The Effect Of Intravesical Resiniferatoxin In Patients With Idiopathic Detrusor Instability Suggests That Involuntary Detrusor Contractions Are Triggered By C-Fiber Input

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The Effect Of Intravesical Resiniferatoxin In Patients With Idiopathic Detrusor Instability Suggests That Involuntary Detrusor Contractions Are Triggered By C-Fiber Input
  THE EFFECT OF INTRAVESICAL RESINIFERATOXIN IN PATIENTSWITH IDIOPATHIC DETRUSOR INSTABILITY SUGGESTS THATINVOLUNTARY DETRUSOR CONTRACTIONS ARE TRIGGERED BY C-FIBER INPUT CARLOS SILVA,* MARIA JOSE´ RIBEIRO  AND  FRANCISCO CRUZ  From the Department of Urology, Hospital Sa˜o Joa˜o and Institute of Histology and Embryology, Faculty of Medicine of Porto and Institute of Biologia Molecular Celular, University of Porto, Porto, Portugal  ABSTRACT Purpose: We evaluated the role of bladder C-fiber input in involuntary detrusor activity inpatients with idiopathic detrusor instability.Materials and Methods: Filling cystometry and a voiding chart were done in 13 patients withidiopathic detrusor instability. The first detrusor contraction, maximal cystometric capacity,daily frequency and the number of episodes of urinary incontinence were determined. A 50 nM.solution of resiniferatoxin, a specific C-fiber neurotoxin, was then instilled in the bladder for 30minutes. Patients were reevaluated 30 and 90 days later.Results: Resiniferatoxin instillation delayed or suppressed involuntary detrusor contractionsduring filling cystometry. The mean first detrusor contraction plus or minus standard deviationincreased from 170  109 ml. at baseline to 440  130 ml. (p  0.0001) at 30 days and to 391  165 ml. (p  0.008) at 90 days. Mean maximal cystometric capacity increased from 291  160 to472  139 ml. (p  0.01) at 30 days and to 413  153 ml. (p  0.1) at 90 days. The mean numberof episodes of urinary incontinence daily decreased from 4.3  2.7 to 0.9  2.7 (p  0.001) at 30days and to 0.7  0.9 (p  0.009) at 90 days. Mean frequency daily also decreased from 12  3.2to 9.7  3.2 (p  0.003) and to 9.9  3.5 (p  0.001) times at the same time points, respectively.Conclusions: C-fiber input seems to have an important role in the generation of involuntarydetrusor contractions and lower urinary tract symptoms in patients with idiopathic detrusorinstability. Substances that block C-fiber input may represent a new strategy for treating thisbladder dysfunction. K  EY   W ORDS : bladder, urodynamics, nerve fibers, urinary incontinence Detrusor instability, which is a leading cause of lowerurinary tract symptoms, is characterized on urodynamics byinvoluntary detrusor contractions during bladder filling inotherwise normal individuals. 1 Despite considerable effortsto clarify the srcin of such abnormal detrusor activity thepathological mechanisms underlying detrusor instability re-main unknown. Evidence to date is balanced between a neu-rogenic 2,3 and a myogenic 4 cause, the former implicating enhanced bladder C-fiber sensory input 2 or the emergence of an abnormal atropine resistant parasympathetic transmis-sion. 3 The lack of a consistent explanation of involuntarydetrusor contractions may be the reason why first line ther-apy to decrease lower urinary tract symptoms in these pa-tients remains essentially limited to anti-muscarinic drugsdespite the intense side effects evoked during prolonged ad-ministration. 5 The participation of bladder C-fibers in involuntary detru-sor contractions was first noted in spinal cord injured pa-tients. Spinal cord lesions interrupt the neuronal pathwaysconnecting the sacral spinal cord and the pontine micturitioncenter, inactivating the supraspinal reflex that controls void-ing in normal adults. 2  As a result, voiding is left under thecontrol of an involuntary sacral reflex that is usually inactivein normal adults. 2 This change is accompanied by a change inthe sensory input that initiates reflex activity. The supraspi-nal reflex is exclusively stimulated by sensory input con- veyed in thin myelinated A    -fibers running in the pelvicnerves,whereasthesacralreflexonlydependsonthatconveyedby unmyelinated C-fibers. 2 This was the rationale for the ther-apeutic application of intravesical capsaicin 6 and resinifera-toxin 7 in patients with spinal detrusor hyperreflexia. Due totheir ability to blockade specifically C-fiber input these sub-stances attenuate or suppress involuntary detrusor activity.Lately evidence has also suggested that involuntary de-trusor contractions in patients with detrusor instabilityalso depend on a C-fiber initiated micturition reflex. Intra- vesical lidocaine decreased involuntary contractions in pa-tients with idiopathic detrusor instability. 8 Because lido-caine more effectively anesthetizes C-fibers than A    -fibers,the contribution of a C-fiber input to abnormal detrusoractivity was strongly suggested. 8 The high density of C-fiber staining for substance P and calcitonin gene-related peptide in the bladder mucosa of patients withidiopathic detrusor instability may provide a rational ex-planation for enhanced bladder C-fiber input in this dis-ease. 9 The high incidence of cold evoked detrusor contrac-tion, a C-fiber mediated micturion reflex not involved innormal voiding, in patients with detrusor instability andbladder outlet obstruction pointed in the same direction. 10  Animal models of chronic bladder outlet obstruction alsoimplied the participation of C-fiber input in the srcin of detrusor instability. 11 Gradual filling of overactive but notof normal bladders caused a premature C-fiber initiatedparasympathetic efferent discharge in the pelvic nerve  Accepted for publication March 22, 2002.Supported by the Portuguese government through Fundac¸a˜oCieˆncia Tecnologia Project POCTI/FEDER32466/NSE/00.* Current address: Department of Urology, Hospital Sa˜o Mareos,Braga, Portugal. 0022-5347/02/1682-0575/0T HE  J OURNAL OF  U ROLOGY   ®   Vol. 168, 575–579, August 2002Copyright © 2002 by A  MERICAN  U ROLOGICAL  A  SSOCIATION , I NC .  ®   Printed in U.S.A. 575  that preceded the normal A    -dependent outflow. 11 Inter-estingly the sprouting of bladder C-fiber terminals aroundsacral parasympathetic motor neurons innervating thebladder also occurred in these animals. 11 In the current study we evaluated the hypothesis that amicturition reflex triggered by bladder C-fiber input under-lies involuntary detrusor contractions in patients with idio-pathic detrusor instability. To test it we induced specificblockade of bladder C-fiber input with intravesical resinif-eratoxin. Concentrations were used that abolished involun-tary detrusor contractions in patients with spinal detrusorhyperreflexia 7 but had no effect on bladder capacity in nor-mal subjects. 12 We investigate whether an intravesical res-iniferatoxin solution delays or abolishes involuntary detrusorcontractions and whether intravesical resiniferatoxin im-proves lower urinary tract symptoms. Preliminary data werepresented in abstract form. 13 MATERIALS AND METHODS Two men and 11 women 24 to 70 years old (mean age 50)with more than a 1-year history of lower urinary tract symp-toms and urodynamically proved idiopathic detrusor insta-bility provided written informed consent approved by theethics committee at our institution to participate in thisstudy (see table). Clinical history, physical examination in-cluding neurological assessment and ultrasound of the wholeurinary tract were done in all patients before entering thestudy to diagnose concomitant neurological or bladder dis-ease that could influence bladder function. In addition, pa-tients with cardiovascular, renal, hepatic, psychiatric or ma-lignant disorders and pregnancy patients were excluded fromanalysis. Hematological or biochemical blood tests were nor-mal in the 13 patients and all had negative microbiologicalurinary investigations. Patient 4, who was on anticholin-ergics at a dose that could influence bladder performance (5mg. oxybutinin 3 times daily) was included in the studybecause the daily oxybutinin dose remained unchangedthroughout the study.Filling cystometry was performed in all patients with aDantec instrument (Dantec, Skovlunde, Denmark). A 2-way8Fr catheter was inserted in the urethra for saline infusionat 50 ml. per minute and simultaneous recording of bladderpressure. Volume at the first detrusor contraction above 15cm. water and at maximal cystometric capacity was deter-mined (see table). In addition, all patients completed a void-ing chart, in which voiding and incontinence episodes wererecorded for at least 3 consecutive days. A 10 mM. stock solution of resiniferatoxin in pure ethanolwas prepared and maintained in the dark at 4C in a glasscontainer. For each instillation 100 ml. 50 nM. solution of 10% ethanol in saline as vehicle was prepared by adding 0.5ml. stock solution to 90 ml. saline and 9.5 ml. pure ethanol.This solution was prepared immediately before each instilla-tion to decrease the contact of resiniferatoxin with plasticcontainers.Patients underwent clean catheterization with a 3-way20Fr indwelling Foley catheter to allow resiniferatoxin infu-sion and simultaneous bladder pressure recording. The blad-der was emptied. A balloon was inflated to 10 ml. and main-tained with gentle pulling against the bladder neck todecrease resiniferatoxin solution leakage into the urethra.Bladderinstillationof100ml.50nM.resiniferatoxinsolutionwas then done for 30 minutes. Vital signs were recordedimmediately before, during and at the end of instillation. Inaddition, patients were asked to estimate the discomfortexperienced during resiniferatoxin instillation on a visualanalog scale of 0—no discomfort to 10—intense pain requir-ing analgesic treatment or bladder emptying. At the endresiniferatoxin was evacuated, the bladder was rinsed withnormal saline, the Foley catheter was removed and the pa-tients were discharged home. All patients were followed at 30 days after treatment. Atthis point they were clinically reevaluated, a voiding chartwas obtained and filing cystometry was repeated. Patients 1to 8 and 12 agreed to complete a similar protocol at 90 days.Patient 11 agreed to complete a voiding chart at this date butrefused urodynamic testing. Prophylactic antibiotics wereadministered after resiniferatoxin instillation and after eachurodynamic study.The table shows first detrusor contraction, maximal cysto-metric capacity, the number of incontinence episodes dailyand daily frequency in each patient at baseline, and at 30 and90 days. The number of incontinence episodes and frequencywere determined by counting those reported in the voiding chart and dividing the sum by the number of days. In addi-tion, mean volume at the first detrusor contraction, meanmaximal cystometric capacity, mean daily frequency, and themean number of incontinence episodes at baseline, and at 30and 90 days plus or minus standard deviation were calcu-lated and compared by the 2-tailed paired t test for means. RESULTS General considerations.  Before resiniferatoxin instillationthe mean volume at the first detrusor contraction and meanmaximal cystometric capacity were 170  109 and 291  160ml., respectively. Except for patient 2 all reported episodes of urinary incontinence (mean 4.3  2.7 episodes daily at base-line) (see table). Mean urinary frequency at the same timepoint was 12  3.2 times daily.Generally resiniferatoxin evoked a series of phasic detru-sor contractions that started shortly after the beginning of instillation and remained throughout it, although it becamegradually more spaced toward the end. During phasic con-tractions patients noticed the urge sensation to urinate, Urodynamic and clinical details on 13 patients at baseline, and 30 and 90 days after 50 nm. resiniferatoxin Pt.—Age—Sex Vol. at First DetrusorContraction (ml.)Max. Cystometric Capacity(ml.) Daily Urinary Frequency Daily Urinary IncontinenceEpisodesNo. 0 Days 30 Days 90 Days 0 Days 30 Days 90 Days 0 Days 30 Days 90 Days 0 Days 30 Days 90 Days1 —44 —F 70 295 184 184 297 195 14 11 12 7.5 2.5 1.252 —49 —M 300 420 394 350 422 483 15 9 10 — — —3 —30 —F 100 364 563 654 364 563 12 14 7 8 0 04 —70 —M 150 460 618 170 460 620 11 8 8 3 0 05 —24 —F 333 492 364 350 664 364 10 8 8 1.5 0.8 0.66 —58 —F 135 483 528 173 556 538 9.3 8 8 3 0.7 1.57 —64 —F 37 534 439 405 534 443 18 15 16 4 0.6 0.48 —42 —F 65 476 283 141 476 283 13 6 6 7.8 0 09 —55 —F 44 525 — 76 525 — 11 9 — 1.8 1.2 —10 —76 —F 194 251 — 238 262 — 11 9 — 8 2 —11 —52 —F 356 326 — 506 484 — 9 8 8 0.9 0.4 0.112 —64 —F 225 351 146 279 351 231 17 16 16 2.3 2.3 2.513 —28 —F 203 750 — 273 750 — 7 6 — 3.7 0.7 — EFFECT OF RESINIFERATOXIN ON DETRUSOR INSTABILITY  576  which subsided as soon as detrusor pressure returned tonormal. In addition, patients experienced iching or a warmsensation in the lower abdomen during the initial minutes of resiniferatoxin administration, which waned thereafter.Patients did not complain of severe discomfort or overtpain during resiniferatoxin instillation and they did not askfor any type of analgesic medication, although the wholeprocedure was performed without local anesthesia. Averagediscomfort score on the visual analog scale was 3, the mini-mum score was 0 in 3 patients and the maximum was 8 in 1.Blood pressure and heart rate remained stable during res-iniferatoxin instillation in all cases. Urodynamic and clinical findings.  Resiniferatoxin delayedor suppressed involuntary detrusor contractions during fill-ing cystometry (fig. 1). Consequently the volume of bladderfilling at which the first detrusor contraction occurred wasincreased in 12 patients (92%) at 30 days and was still abovebaseline in 8 of the 9 (88%) who underwent cystometry atthat date (see table). Mean volume at the first detrusorcontraction was 440    130 ml. (p    0.0001) at 30 days and391    165 ml. (p    0.008) at 90 days (fig. 2). Maximalcystometric capacity was also increased in 11 patients at 30days but it was almost at baseline in 5 of the 9 who under-went cystometry at 90 days (see table). Mean maximal cys-tometric capacity was 472  139 ml. (p  0.01) at 30 days and413  153 ml. (p  0.1) at 90 days (fig. 2).Intravesical instillation of resiniferatoxin improved uri-nary incontinence in 11 (91%) patients of the 12 (91%) withincontinence. In 3 cases (25%) complete continence wasachieved, in 6 (50%) the average number of incontinenceepisodes daily decreased more than 50% and in 2 (17%) thisimprovement did not achieve 50% (see table). The meannumber of incontinence episodes daily was 0.9    2.7 (p   0.001) at 30 days and 0.7  0.9 (p  0.009) at 90 days (fig. 3).Mean urinary frequency also decreased. It was 9.7    3.2times daily at 30 days (p    0.003) and 9.9    3.5 at 90 days(p  0.001, fig. 3). DISCUSSION Resiniferatoxin is an extract of the dry latex of Euphorbiaresinifera, a cactus-like plant that is abundant in northern Africa and shares with capsaicin a homovanillic ring. Previ-ous studies have shown that resiniferatoxin is a strong ago-nist of vanilloid receptor type 1, an ion channel present inrats 14,15 and humans. 16 Using in situ hybridization tech-niques vanilloid receptor type 1 gene expression in periph-eral tissues was shown to be restricted to the small dorsalroot ganglion neurons that give rise to type C primary affer-ent fibers. 14–16  Accordingly in bladder tissue vanilloid recep-tor type 1 immunohystochemical staining was confined tounmyelinated nerve fibers. 17,18 Therefore, the principal find-ing of the current study (the increment of bladder volume atthe first detrusor contraction) should be attributable to theeffect of resiniferatoxin on vanilloid receptor type 1 receptorsin bladder C-fibers. F IG . 1. Filling cystometry in patient 6 at baseline (  A ) and 30 days after 50 nM. resiniferatoxin instillation (  B ). Volume at first detrusorcontraction increased from 135 to 483 ml.  Pdet , detrusor pressure.  Pves , vesical pressure.  Pabd , abdominal pressure.  Vinfus , infusion volume.F IG . 2. Mean volume at first detrusor contraction (  FDC ) and max-imal cystometric capacity (  MCC ) at baseline, and 30 and 90 daysafter 50 nM. resiniferatoxin.F IG . 3. Mean daily frequency and number of episodes of urinaryincontinence at baseline, and 30 and 90 days after 50 nM. resinif-eratoxin.EFFECT OF RESINIFERATOXIN ON DETRUSOR INSTABILITY   577  Resiniferatoxin inactivates C-fibers after initial and brief excitation. 15  After resiniferatoxin binding vanilloid receptortype 1 channels open, allowing a massive inflow of calciumand other ions into C-fibers. Ion overload may generate ac-tion potentials, and the release of substance P and calcitoningene-related peptide from peripheral nerve endings, 15 whichcontribute to the painful or itch sensations and detrusorcontractions felt by patients during resiniferatoxin instilla-tion. 7  A period of decreased bioelectrical activity of C-fibersusually known as desensitization then succeeds. 14,15 It hasnot yet been determined whether desensitization of bladderC-fibers is a functional state 18 or if it involves the degenera-tion of nerve terminals in the bladder wall. 6 However, what-ever the mechanisms desensitization caused by resinifera-toxin decreases sensory input conveyed in bladder C-fibersand decreases the number of spinal neurons that becomeexcited by bladder stimuli. 19 Therefore, the potential of in-travesical resiniferatoxin to suppress involuntary detrusorcontractions in patients with idiopathic detrusor instabilitystrongly suggests that the C-fiber rather than the A    -fiberinput triggers the abnormal detrusor activity associated withthis bladder dysfunction.In normal adults C-fiber input does not have a significantrole in voiding control. 2,12 Desensitization of bladder C-fibersin normal adult cats 2 and humans 12 does not change filling cystometry or bladder capacity. Therefore, understanding why C-fiber input becomes preponderant in the voiding con-trol of patients with idiopathic detrusor instability may con-tribute to elucidating the physiopathology of this disorder.The emergence of a strong C-fiber micturition reflex was firstidentified in chronic spinal cord injured mammals, including humans. 2,6 In this case the preponderance of the C-fiberreflex was explained by abolition of the A    -fiber reflex causedby interruption of the neuronal pathways connecting thesacral spinal cord to the pontine micturition center. 2 How-ever, this mechanism was unlikely in our patients, who wereneurologically normal. Another possibility may be the in-crease in C-fiber input that reaches the spinal cord afterC-fiber sensitization by neurotrophic factors produced in ex-cess in the bladder, namely nerve growth factor (NGF). 11 Infact, smooth muscle of unstable obstructed bladders has beenshown to produce high amounts of NGF. 11 Interestingly in-activation of this neurotrophic factor could abolish bladderinstability. 11 Therefore, studies designed to measure NGFand other trophic factors in the bladder of patients withidiopathic and other types of detrusor instability may beworthwhile in the future. Although the current study suggests the involvement of bladder C-fibers in idiopathic detrusor instability, it cannotbe ignored that other abnormalities have already been iden-tified in patients with this disease. Recently it was shownthatthedensityofaligand-gatedpurinergicreceptorsubtypeis increased in the detrusor muscle of female patients withidiopathic detrusor instability, which could explain the emer-gence of atropine resistant, parasympathetic induced detru-sor contractions. 3 On the other hand, spontaneous tetaniccontractions have been identified in detrusor strips frompatients with detrusor instability, a finding that presupposesfacilitated electrical coupling of smooth muscle cells. 4 Such afinding that supports a myogenic srcin of the disease 4 wastentatively explained by an increased number of ultra close junctions linking myocites. 20 However, these data and ourfindings are not mutually exclusive, but rather may be com-plementary. Bladder C-fibers are numerous in the detrusorlayer, where they lie in intimate contact with smooth musclecells. 18 Thus, any spontaneous activity of the muscle cells isprone to excite C-fibers, which eventually become more ex-citable by an excess of neurotrophic factors. This situationcan generate a parasympathetic outflow leading to the con-traction of detrusor smooth muscle cells, which is eventuallyfacilitated by the surplus of ligand-gated purinergic receptorsubtypes 3 and by the abnormal electrical coupling providedby the ultra close junctions. 20 By inactivating C-fibers res-iniferatoxin would interrupt this circuit. Another important finding in the current study was thelong lasting decrease in lower urinary tract symptoms,namely urinary incontinence, reported by our patients afterintravesical resiniferatoxin. To our knowledge the reason forthe prolonged effect of resiniferatoxin is still unknown but itmay involve long lasting down-regulation of C-fiber receptorsand neuropeptides, such as substance P or calcitonin gene-related peptide, 18 and even C-fiber loss. 6 Whatever the mech-anisms involved, our clinical findings may expand the indi-cations of human bladder desensitization, which has beenlimited to date to detrusor hyperreflexia. In this conditionintravesical capsaicin 6 or resiniferatoxin 7 has been assayedwith the latter substance preferable due to decreased pun-gency 7 and lack of toxicity to the human bladder mucosa. 21 However, before recommending intravesical resiniferatoxinfor treating idiopathic detrusor instability it may be prudentto wait for a large, placebo controlled trial. CONCLUSIONS This study suggests that involuntary detrusor contractionsare triggered by bladder sensory input conveyed in C-fibers.These primary afferents may be a new target for the medicaltreatment of idiopathic detrusor instability.Dr. Antonio Avelino prepared resiniferatoxin solutions andProf. Antonio Coimbra critically read the manuscript. REFERENCES 1. Abrams, P., Blaivas, J. G., Stanton, S. L. and Andersen, J. T.:Standardisation of terminology of lower urinary tract function.Neurourol Urodynam,  7:  403, 19882. de Groat, W. C.: A neurologic basis for the overactive bladder.Urology, suppl.,  50:  36, 19973. O’Reilly, B., Kosaka, A. H., Knight, G. F., Chang, T. K., Ford, A. P., Rymer, J. M. et al: P2X receptors and their role in femaleidiopathic detrusor instability. J Urol,  167:  157, 20024. Brading, A. F.: A myogenic basis for the overactive bladder.Urology, suppl.,  50:  57, 19975. Chapple, C. R.: Muscarinic receptor antagonists in the treatmentof overactive bladder. Urology, suppl.,  55:  33, 20006. Fowler, C. J.: Intravesical treatment of overactive bladder.Urology, suppl.,  55:  60, 20007. Silva, C., Rio, M. E. and Cruz, F.: Desensitization of bladdersensory fibres by intravesical resiniferatoxin, a capsaicin an-alogue: long-term results for the treatment of detrusor hyper-reflexia. Eur Urol,  38:  444, 20008. Yokoyama, O., Komatsu, K., Kodama, K., Yotsuyanagi, S.,Niikura, S. and Namiki, M.: Diagnostic value of intravesicallidocaine for overactive bladder. J Urol,  164:  340, 20009. Chai, T. C., Gray, M. L. and Steers, W.: The incidence of apositive ice water test in bladder outlet obstructed patients:evidence for bladder neural plasticity. J Urol,  160:  34, 199810. Smet, P. J., Moore, K. H. and Jonavicius, J.: Distribution andcolocalization of calcitonin gene-related peptide, tachykinins,and vasoactive intestinal peptide in normal and idiopathicunstable human urinary bladder. Lab Invest,  77:  37, 199711. Steers, W. D.: Rat overview and innervation. Neurourol Urodyn, 13:  97, 199412. Lazzeri, M., Beneforti, P. and Turini, D.: Urodynamic effects of intravesical resiniferatoxin in humans: preliminary results instable and unstable detrusor. J Urol,  158:  2093, 199713. Cruz, F. and Silva, C.: Can desensitization of bladder sensoryfibers relieve urinary symptoms in patients with detrusorinstability? Preliminary report with intravesical resinifera-toxin. Neurourol Urodyn,  19:  379, 200014. Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A.,Levine, J. D. and Julius, D.: The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature,  389:  816,199715. Szallasi, A. and Blumberg, P. M.: Vanilloid (Capsaicin) receptorsand mechanisms. Pharmacol Rev,  51:  159, 199916. Hayes, P., Meadows, H. J., Gunthorpe, M. J., Harries, M. H.,EFFECT OF RESINIFERATOXIN ON DETRUSOR INSTABILITY  578  Duckworth, D. M., Cairns, W. et al: Cloning and functionalexpression of a human orthologue of rat vanilloid receptor-1.Pain,  88:  205, 200017. Yiangou, Y., Facer, P., Ford, A., Brady, C., Wiseman, O., Fowler,C. J., et al: Capsaicin receptor VR1 and ATP-gated ion channelP2X3 in human urinary bladder. BJU Int,  87:  774, 200118. Avelino,A.,Cruz,C.,Nagy,I.,Cruz,F.:Vanilloidreceptor1expres-sion in the rat urinary tract. Neuroscience,  109:  787, 200219. Avelino, A., Cruz, F. and Coimbra, A.: Intravesical resiniferatoxindesensitizes rat bladder sensory fibres without causing intensenoxious excitation. A c-fos study. Eur J Pharmacol, 378: 17, 199920. Tse, V., Wills, E., Szonyi, G. and Khadra, M. H.: The applicationof ultrastructural studies in the diagnosis of bladder dysfunc-tion in a clinical setting. J Urol,  163:  535, 200021. Silva, C., Avelino, A., Souto-Moura, C. and Cruz, F.: A light- andelectron-microscope histopathological study of the humanbladder mucosa after intravesical resiniferatoxin application.BJU Int,  88:  355, 2001EFFECT OF RESINIFERATOXIN ON DETRUSOR INSTABILITY   579
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