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Improving the global management of the neurogenic bladder patient: part II. Future treatment strategies.

BACKGROUND: Patients with neurogenic bladder represent a small fraction of the total overactive bladder population. As a consequence, development of new therapies in this area has largely focused on idiopathic urinary incontinence. The absence of data for patients with neurological disease has far-reaching implications, affecting reimbursement and physicians' willingness to prescribe therapies, and limiting access of potential valuable treatments to patients whose lives are significantly impaired by inadequately managed bladder symptoms. SCOPE: The range of new therapies is increasing. Although many reviews of the overall safety, efficacy and mode of action of such treatments are available, there is limited information on how these treatments will best be used in clinical practice. We considered the current benefits and limitations of the various new licensed and unlicensed therapies and what role each would have in the future management of neurogenic urinary incontinence. CONCLUSIONS: A wide range of new treatments have been investigated for the management of overactive bladder; few, however, have been evaluated extensively in neurogenic urinary incontinence. Further studies are required to determine the optimal dosing regimes and formulations for individual sub-populations of neurogenic bladder patients and to determine the cost-effectiveness of these interventions. With the current experience available, two treatment algorithms for a subset of patients with neurological disease have also been proposed, which suggest at which stage of management and in which patients individual therapies for neurogenic urinary incontinence could be used.

Algorithms↗

[Surgery (TUR-P) as a recommended initial treatment modality for the presented case].

The pathophysiology of lower urinary tract dysfunction in the presented case comprised voiding dysfunction and overactive bladder. Two etiologies for voiding dysfunction in this case could be considered, bladder outlet obstruction due to benign prostatic hyperplasia (BPH) or detrusor underactivity. Prospected efficacies of pharmacological and surgical treatment (transurethral resection of prostate: TUR-P) for this case were compared based on a literature review. Alpha-1 blockers improve both voiding and storage symptoms in patients with BPH. However, improvement of maximum flow rate (Qmax) on uroflowmetry is limited within a small range and there is no evidence of significant reduction in residual urine volume. Alpha-1 blockers have no significant efficacy in improvement of objective measures in patients with detrusor underactivity. Although anticholinergics improve overactive bladder symptoms, they are contraindicated for patients with severe voiding dysfunction with residual urine. There is a lack of study on efficacy of apha-1 blocker administration combined with anticholinergics available in our hands for patients with BPH and overactive bladder. On the other hand, TUR-P brings remarkable improvement in voiding and storage symptoms, increase of flow rate and reduction of residual urine as a gold-standard surgical treatment for BPH. Urge incontinence and uninhibited detrusor contraction on cystometry reportedly disappeared in 60% of patients following TUR-P. TUR-P also improves subjective symptom and objective measures in patients with BPH and detrusor underactivity. Based on the literature review, surgery is recommended as a standard initial therapy for the presented patient with significant voiding dysfunction (Qmax 9.4 ml/sac and residual urine 72 ml).

Adrenergic alpha-Antagonists↗

Posterior tibial nerve stimulation as neuromodulative treatment of lower urinary tract dysfunction.

PURPOSE: Recently, intermittent percutaneous posterior tibial nerve stimulation was introduced as a treatment modality filling the gap between conservative and surgical therapies in patients with certain types of lower urinary tract dysfunction. MATERIALS AND METHODS: In a prospective multicenter trial posterior tibial nerve stimulation was evaluated in 37 patients who presented with symptoms of bladder overactivity, that is the urgency and frequency syndrome and/or urge incontinence, and 12 with nonobstructive urinary retention. Results were recorded in voiding diaries and on quality of life questionnaires before and after treatment. Patients were classified as responders, including those in whom therapy was successful and chose to continue treatment after the initial 12 weeks, and nonresponders, those who chose to stop treatment. RESULTS: Overall, a positive response was seen in 60% of all patients. In patients with bladder overactivity a statistically significant decrease was observed in leakage episodes, number of pads used, voiding frequency and nocturia, and an equal increase in mean and smallest volume voided. Improvements were also seen in nonobstructive urinary retention, including number of catheterizations, total and mean volume catheterized, and total and mean volume voided. Disease specific quality of life and some domains of general quality of life improved, especially of bladder overactivity. Only mild side effects were observed. CONCLUSIONS: Posterior tibial nerve stimulation is a minimally invasive and successful treatment option for patients with certain types of lower urinary tract dysfunction.

Adult↗

Parity, mode of delivery, and pelvic floor disorders.

OBJECTIVE: This study aimed to assess the associations between parity, mode of delivery, and pelvic floor disorders. METHODS: The prevalence of pelvic organ prolapse, stress urinary incontinence, overactive bladder, and anal incontinence was assessed in a random sample of women aged 25-84 years by using the validated Epidemiology of Prolapse and Incontinence Questionnaire. Women were categorized as nulliparous, vaginally parous, or only delivered by cesarean. Adjusted odds ratios and 95% confidence intervals (CIs) for each disorder were calculated with logistic regression, controlling for age, body mass index, and parity. RESULTS: In the 4,458 respondents the prevalence of each disorder was as follows: 7% prolapse, 15% stress urinary incontinence, 13% overactive bladder, 25% anal incontinence, and 37% for any one or more pelvic floor disorders. There were no significant differences in the prevalence of disorders between the cesarean delivery and nulliparous groups. The adjusted odds of each disorder increased with vaginal parity compared with cesarean delivery: prolapse = 1.82 (95% CI 1.04-3.19), stress urinary incontinence = 1.81 (95% CI 1.25-2.61), overactive bladder = 1.53 (95% CI 1.02-2.29), anal incontinence = 1.72 (95% CI 1.27-2.35), and any one or more pelvic floor disorders = 1.85 (95% CI 1.42-2.41). Number-needed-to-treat analysis revealed that 7 women would have to deliver only by cesarean delivery to prevent one woman from having a pelvic floor disorder. CONCLUSION: The risk of pelvic floor disorders is independently associated with vaginal delivery but not with parity alone. Cesarean delivery has a protective effect, similar to nulliparity, on the development of pelvic floor disorders when compared with vaginal delivery. LEVEL OF EVIDENCE: II-2.

Adult↗

Lower urinary tract symptoms and bladder control in advanced Parkinson's disease: effects of deep brain stimulation in the subthalamic nucleus.

Deep brain stimulation in the subthalamic nucleus (STN) leads to significant improvement in motor function in patients with advanced Parkinson's disease (PD). In this prospective study including 16 patients with PD, we investigated (1) lower urinary tract symptoms (LUTS) by questionnaires International Prostate Symptom Score (IPSS, symptoms only) and Danish Prostate Symptom Score (DanPSS, symptoms and bother of symptoms) and (2) bladder control (assessed by urodynamics) before and after implantation of electrodes in the STN. PD symptoms (Unified Parkinson's Disease Rating Scale score) improved significantly (P < 0.0001), and symptoms of overactive bladder (IPSS) decreased along with the troublesome symptoms of overactive bladder (DanPSS; P < 0.01 for both). Urodynamic parameters before and after implantation of electrodes in the STN, evaluated with and without the stimulation on, did not change significantly.

Adult↗

Synthesis and structure-activity relationships of a novel series of 2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide K(ATP) channel openers: discovery of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9- hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a potent K(ATP) opener that selectively inhibits spontaneous bladder contractions.

Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K(ATP) openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K(ATP) channel openers may have utility in the treatment of overactive bladder.

Adenosine Triphosphate↗

Pharmacological characterization of urinary bladder smooth muscle contractility following partial bladder outlet obstruction in pigs.

Partial bladder outlet obstruction of the pig is considered as a valuable preclinical model for evaluating the profile of compounds for the treatment of bladder overactivity. In this study, we characterized the pharmacological properties of isolated bladder smooth muscle from pigs following partial outlet obstruction and its sensitivity to potassium channel openers. Bladder strips from obstructed animals showed significantly lower maximal efficacy (E(max)) and sensitivity to stimulation by ATP and carbachol, but not to those evoked by serotonin, compared to age-matched controls. Tissue strips from obstructed animals also showed a 2.5-fold increase in the potency and significantly reduced maximum response following K+ depolarization. With respect to spontaneous activity, bladder strips from control strips demonstrated little spontaneous phasic activity at all preloads examined. In contrast, bladder strips from obstructed animals showed large preload-dependent increases in spontaneous phasic activity at preload values of 16-32 g. The potencies of K(ATP) channel openers to relax carbachol-evoked contractions showed a good 1:1 correlation (r(2)=0.90) between obstructed and control bladder strips. These studies demonstrate that obstructed pig bladders show enhanced spontaneous phasic activity especially at elevated preloads, which may underlie unstable myogenic bladder contractions reported in cystometrographic measurements in vivo. The impaired responses to electrical field stimulation could be attributed to reduced efficacies and/or lower sensitivities of muscarinic and purinergic signaling pathways. K(ATP) channel sensitivities remain essentially unimpaired in the obstructed bladder and could be effectively modulated by openers with potential for the treatment of overactive bladder secondary to outlet obstruction.

Adenosine Triphosphate↗

Female, but not male, serotonin reuptake transporter (5-HTT) knockout mice exhibit bladder instability.

Correlations exist between the incidence of depression, irritable bowel syndrome (IBS) and overactive bladder [Masand, P.S., Kaplan, D.S., Gupta, S., Bhandary, A.N., Nasra, G.S., Kline, M.D., Margo, K.L., 1995. Major depression and irritable bowel syndrome: is there a relationship? J. Clin. Psychiatry 56, 363-367.; Cukier, J.M., Cortina-Borja, M., Brading, A.F., 1997. A case-control study to examine any association between idiopathic detrusor instability and gastrointestinal tract disorder, and between irritable bowel syndrome and urinary tract disorder. Br. J. Urol. 79, 865-878.; Monga, A.K., Marrero, J.M., Stanton, S.L., Lemieux, M.C., Maxwell, J.D., 1997. Is there an irritable bladder in the irritable bowel syndrome? Br. J. Obstet. Gynaecol. 104, 1409-1412.; Zorn, B.H., Montgomery, H., Pieper, K., Gray, M., Steers, W.D., 1999. Urinary incontinence and depression. J. Urol. 162, 82-84.]. Furthermore, alterations in serotonergic neurotransmission may play a common role in the etiology of these disorders. Serotonin reuptake transporter knockout mice (5-HTT(-/-)) display phenotypes consistent with clinical features of mood and bowel disorders including anxiety and abnormal gastrointestinal motility [Holmes, A., Murphy, D.L., Crawley, J.N., 2003. Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol. Psychiatry 54, 953-959.]. In the present study, we evaluated bladder function in 5-HTT(-/-) mice. We have found that female 5-HTT(-/-) mice exhibit bladder dysfunction, characterized by significant increases in the frequency of spontaneous non-voiding bladder contractions and decreases in void volume compared to control female mice. These differences were not observed in male knockout mice. These studies provide significant supporting data for a mechanistic link between alterations in 5-HT, depression, IBS and overactive bladder in women.

Animals↗

Modulation of autonomous contractile activity in the isolated whole bladder of the guinea pig.

OBJECTIVE: To investigate the actions of the nonhydrolysable analogue of ATP, alpha,beta-methylene ATP (alpha,beta-MATP) and the sensory peptide, substance P, on the phasic activity generated by muscarinic stimulation in the isolated whole bladder. Isolated bladder can generate complex contractions resulting in phasic rises in intravesical pressure (the autonomous bladder): activity thought to underlie nonmicturition activity in vivo and which may be important in generating bladder sensations. MATERIALS AND METHODS: Experiments were conducted on whole isolated bladders from female guinea pigs (270-300 g). Bladders were cannulated via the urethra, suspended in a heated chamber containing oxygenated solution at 33-36 degrees C and intravesical pressure recorded. All drugs were added to the solution bathing the abluminal surface of the bladder. RESULTS: When alpha,beta-MATP (30-3000 nmol/L) or substance P (30-300 nmol/L) was added to resting bladders there were small rises in intravesical pressure (<2 cmH2O). However, in the presence of phasic activity generated by exposing the bladder to the muscarinic agonist arecaidine (100-300 nmol/L) or the nicotinic ligand lobeline (10-30 micromol/L) similar or lower concentrations of alpha,beta-MATP or substance P produced more dramatic effects: alpha,beta-MATP and substance P (both at 100 nmol/L) activated a rise in basal pressure of > 15 cmH2O and increased the frequency of the phasic activity. On removing alpha,beta-MATP or substance P, there was a slowing of phasic activity indicative of an inhibitory mechanism. CONCLUSION: In addition to direct effects on smooth muscle the agonists alpha,beta-MATP and substance P appear to be potent regulators of the mechanisms generating phasic activity. A developing concept is that the mechanisms responsible for generating phasic activity underlie nonmicturition activity are the target for excitatory and inhibitory inputs. Regulating such activity may be a factor in generating or modifying bladder sensation. Inappropriate or exaggerated phasic activity could underpin the pathological changes which cause the overactive bladder, thus adding another hypothesis to the neurogenic and myogenic hypotheses of bladder overactivity, i.e. that of the autonomous bladder.

Action Potentials↗

Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra.

OBJECTIVES: To detail, in a review, one institution's 6-year experience using botulinum toxin A (BTX-A) in the bladder and urethra in 110 patients for a variety of lower urinary tract disorders. METHODS: A total of 110 patients (35 men and 75 women, age range 19 to 82 years) received injections of BTX-A into the bladder (n = 42) or urethra (n = 68). Voiding dysfunction included neurogenic detrusor overactivity and/or detrusor sphincter dyssynergia, overactive bladder, bladder neck obstruction, and interstitial cystitis. Under light sedation in most cases, patients were treated with either 100 to 200 U of BTX-A in 4 mL divided in equal doses into the four quadrants of the external sphincter or by injection into the bladder base using 100 to 300 U of BTX-A diluted in approximately 10 to 30 mL of sterile saline. At last follow-up, 27 patients had received additional injections (up to six) at intervals of 6 months or longer. RESULTS: All patients who underwent bladder BTX-A injection had preoperative evidence of involuntary detrusor contractions during urodynamic testing. Analysis of the 110 patients indicated that 67.3% reported a decrease or absence of incontinence. Diaries indicated a decrease in both daytime and nighttime voiding symptoms. Maximal efficacy occurred between 7 and 30 days and lasted for at least 6 months. Condition-specific quality-of-life symptom scores also demonstrated improvement. No long-term complications had occurred at last follow-up. Two women with multiple sclerosis and mild baseline stress urinary incontinence reported increased leakage with stress after BTX-A external sphincter injection, and one woman with multiple sclerosis noted new onset stress urinary incontinence after external sphincter injection. However, they all reported significant improvement in their detrusor sphincter dyssynergia with decreased postvoid residual urine volume, improved uroflow, decreased urge incontinence, and decreased daytime and nighttime frequency. One woman with multiple sclerosis who underwent bladder injection had increased postvoid residual urine volume from 78 to 155 mL. She did not have to perform intermittent catheterization. CONCLUSIONS: BTX-A injection is a safe and promising treatment modality for a variety of lower urinary tract dysfunctions for both skeletal and smooth muscle dysfunction. In our series, BTX-A is equally effective in women as it is in men. When injected into the sphincter, the risk of stress incontinence is low. Bladder injections with BTX-A are effective for not only neurogenic detrusor overactivity, but also overactive bladder. BTX-A can even be considered for interstitial cystitis.

Adolescent↗

Neurogenic bladder in patients with cervical compressive myelopathy.

We examined the urinary disturbances in 56 consecutive patients with cervical compressive myelopathy using the latest International Continence Society classification. Of the 56 patients with cervical compressive myelopathy, 29 (52%) had some urinary subjective complaints, whereas the remaining 27 (48%) had none. Urologic examination indicated that 8 of these 29 (28%) patients with urinary complaints had urologic disorders other than neurogenic bladder. Of the remaining 21 patients, only 6 (25%) were judged to have neurogenic bladder on urodynamic study. Urodynamic study may be of limited value in diagnosing urinary disturbance in cervical myelopathy. Further, four cases (83%) showed underactive bladder activity in voiding phase, and only one case (17%) showed overactive bladder activity in filling phase. These results were contrary to those of previous studies indicating that cervical compressive myelopathy is associated with overactive bladder activity in filling phase. There were no significant differences in motor or sensory Japanese Orthopedic Association scores between the patients with and without urinary complaints. However, the patients with urinary complaints had significantly longer durations of myelopathy and delayed motor evoked potential latencies than those without urinary complaints. After surgery, 19 of the 21 (90%) patients with urinary complaints showed recovery from urinary disturbance. Operations in patients with cervical myelopathy were also effective against urinary disturbance. Urinary complaints may be an indication for surgical treatment despite the results of urodynamic study.

Cervical Vertebrae↗

Detrusor overactivity. Does it represent a difference if patients feel the involuntary contractions?

PURPOSE: We evaluated the differences between patients with overactive bladder (OAB) who felt involuntary detrusor contractions during cystometry (detrusor overactivity [DO]) and those who did not feel them. MATERIALS AND METHODS: We prospectively studied 45 patients with symptoms of nonneurogenic, nonobstructed overactive bladder and with DO on cystometry. All patients underwent videourodynamics, the ice water test and electrical perception threshold determination. Continence, urodynamic parameters, data from specific sensory evaluation and outcome of drug treatment were examined. RESULTS: Almost half of our patients did feel the contractions of DO and half did not. The groups differed significantly. Those without DO sensation were more frequently incontinent, had more involuntary detrusor contractions and these occurred earlier during bladder filling. They had involuntary start of voiding more frequently, more pathological sensation of bladder filling and lower electrical sensory thresholds. The results of drug treatment were better in the group who felt DO. CONCLUSIONS: Contractions of DO are felt by some of the patients and they differ from those patients who do not feel such contractions. It is likely that this finding reflects the existence of different OAB conditions with a different neuropathological cause and a different treatment outcome. Therefore, we suggest that specific tests for the evaluation of sensation in the lower urinary tract should be part of the diagnosis of patients with DO and symptoms of OAB.

Adult↗

(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637): a novel ATP-sensitive potassium channel opener efficacious in suppressing urinary bladder contractions. II. in vivo characterization.

ATP-sensitive potassium (K(ATP)) channel openers (KCOs) have been shown to inhibit spontaneous myogenic contractile activity of the urinary bladder, a mechanism hypothesized to underlie detrusor instability and symptoms of overactive bladder. However, the therapeutic utility of KCOs has been limited by a lack of differentiation of bladder versus vascular effects. In this study, we evaluated the in vivo potency and bladder selectivity of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (A-278637), a novel dihydropyridine KCO, in a pig model of detrusor instability secondary to partial bladder outlet obstruction. For comparison, we profiled two KCOs, ((R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile (WAY-133537) and (S)-N-(4-benzoylphenyl)-3,3,3-trifluro-2-hydroxy-2-methyl-propionamide (ZD6169), reported previously to have improved bladder selectivity in vivo and a calcium channel blocker, nifedipine. Effective doses of A-278637, WAY-133537, ZD6169, and nifedipine to inhibit unstable contraction area under the curve by 35% and to decrease mean arterial pressure by 10% were 4.2 and 12, 109 and 51, 661 and 371, and 136 and 30 nmol/kg i.v., yielding corresponding bladder selectivity ratios of 3, 0.5, 0.6, and 0.2. Therefore, A-278637 was approximately 5- to 6-fold more bladder-selective than the other KCOs and 15-fold more selective than nifedipine, the latter approximately 4.5-fold vascular-selective. The potency of KCOs to inhibit unstable contraction in vivo was accurately predicted by their potency to inhibit spontaneous contractile activity of pig detrusor strips in vitro. These results indicate that A-278637, with enhanced potency and bladder selectivity compared with the other compounds evaluated, could serve as a useful tool in the investigation of smooth muscle K(ATP) channel openers as novel therapeutic agents for the treatment of overactive bladder.

ATP-Binding Cassette Transporters↗

Muscarinic receptor function, density and G-protein coupling in the overactive diabetic rat bladder.

1 Bladder smooth muscle sensitivity to muscarinic agonists is increased in the overactive bladder. Treatment of rats with streptozotocin induces a diabetic state in which the bladder muscle is overactive and also supersensitive to muscarinic agonists. This study has examined bladder contraction, muscarinic receptor density and receptor/G-protein coupling in the streptozotocin-induced overactive bladder of the rat. 2 Diabetes was induced by a single intraperitoneal dose of streptozotocin. Seven days later contraction of isolated detrusor muscle strips was assessed in tissue bath experiments, while receptor density was assayed in saturation experiments with [3H]-QNB (quinuclidinyl benzilate, L-[benzilic-4,4'-3H]) and receptor/G-protein coupling was determined in agonist displacement experiments with this radioligand. 3 Isolated detrusor strips from diabetic animals displayed an enhanced degree of spontaneous activity (0.060 +/- 0.016 g mg(-1), compared with 0.015 +/- 0.004 g mg(-1), P < 0.05). Carbachol produced contractile responses in tissues from both control and diabetic rats, but the diabetic tissues were more sensitive to this agonist, the pEC50 being 6.52 +/- 0.17 compared with 5.93 +/- 0.06 in controls (P < 0.001). Maximum responses to carbachol were similar in both groups of animals. The increase in carbachol potency was accompanied by a 40% increase in receptor density from 158 +/- 5 to 221 +/- 22 fmol mg(-1) protein (P < 0.05), but this was not enough to fully account for the change in tissue sensitivity. 4 In the absence of GTP-gamma-S, carbachol displaced [3H]-QNB from two binding sites, the high-affinity site (pKi = 7.06 +/- 0.26) which represents the receptors coupled to G-proteins made up 43.1 +/- 5.9% of the total binding sites in control tissues and this value was similar (41.0 +/- 4.0%) in the diabetic tissues (pKi = 6.64 +/- 0.31). In the presence of GTP-gamma-S, carbachol displaced [3H]-QNB from a single binding site which had a low-affinity, similar to the low-affinity site observed in the absence of GTP-gamma-S. 5 These data demonstrate that detrusor supersensitivity is observed after only 1 week of untreated diabetes in the rat. The overactivity is associated with an enhanced sensitivity to carbachol, which is partly explained by an increase in receptor density, but there appears to be no change in receptor/G-protein coupling.

Animals↗

[Bladder sphincter disorders in Parkinson's disease].

Parkinson's disease related to degeneration of the extrapyramidal structures is characterized in its typical form by the classic triad of tremors, rigidity and akinesia, constituting Parkinson's syndrome. These are combined with neurovegetative disorders, responsible for sexual and bladder sphincter dysfunction. The Latter occurs in from 30% to 90% of cases, depending on the stage of progression of the disease. The dopamine deficiency in the nigrostriataL tract leads to a lifting of the inhibition which is probably the cause of the bladder hyperreflexia. Irritative signs are most frequently observed. The flowmetry data are contradictory, depending on the publication whereas the bladder overactivity, objectified by cystomanometry, is described in most of the studies although certain authors report, on the contrary, bladder hypoactivity. Conflicting data have also been published on bladder sphincter dyssynergia although in most studies, micturition was described as synergic in Parkinson's disease patients. L-dopa, the main drug for Parkinson's disease, has, according to the publication, either no action, or contradictory effects with bladder hypoactivity or hyperactivity. Anticholinergics are effective on overactive bladder, the alphablockers on the urethral hypertonia at the price of a higher risk of arterial hypotension in this diathesis. The indication for prostatic surgery must be carefully considered and preceded by precise clinical, urodynamic and sometimes electromyography evaluation. There is a high risk of post surgical incontinence. Endourethral prostheses provide an attractive alternative in the case of prostatic obstruction.

Animals↗

TRPV1 (vanilloid receptor) in the urinary tract: expression, function and clinical applications.

The transient receptor potential vanilloid subfamily 1 (TRPV1) is an ion channel activated by capsaicin, heat, protons and endogenous ligands such as anandamide. It is largely expressed in the urinary tract of mammals. Structures in which the receptor expression is firmly established include sensory fibers and urothelial cells, although the presence of TRPV1 in other cell types has been reported. As in other systems, pain perception was the first role attributed to TRPV1 in the urinary tract. However, it is now increasingly clear that TRPV1 also regulates the frequency of bladder reflex contractions, either through direct excitation of sensory fibers or through urothelial-sensory fiber cross talk involving the release of neuromediators from the epithelial cells. In addition, the recent identification of the receptor in urothelial and prostatic cancer cells raise the exciting hypothesis that TRPV1 is involved in cell differentiation. Desensitization of the receptor by capsaicin and resiniferatoxin has been investigated for therapeutic purposes. For the moment, lower urinary tract dysfunctions in which some benefit was obtained include painful bladder syndrome and overactive bladder of neurogenic and non-neurogenic origin. However, desensitization may become obsolete when non-toxic, potent TRPV1 antagonists become available.

Animals↗

Trypanosoma cruzi infection induced changes in the innervation, structure and function of the murine bladder.

PURPOSE: The involvement of the lower urinary tract in chronic Chagas' disease has received little attention. Therefore, we investigated pathology and functional alterations in the bladder of Trypanosoma cruzi infected mice. MATERIALS AND METHODS: CD1 mice were infected with 5 x 10 T. cruzi trypomastigotes of the Brazil strain of T. cruzi. At day 100 after infection bladder structure and function were examined by pathological evaluation, magnetic resonance imaging and cystometric studies. RESULTS: The bladder in infected mice weighed more and were large, dilated, deformed, friable and thin walled compared with control mice. Magnetic resonance imaging confirmed these observations. Inflammation, fibrosis and ganglionitis was observed. Cystometric studies revealed that baseline, threshold and micturition pressures were increased in infected mice. Bladder overactivity and decreased bladder compliance were also noted in infected mice. There were no detectable differences in bladder capacity, micturition volume or residual volume between infected and uninfected mice. CONCLUSIONS: Bladder abnormalities may be a more common clinical sequelae of T. cruzi infection than previously appreciated.

Animals↗

alpha1-adrenoceptors and bladder function.

OBJECTIVE: To discuss the role of alpha-adrenoceptors (alpha-ARs) in the control of lower urinary tract function with special emphasis on their importance in the pathologically changed bladder. METHODS: Evaluation of published information. RESULTS: The functional role of the alpha-ARs in the normal detrusor muscle has not been established. Changes in the function of these alpha-ARs may occur in e.g., bladder outflow obstruction, bladder overactivity, and 'neurogenic' bladders. The filling (irritative) symptoms in patients with benign prostatic hyperplasia and outflow obstruction, which are relieved by alpha-AR antagonist treatment, have been associated with bladder dysfunction produced by the obstruction. There is evidence for involvement of alpha-ARs in the spinal control of both the sympathetic, somatic (filling) and parasympathetic (voiding) efferent activity to the lower urinary tract. The beneficial effects of alpha-AR antagonists on filling symptoms, which can be obtained even in the absence of outflow obstruction, give support for the involvement of extravesical, possibly spinal, alpha-ARs in their pathogenesis. CONCLUSIONS: A more complete understanding of the role of alpha-ARs in the control of the normal or functionally changed bladder should be helpful in the development of drugs for treatment of lower urinary tract disorders.

Adrenergic alpha-1 Receptor Antagonists↗