BoNT-A or low energy show waves (LESWs), which enable the BoNT-A molecule to penetrate into the urothelium and suburothelial space without affecting the detrusor contractility. Liposome encapsulated BoNT-A or combined LESWs and BoNT-A instillation might be future treatment alternatives for bladder oversensitivity in sensory bladder disorders.

Pacemaker Mechanisms Driving Pyeloureteric Peristalsis: Modulatory Role of Interstitial Cells.

The peristaltic pressure waves in the renal pelvis that propel urine expressed by the kidney into the ureter towards the bladder have long been considered to be 'myogenic', being little affected by blockers of nerve conduction or autonomic neurotransmission, but sustained by the intrinsic release of prostaglandins and sensory neurotransmitters. In uni-papilla mammals, the funnel-shaped renal pelvis consists of a lumen-forming urothelium and a stromal layer enveloped by a plexus of 'typical' smooth muscle cells (TSMCs), in multi-papillae kidneys a number of minor and major calyces fuse into a large renal pelvis. Electron microscopic, electrophysiological and Ca2+ imaging studies have established that the pacemaker cells driving pyeloureteric peristalsis are likely to be morphologically distinct 'atypical' smooth muscle cells (ASMCs) that fire Ca2+ transients and spontaneous transient depolarizations (STDs) which trigger propagating nifedipine-sensitive action potentials and Ca2+ waves in the TSMC layer. In uni-calyceal kidneys, ASMCs predominately locate on the serosal surface of the proximal renal pelvis while in multi-papillae kidneys they locate within the sub-urothelial space. 'Fibroblast-like' interstitial cells (ICs) located in the sub-urothelial space or adventitia are a mixed population of cells, having regional and species-dependent expression of various Cl-, K+, Ca2+ and cationic channels. ICs display asynchronous Ca2+ transients that periodically synchronize into bursts that accelerate ASMC Ca2+ transient firing. This review presents current knowledge of the architecture of the proximal renal pelvis, the role Ca2+ plays in renal pelvis peristalsis and the mechanisms by which ICs may sustain/accelerate ASMC pacemaking.

Interstitial cell modulation of pyeloureteric peristalsis in the mouse renal pelvis examined using FIBSEM tomography and calcium indicators.

Typical and atypical smooth muscle cells (TSMCs and ASMCs, respectively) and interstitial cells (ICs) within the pacemaker region of the mouse renal pelvis were examined using focused ion beam scanning electron (FIB SEM) tomography, immunohistochemistry and Ca2+ imaging. Individual cells within 500-900 electron micrograph stacks were volume rendered and associations with their neighbours established. 'Ribbon-shaped', Ano1 Cl- channel immuno-reactive ICs were present in the adventitia and the sub-urothelial space adjacent to the TSMC layer. ICs in the proximal renal pelvis were immuno-reactive to antibodies for CaV3.1 and hyperpolarization-activated cation nucleotide-gated isoform 3 (HCN3) channel sub-units, while basal-epithelial cells (BECs) were intensely immuno-reactive to Kv7.5 channel antibodies. Adventitial to the TSMC layer, ASMCs formed close appositions with TSMCs and ICs. The T-type Ca2+channel blocker, Ni2+ (10-200μM), reduced the frequency while the L-type Ca2+ channel blocker (1μM nifedipine) reduced the amplitude of propagating Ca2+ waves and contractions in the TSMC layer. Upon complete suppression of Ca2+ entry through TSMC Ca2+ channels, ASMCs displayed high-frequency (6min-1) Ca2+ transients, and ICs distributed into two populations of cells firing at 1 and 3min-1, respectively. IC Ca2+ transients periodically (every 3-5min-1) summed into bursts which doubled the frequency of ASMC Ca2+ transient firing. Synchronized IC bursting and the acceleration of ASMC firing were inhibited upon blockade of HCN channels with ZD7288 or cell-to-cell coupling with carbenoxolone. While ASMCs appear to be the primary pacemaker driving pyeloureteric peristalsis, it was concluded that sub-urothelial HCN3(+), CaV3.1(+) ICs can accelerate ASMC Ca2+ signalling.

265 IMPACT OF ALLYL ISOTHIOCYANATE, TRANSIENT RECEPTOR POTENTIAL A1 AGONIST, ON BLADDER MECHANOSENSITIVE AFFERENT ACTIVITY IN THE RAT

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology I1 Apr 2012265 IMPACT OF ALLYL ISOTHIOCYANATE, TRANSIENT RECEPTOR POTENTIAL A1 AGONIST, ON BLADDER MECHANOSENSITIVE AFFERENT ACTIVITY IN THE RAT Tomonori Minagawa, Naoki Aizawa, Yasuhiko Igawa, and Jean-Jacques Wyndaele Tomonori MinagawaTomonori Minagawa Wilrijk, Belgium More articles by this author , Naoki AizawaNaoki Aizawa Tokyo, Japan More articles by this author , Yasuhiko IgawaYasuhiko Igawa Tokyo, Japan More articles by this author , and Jean-Jacques WyndaeleJean-Jacques Wyndaele Wilrijk, Belgium More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.322AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Transient receptor potential ankyrin 1 (TRPA1) is a member of the TRP superfamily of ion channels, which have been conducted in multiple-sensation modalities including thermo-, osmo- and mechano-sensation. It has been reported TRPA1 ion channels are expressed in the urothelial cells and sensory nerve fibers in the urothelium and suburothelial space of the bladders. Although it has been speculated that TRPA1 might be involved in the bladder afferent transduction as a mechano-transducer, no direct demonstration has been reported. We investigated the effects of allyl isothiocyanate (AI), a TRPA 1 agonist, on the single unit mechanosensitive afferent activities (SAAs) primarily originating from the bladder in the rat. METHODS Female Sprague-Dawley rats were used. Under urethane anesthesia, SAA primarily originating from the bladder were identified by electrical stimulation of the left pelvic nerve and by bladder distension. Nerves with conduction velocity (CV) ≥ 2.5 m/sec were determined as myelinated AΔ-fibers and those with < 2.5 m/sec as unmyelinated C-fibers. Before drug administration, the baselines of SAA were recorded during cystometry with saline instillation at a rate of 0.08 ml/min until intravesical pressure reached 30cmH2O. Then, AI-solution (10 μM) was instilled intravesically three times. As the vehicle of AI, 0.01% ethanol was used. The SAAs are expressed as a percentage of baseline activity, integrated during the whole filling phase, which is based on pressure and volume. RESULTS Twenty-three SAAs were isolated in 13 rats. Ten units corresponded to criteria for AΔ-fibers (CV: 9.09 ± 9.15 m/sec.), and 13 for C-fibers (CV: 1.03 ± 0.55 m/sec.). Neither AI-instillation nor vehicle-instillation changed bladder compliance significantly (data not shown). SAA of both AΔ- and C-fibers significantly increased after AI-instillation, but not after vehicle-instillation (Figure). The difference between the groups was statistically significant. CONCLUSIONS The results of the present study demonstrate that AI can stimulate the afferent activities of both mechanosensitive AΔ- and C-fibers in the rat bladder. To our knowledge, this is the first direct demonstration of the stimulatory effect of the TRPA 1 agonist on bladder mechanosensitive afferent activities. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e107-e108 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Tomonori Minagawa Wilrijk, Belgium More articles by this author Naoki Aizawa Tokyo, Japan More articles by this author Yasuhiko Igawa Tokyo, Japan More articles by this author Jean-Jacques Wyndaele Wilrijk, Belgium More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Modulation of spontaneous activity in the overactive bladder: the role of P2Y agonists

Spinal cord transection (SCT) leads to an increase in spontaneous contractile activity in the isolated bladder that is reminiscent of an overactive bladder syndrome in patients with similar damage to the central nervous system. An increase in interstitial cell number in the suburothelial space between the urothelium and detrusor smooth muscle layer occurs in SCT bladders, and these cells elicit excitatory responses to purines and pyrimidines such as ATP, ADP, and UTP. We have investigated the hypothesis that these agents underlie the increase in spontaneous activity. Rats underwent lower thoracic spinal cord transection, and their bladder sheets or strips, with intact mucosa except where specified, were used for experiments. Isometric tension was recorded and propagating Ca(2+) and membrane potential (E(m)) waves were recorded by fluorescence imaging using photodiode arrays. SCT bladders were associated with regular spontaneous contractions (2.9 ± 0.4/min); ADP, UTP, and UDP augmented the amplitude but not their frequency. With strips from such bladders, a P2Y(6)-selective agonist (PSB0474) exerted similar effects. Fluorescence imaging of bladder sheets showed that ADP or UTP increased the conduction velocity of Ca(2+)/E(m) waves that were confined to regions of the bladder wall with an intact mucosa. When transverse bladder sections were used, Ca(2+)/E(m) waves originated in the suburothelial space and propagated to the detrusor and urothelium. Analysis of wave propagation showed that the suburothelial space exhibited properties of an electrical syncitium. These experiments are consistent with the hypothesis that P2Y-receptor agonists increase spontaneous contractile activity by augmenting functional activity of the cellular syncitium in the suburothelial space.

Intravesical Chondroitin Sulfate Inhibits Recruitment of Inflammatory Cells in an Acute Acid Damage “Leaky Bladder” Model of Cystitis

To investigate whether a physiologic effect of "glycosaminoglycan (GAG) replenishment therapy" altered recruitment of inflammatory cells in an acute bladder damage model. Replacement of the GAG layer with intravesically administered GAGs is an effective therapy for interstitial cystitis in at least some patients. Intravesically administered chondroitin sulfate was previously shown to bind to and restore the impermeability of surface-damaged ("leaky") urothelium to small ions. Rat bladders were damaged with 10 mM HCl. Negative control bladders were treated with phosphate-buffered saline. On the following day, the animal bladders were treated with 20 mg/mL chondroitin sulfate in phosphate-buffered saline, and the negative and positive controls were treated with phosphate-buffered saline alone. At 2 and 4 days after treatment with chondroitin sulfate, the rats were killed, and sections of their bladders were analyzed using toluidine blue staining for mast cell immunohistochemical labeling using antibodies against CD45 for lymphocytes and myeloperoxidase for neutrophils. Chondroitin sulfate treatment reduced the recruitment, in a statistically significant manner, of inflammatory cells, including neutrophils and mast cells to the suburothelial space but did not alter recruitment of CD45-positive lymphocytes. For the first time, we have demonstrated that intravesical GAG replenishment therapy also produces a physiologic effect of decreasing recruitment of inflammatory cells in an acute model of the damaged bladder. These findings support the use of intravesically administered GAG for bladder disorders that result from a loss of impermeability, including interstitial, radiation, and chemical cystitis, and possibly others as well.

Recent Advances in Intravesical Treatment of Overactive Bladder

The traditional medication for overactive bladder (OAB) is antimuscarinic agent, which targets muscarinic receptors. Recent investigations have revealed that muscarinic receptors are present in the urothelium and suburothelial sensory fibers, as well as in the detrusor. Urothelial dysfunction and abnormality of sensory receptor expression or transmitter release in suburothelial nerves could contribute to OAB refractory to antimuscarinics. Intravesical treatment to inhibit abnormal receptor expression or transmitter release in the sensory nerve terminals in the suburothelial space might provide beneficial therapeutic effects in the treatment of OAB. Intravesical resiniferatoxin (RTX) instillation and intravesical botulinum toxin A (BoNT‐A) injection are two promising treatment alternatives for refractory OAB. RTX at a high dose may cause undesired adverse events, such as hematuria, bladder pain or autonomic dysreflexia. RTX at a low concentration can decrease sensory urgency without influencing detrusor contractility; multiple instillations of low‐dose RTX may be required to achieve adequate desensitization of OAB. BoNT‐A, however, has a beneficial effect on detrusor contractility and causes large post‐void residual after injection in some patients. Therefore, careful dosage and injection site adjustment is mandatory to achieve satisfactory results using intravesical therapy.

Transient Receptor Potential A1 (TRPA1) Activity in the Human Urethra—Evidence for a Functional Role for TRPA1 in the Outflow Region

BackgroundA role for the transient receptor potential (TRP) A1 ion channel in rat lower urinary tract (LUT) sensation and disease has been proposed, but in the human LUT no information on TRPA1 activity is available. ObjectivesTo investigate the distribution of TRPA1 in the human urethra and to study the effect of TRPA1 agonists on isolated urethral strip preparations. Design, settings, and participantsUrethral specimens were obtained preoperatively from 10 patients and were freshly prepared for Western blot, immunohistochemistry, and functional in vitro investigations. MeasurementsThe expression patterns of TRPA1 were studied with Western blot and immunohistochemistry. The effects of allyl isothiocyanate (AI), cinnamaldehyde (CA), and NaHS (donor of H2S) on tension of urethral strips were investigated in tissue baths. Results and limitationsTRPA1 immunoreactivity (-IR) was found in nerve fibres in the suburothelial space and was also located to nerve fibres of the muscle layer. Single TRPA1-IR nerves extended into the urothelium. A majority, but not all TRPA1-IR nerves also expressed immunoreactivity for CGRP or TRPV1. In the urothelium, TRPV1 was located to the outer layers whereas TRPA1 was observed in basal urothelial cells. Interspersed between strands of smooth muscle cells of the urethral wall, TRPA1- and vimentin-IR cells containing central nuclei and slender cytoplasmatic extensions were observed.In functional experiments, TRPA1-agonists had no contractile effect in urethral preparations. After precontraction with phenylephrine, AI, CA, and NaHS caused concentration-dependent relaxations of urethral strip preparations. ConclusionsThe localization of TRPA1 to nerves that also express TRPV1 and CGRP, and in urothelial cells and interstitial cells, as well as the findings that TRPA1 agonists can modify tone of urethral preparations, propose a role for TRPA1 in afferent and efferent sensory signaling of the human outflow region.

Distribution and Function of the Hydrogen Sulfide–Sensitive TRPA1 Ion Channel in Rat Urinary Bladder

ObjectivesTo investigate the distribution of the transient receptor potential (TRP) A1 ion channel in the rat urinary bladder, and to study the effects of hydrogen sulfide (H2S) and known TRPA1 activators on micturition in conscious rats and on heterologously expressed ion channels. MethodsThe expression of TRPA1 in urinary bladder was studied with fluorescence immunohistochemistry and real-time PCR in female Sprague-Dawley rats. Cystometric investigations were performed in conscious animals subjected to intravesical administration of sodium hydrogen sulfide (NaHS, donor of H2S), allyl isothiocyanate (AI), and cinnamaldehyde (CA). Fluorometric calcium imaging was used to study the effect of NaHS on human and mouse TRPA1 expressed in CHO cells. ResultsTRPA1 immunoreactivity was found on unmyelinated nerve fibres within the urothelium, suburothelial space, and muscle layer as well as around blood vessels throughout the bladder. All TRPA1 immunoreactive nerves fibres also expressed TRPV1 immunoreactivity and vice versa. TRPA1 was also detected in urothelial cells at both transcriptional and protein levels. AI increased micturition frequency and reduced voiding volume. CA and NaHS produced similar changes in urodynamic parameters after disruption of the urothelial barrier with protamine sulfate. NaHS also induced calcium responses in TRPA1-expressing CHO cells, but not in untransfected cells. ConclusionsThe expression of TRPA1 on C-fibre bladder afferents and urothelial cells together with the finding that intravesical TRPA1 activators initiate detrusor overactivity indicate that TRPA1 may have a role in sensory transduction in this organ. The study also highlights H2S as a TRPA1 activator potentially involved in inflammatory bladder disease.

Expression of cyclooxygenase-2 in urinary bladder in rats with cyclophosphamide-induced cystitis

These studies examined the expression of cyclooxygenase-2 (COX-2) expression in the urothelium and suburothelial space and detrusor from rats treated with cyclophosphamide (CYP) to induce acute (4 h), intermediate (48 h), or chronic (10-day) cystitis. Western blot analysis and immunohistochemistry were used to demonstrate COX-2 expression. In whole mount preparations of urinary bladder, nerve fibers in the suburothelial plexus, and inflammatory cell infiltrates were characterized for COX-2 expression after CYP-induced cystitis. COX-2 expression significantly (P <or= 0.01) increased in the urothelium + suburothelium and detrusor smooth muscle with acute, intermediate, and chronic (10-day) CYP-induced cystitis, but expression in urothelium + suburothelium was significantly greater. CYP-induced upregulation of COX-2 showed by immunostaining in the urothelium + suburothelium was similar to that observed with Western blot analysis and also demonstrated COX-2 inflammatory cell infiltrates (CD86+) and nerve fibers (PGP+) in the suburothelial plexus. Although COX-2 expression was significantly (P <or= 0.01) increased in detrusor smooth muscle, immunohistochemistry failed to demonstrate an obvious change in COX-2-immunoreactivity (IR) in detrusor muscle, but COX-2 inflammatory infiltrates were present throughout the detrusor. COX-2-IR nerve fibers exhibited increased density in the suburothelial plexus with acute or chronic CYP-induced cystitis. COX-2-IR macrophages (CD86+) were present throughout the urinary bladder with acute and chronic CYP-induced cystitis. These studies demonstrate cellular targets in the urinary bladder where COX-2 inhibitors may act.

934 P2X 3 RECEPTOR-EXPRESSION IN FETAL AND INFANT BLADDERS - THE BASIS FOR A NEW THERAPEUTIC CONCEPT FOR OVERACTIVE BLADDERS IN CHILDREN

Introduction. The urothelium plays an active role in the regulation of urinary bladder function due to its sensorial properties. P2X3 receptors are critical components of this sensory pathway. They convey afferent information creating central nervous pain perception. We report the expressional time course of P2X3-receptors from fetal life to adulthood to rule out their possible implications in various bladder pathologies. Material and methods. Fetal, neonatal, and adult bladder specimens were obtained and immunostained with anti-P2X3 antibodies. A computer assisted microscope evaluated the intensity, extension, and tissue distribution. results. P2X3-receptors are widely abundant in the suburothelial space containing the nerve plexuses. These suburothelial nerve fibers expressing P2X3 were demonstrated in fetal as well as infant bladder tissue. However, the overall P2X3 expression was less intense in fetuses when compared to infants. In contrast to previously described adult specimens, we found a higher density of P2X3 receptors in infants and fetuses. Conclusions. This is the first study investigating the expressional time course of P2X3 receptors during human fetal development as well as in infancy. The disproportionately strong expression of P2X3-receptors in infants may explain the process of reflective bladder emptying in non-toilet trained children. However, P2X3 is less abundant in adults with a normal voiding pattern. Correspondingly, overexpression or deregulation of the P2X3 receptor complex may explain the lack of significant pathological findings in children with overactive bladder. Nonetheless, the inconsistent expression of P2X3 receptors in fetuses and infants may permit new therapeutic concepts.

Will suburothelial injection of small dose of botulinum A toxin have similar therapeutic effects and less adverse events for refractory detrusor overactivity?

Objectives To investigate whether suburothelial injection of different doses of botulinum A toxin (BTX-A) will have a similar therapeutic effect but fewer adverse events than 200 U BTX-A in patients with refractory detrusor overactivity. Methods A total of 75 patients with detrusor overactivity refractory to anticholinergics were enrolled and randomized to receive 100, 150, or 200 U of BTX-A injected into the suburothelial space at 40 sites. Urinary incontinence was graded on a self-reported scale of 0 to 3, representing continence and mild, moderate and severe incontinence, respectively. The therapeutic effects, adverse events, and urodynamic parameters were assessed at 3 months. Results An excellent result at 3 months was obtained in 34.8%, 36%, and 40.7% of patients treated with 100, 150, and 200 U of BTX-A, respectively. The patients who received 100 U of BTX-A had a lower incidence of a large postvoid residual urine volume (150 mL or more) than did those who received 150 or 200 U (30.4% versus 52% and 72%, respectively, P = 0.011) after treatment. The posttreatment urodynamic parameters were similar between the patients who received 150 or 200 U of BTX-A, but the changes in bladder capacity and postvoid residual urine volume were greater than those for the patients who received 100 U. The duration of therapeutic effectiveness was significantly shorter for the patients treated with 100 U compared with that for those treated with 150 or 200 U of BTX-A. Conclusions Suburothelial injection of 100 U of BTX-A achieved a similar rate of excellent results and had significantly fewer adverse events compared with 150 or 200 U. The dose of suburothelial BTX-A also affected the duration of therapeutic effectiveness.

Reply by the authors

Evidence has shown that urgency and urge incontinence in IDO or overactive bladder can be mediated by overexpression of the sensory receptors or overproduction of transmitters in the suburothelial sensory nerves. This abnormal sensory expression can be reduced after detrusor injections of BTX-A.1 Therefore, it seems rational to inject BTX-A directly into the suburothelial space to obtain a greater effect on the inhibition of sensory neuropeptide-mediated DO.

Characterization of the purinergic receptor subtype on guinea‐pig suburothelial myofibroblasts

To identify particular purinoceptor subtypes by immunohistochemical labelling, as a layer of suburothelial myofibroblasts has been identified in the urinary bladder, and these cells respond to exogenous ATP by generating an intracellular Ca2+ transient, but the particular purinoceptor that responds to ATP is unclear. Tissue sections and isolated cells from the urothelial layer of the guinea-pig bladder were used. Preparations were labelled with primary antibodies to the intermediate-filament protein, vimentin, or the purinoceptors P2X3, P2Y1, P2Y2, P2Y4 and P2Y6. For single-labelling we used a secondary antibody tagged with the fluorescent marker Cy3, and for double-labelling also a secondary antibody tagged with fluorescein isothiocyanate or Cy2. Images were examined using a confocal microscope, with an argon (488 nm) or helium-neon (543 nm) laser. Vimentin-labelling was confined to the suburothelial layer and appeared as discrete signals. Isolated cells labelled with vimentin and strongly for the P2Y6 antibody. There was weaker staining for P2X3, P2Y2 and P2Y4, but none to P2Y1. With frozen sections there was P2Y6 labelling in the urothelial and suburothelial layer. The predominant purinoceptor in suburothelial myofibroblasts, from these labelling studies, is the P2Y6 subtype. However, there was weaker labelling to other subtypes, suggesting multiple receptor subtypes or heterogeneity of receptor subunits. The consequences of there being multiple purinoceptor subtypes in the suburothelial space with respect to sensory signalling are discussed.

Therapeutic effects of suburothelial injection of botulinum a toxin for neurogenic detrusor overactivity due to chronic cerebrovascular accident and spinal cord lesions

Objectives To investigate the therapeutic effects of suburothelial botulinum A toxin for patients with chronic cerebrovascular accident (CVA) and spinal cord lesions. Suburothelial injection of botulinum A toxin can effectively inhibit the occurrence of neurogenic detrusor overactivity. Methods Twenty-four patients with neurogenic detrusor overactivity refractory to anticholinergics were enrolled and treated with 200 U of botulinum A toxin injected into the suburothelial space. The clinical effects on the lower urinary tract symptoms and urodynamic parameters were assessed. Results Of the 24 patients enrolled in the study, 12 had CVA and 12 had suprasacral cord lesions (SCLs). After treatment, the volume of the first involuntary detrusor contraction and bladder capacity increased twofold and the postvoid residual volume fourfold for both patient groups after 1 month, decreasing slightly at 3 months. The detrusor pressure for the SCL group decreased significantly after treatment (39.1 ± 16.6 versus 21.2 ± 14.1, P = 0.002) relative to the CVA patients. Complete continence and improvement of incontinence grade were achieved in 1 (8.3%) and 5 (41.7%) patients with CVA and in 4 (33.3%) and 7 (58.3%) patients with SCLs. However, patients in both groups experienced an increase in voiding difficulty after treatment. The therapeutic effect declined gradually after 3 months, and all patients had experienced symptom relapse by 6 months. Conclusions Suburothelial botulinum A toxin at a dose of 200 U increased bladder capacity and improved the incontinence grade in 91.6% of the patients with SCL, but this was achieved for only 50% of the patients with CVA.

Clinical effects of suburothelial injection of botulinum A toxin on patients with nonneurogenic detrusor overactivity refractory to anticholinergics

Objectives To investigate the clinical and urodynamic effects of suburothelial injection of botulinum A toxin on patients with nonneurogenic detrusor overactivity. Intradetrusor injection of botulinum A toxin has been used to treat patients with detrusor overactivity. Suburothelial injection of botulinum A toxin might effectively inhibit the occurrence of detrusor overactivity mediated by sensory nerves. Methods Twenty patients with nonneurogenic detrusor overactivity refractory to anticholinergics were enrolled and treated with injection of 200 U botulinum A toxin into the suburothelial space. The clinical effects on the lower urinary tract symptoms and urodynamic parameters were assessed. Results At 3 months after treatment, 9 patients had regained continence (45%), 8 had improvement (40%), and treatment had failed in 3 (15%). At 6 months after treatment, 7 patients remained continent, but treatment had failed in 5. Hematuria developed in 1 patient, urinary tract infection in 7 (35%), and a large postvoid residual urine volume requiring catheterization in 6 (30%). Hesitancy in initiation and difficult urination was also noted in 15 patients (75%). The volume of the first sensation of bladder filling and bladder capacity increased about two times; however, the voiding efficiency was reduced by 50% at 2 weeks after treatment. The postvoid residual urine volume was increased by seven times the baseline value at 2 weeks and had decreased to three times greater at 3 and 6 months after treatment. Conclusions The results of this study have shown that suburothelial injection of 200 U botulinum A toxin impairs bladder sensation and voiding efficiency, but is effective in the treatment of nonneurogenic detrusor overactivity. Transient urinary retention and the development of urinary tract infection should be carefully monitored.

Persistence of injectable collagen in human urethra: Case report

A polypoid lesion was found near the bladder neck during cystoscopy in a woman with urinary incontinence who had undergone periurethral collagen (Contigen) injections 3 years before. She had previously received radiation therapy in addition to a radical vulvectomy for vaginal cancer. On transurethral resection of the lesion, particles of unresorbed collagen material extruded from the capsulated suburothelial space. Histologic evaluation verified the material as the foreign collagen. The persistence of glutaraldehyde cross-linked collagen in our patient was much longer than previously reported and may have been due to effects of previous radiation treatment.

Long-term histological results following glutaraldehyde cross-linked collagen injection into the suburothelial space of the mini-pig bladder

Endoscopic correction of vesicoureteric reflux by subureteric injection has become an accepted method of treatment in selected cases. Its efficacy has been demonstrated in the treatment of well over 1,000 ureters. However, there are doubts as to the long-term safety of the commonly injected substance Teflon. Glutaraldehyde cross-linked bovine collagen, a biodegradable substance, was suggested as an alternative material for injection. The aim of this study was to evaluate the histological long-term behavior of glutaraldehyde cross-linked bovine collagen injected into the mini-pig bladder. One hundred and eight deposits of cross-linked collagen, each containing 0.2 ml (n = 36) or 0.6 ml (n = 72) collagen paste, were injected into the suburothelial space of the bladders of 24 mini-pigs. The histological behavior of the implants was studied at monthly intervals over a period of 12 months. After only 2 months a marked invasion of host fibroblasts and formation of endogenous type I and III collagen could be observed. Over 12 months the invasion of fibroblasts and the formation of new collagen increased dramatically. No migration of collagen particles into the local lymphatic system could be observed. A new staining technique (solophenyl red 3BL) was introduced to selectively demonstrate type I and III collagen fibres. In addition, the efficacy of the subureteric collagen injections could be demonstrated by successfully treating reflux that was iatrogenically induced in the mini-pig bladders.