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PubMed2006

Spinal ERK activation contributes to the regulation of bladder function in spinal cord injured rats.

The extracellular signal-regulated kinase 1 and 2 (ERK) pathway, regulated by phosphorylation on specific amino acids, is emerging as an important signaling cascade in neurones, transducing sensory input into cellular responses. In the mammalian nervous system, the ERK pathway has been found to mediate plasticity events. Particularly, in the spinal cord, ERK play an important role in allodynia and hyperalgesia. Recently, it was demonstrated that ERK activation is upregulated in the spinal cord of rats with chronic bladder inflammation and contributes to bladder overactivity. Thus, in this study we sought to assess the involvement of ERK in micturition reflexes associated to spinal cord injury (SCI) in the rat. Bladder function in chronic SCI rats was altered compared to spinal intact rats. PhosphoERK levels were upregulated in the L6 spinal cord segment, particularly after saline infusion for 2 h. The increase in spinal ERK phosphorylation was specifically restricted to L6 spinal segment. No variation in the levels of total ERK protein was observed. Intrathecal administration of PD98059, a specific inhibitor of ERK phosphorylation, reduced the frequency and amplitude of bladder contractions in SCI animals but not in spinal intact ones. Overall, our results demonstrate increased activation of the ERK pathway in the spinal cord from SCI rats, restricted to spinal segments that receive sensory input arising from the bladder. Since the use of PD98059 reduced the frequency and amplitude of bladder contractions, ERK inhibitors may provide a new therapeutic approach to the treatment of bladder overactivity after spinal injuries.

Animals↗
PubMed1997

Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine.

PNU-200577 (labcode DD 01 [(R)-N, N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine ) is a major pharmacologically active metabolite of tolterodine, a new muscarinic receptor antagonist intended for the treatment of an overactive bladder. In vitro, PNU-200577 produced a competitive and concentration-dependent inhibition of carbachol-induced contraction of guinea-pig isolated urinary bladder strips (KB = 0.84 nM; pA2 = 9.14). In vivo, PNU-200577 was significantly more potent at inhibiting acetylcholine-induced urinary bladder contraction than electrically induced salivation in the anaesthetised cat (ID50 15 and 40 nmol.kg-1, respectively; P < 0.01). In radioligand binding studies carried out in homogenates of guinea-pig tissues and Chinese hamster ovary cell lines expressing human muscarinic m1-m5 receptors, PNU-200577 was not selective for any muscarinic receptor subtype. Thus, PNU-200577 is similar to tolterodine in terms of antimuscarinic potency, functional selectivity for the urinary bladder in vivo and absence of selectivity for muscarinic receptor subtypes in vitro. The results of this study clearly indicate that PNU-200577 contributes to the therapeutic action of tolterodine, in view of its high antimuscarinic potency, similar serum concentration and lower degree of protein binding.

Acetylcholine↗
PubMed2006

PACAP enhances mouse urinary bladder contractility and is upregulated in micturition reflex pathways after cystitis.

Pituitary adenylate cyclase-activating polypeptide (PACAP) elicits a transient contraction, sustained increase in the amplitude of spontaneous phasic contractions, and significantly increases the amplitude of nerve-mediated contractions in mouse urinary bladder smooth muscle (UBSM) strips. PACAP immunoreactivity (IR) is increased in micturition reflex pathways following cystitis. PACAP may contribute to altered sensation and bladder overactivity in the chronic bladder inflammatory syndrome, interstitial cystitis.

Animals↗
PubMed2004

Spontaneous activity and electrical coupling in human detrusor smooth muscle: implications for detrusor overactivity?

Large uncontrollable detrusor contractions, decreased compliance that increases luminal pressures during filling, and detrusor underactivity are all examples of abnormal bladder function. Studies of the nervous control of lower urinary tract function and measurement of the cellular properties of the component tissues of the bladder wall have been performed to deepen our knowledge of these problems. The resultant data have suggested that lower urinary tract smooth muscle should not be regarded solely as a collection of independent cellular contractile units that are each activated by separate neural inputs, but also as a syncytium of cells. Although this syncytial arrangement may not be as well developed as in other tissues, it should impose a new layer of activity that will affect overall bladder function. Recent studies have addressed this issue through investigation of spontaneous contractile activity, the cellular basis of syncytial function, and their normal and abnormal functional consequences. The results suggest that individual detrusor cells possess membrane properties that may lead to spontaneous activity fluctuations, which can affect adjacent cells and, thus, produce multicellular aberrant responses. It remains unclear whether these responses manifest themselves as dysfunctional activity in the whole bladder defects because the extent of local multicellular abnormalities is not known at present. The data do imply that myogenic defects can contribute to abnormal bladder function and, thus, suggest several new targeted drug models that should be explored.

Animals↗
PubMed2006

Partial urethral obstruction enhances NADPH-diaphorase activity in the monkey (Macaca fascicularis) bladder: light and electron microscopic studies.

The effect of partially obstructing the urethra on the nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) activity in neurons of the intramural ganglia of the monkey (Macaca fascicularis) bladder was examined by light and electron microscopy. Partial urethral ligation was done in adult male monkeys. The animals were sacrificed 2, 4 weeks after partial urethral obstruction. This was compared to controls (normal and sham operated). Urethral obstructed animals were observed to have increased urinary frequency and decreased urinary flow rate. Two weeks after urethral obstruction, the overall NADPH-d activity in the intramural ganglia of the bladder base was enhanced compared to control animals. The frequency of intensely stained NADPH-d positive neurons was increased compared to the control animals. About one-third of intensely stained NADPH-d positive neurons appeared to undergo degenerative changes. At 4 weeks after urethral obstruction, a wide occurrence of NADPH-d positive neurons in advanced stages of degeneration in the bladder base was observed. Cellular debris was strewn among normal looking ganglion cells and along the nerve processes. The proportion of intensely stained NADPH-d positive neurons was relatively lower than the controls. The total number of NADPH-d positive neurons and the nerve fibres in the entire bladder was significantly reduced when compared to control animals. Electron microscopy showed some NADPH-d activity in intramural ganglion cells in 2 weeks after partial urethral obstruction. NADPH-d reaction product (formazan) was deposited on the membranes of the rough endoplasmic reticulum, and the outer membranes of some mitochondria in the intramural neuron. At 4 weeks after urethral obstruction, NADPH-d was present in the membrane of the mitochondria and some mitochondria appeared swollen with disrupted cristae. Present results show that NADPH-d activity in neurons of the intramural ganglia of the monkey (Macaca fascicularis) urinary bladder was increased after two weeks and reduced after 4 weeks of partial urethral obstruction. It is speculated that the increased NADPH-d activity associated with partial urethral obstruction would lead to neuronal damage and death, which may contribute to detrusor overactivity. However, it warrants further investigation to understand the mechanism of neuronal cell death after partial urethral obstruction.

Animals↗
PubMed1997

Diagnosis and significance of idiopathic overactive bladder.

OBJECTIVES: To offer a critical overview of the basis for the International Continence Society (ICS) classification of detrusor instability, to summarize current diagnostic methodologies, and to outline the etiologic factors that should be excluded in the diagnosis of idiopathic overactive bladder. METHODS: The current ICS definitions of overactive bladder are discussed. Issues related to the diagnosis of detrusor instability (DI) are addressed through a review of the literature. RESULTS: The term idiopathic overactive bladder reflects the present lack of knowledge concerning vesicourethral function and dysfunction. The term is used to apply to a wide spectrum of different conditions that may have a common final pathophysiologic pathway. This heterogeneous group of conditions could be subdivided on the basis of presumptive etiopathogenesis, urodynamic patterns, and response to treatment. The diagnosis of DI, its rate of detection, and its urodynamic patterns depend on the type of urodynamic test used and the way the test is performed. The ICS definitions of DI have been called into question by the results of studies using urodynamic tests in addition to, or instead of, provocative cystometry--for instance, ambulatory urodynamics, urethrocystometry, the ice-water test, and evaluation of the voiding phase. The literature supports a broadening of the ICS criteria for excluding all known causes of DI when establishing the diagnosis of idiopathic overactive bladder. CONCLUSIONS: Appropriate longitudinal studies, using contemporary urodynamic tests and knowledge, are needed to improve the identification of subsets of patients with overactive bladder who have different prognoses and outcomes. The ICS definitions and classification should be updated.

Humans↗
PubMed2000

Intravesical neuromodulatory drugs: capsaicin and resiniferatoxin to treat the overactive bladder.

Current pharmacologic treatment of the overactive bladder relies on anticholinergic drugs. However, these drugs often have troublesome side effects and frequently are given in doses insufficient to restore continence in patients with detrusor instability. We present the background and basic and clinical research dealing with intravesical instillation of capsaicin and resinfferatoxin as treatments for the overactive bladder. Capsaicin is the main pungent ingredient in "hot" peppers of the genus Capsicum. It is a specific neurotoxin that desensitizes C-fiber afferent neurons, which may be responsible for the signals that trigger detrusor overactivity. Studies with capsaicin over the past 8 years have demonstrated clinical efficacy with minimal long-term complications. Most of these studies have also shown that the acute pain and irritation associated with capsaicin are a major deterrent to widespread use. Resiniferatoxin (RTX), an ultrapotent analog of capsaicin that appears to have similar efficacy but with much less acute side effects may be more useful. Intravesical instillation of capsaicin or resiniferatoxin is a promising treatment for the overactive bladder.

Administration, Intravesical↗
PubMed1994

Lower urinary tract dysfunction in children with benign sacrococcygeal teratoma.

We evaluated 8 girls and 3 boys with benign sacrococcygeal teratoma for lower urinary tract dysfunction. All children underwent ultrasonography of the urinary tract, voiding cystourethrography and at least 2 standard urodynamic evaluations. Mean patient age at first urodynamic study was 59 months (range 1 to 136). Nine of the 11 children had abnormal studies, including detrusor instability and associated pelvic floor overactivity during micturition in 2, an anatomical infravesical obstruction in 2 and neurogenic bladder-sphincter dysfunction in 5 (2 detrusor hyperreflexia with sphincter dyssynergia, 2 hyporeflexic bladder-sphincter function and 1 detrusor hyporeflexia with normal sphincter function). Although the major cause of neurogenic lower urinary tract dysfunction seems to be related to surgical trauma of the pelvic plexus and sacral nerves, we observed tethered spinal cord as a primary cause in 2 patients. The incidence of voiding dysfunction in children with sacrococcygeal teratoma is high and is usually neurogenic in origin.

Abdominal Neoplasms↗
PubMed2002

Trospium chloride in patients with detrusor overactivity: meta-analysis of placebo-controlled, randomized, double-blind, multi-center clinical trials on the efficacy and safety of 20 mg trospium chloride twice daily.

OBJECTIVES: Primary objective of this meta-analysis was to produce a systematic and quantitative review of two independent clinical trials of 20 mg trospium chloride (TCI) twice daily (b.i.d.) in patients with detrusor overactivity [Alloussi et al. 1998, Cardozo et al. 2000]. PATIENTS AND METHODS: In two placebo-controlled, double-blind, multi-center studies, the effect of TCl on detrusor function was evaluated using urodynamic measurements. All 517 patients were randomized to receive TCl or placebo for 3 weeks. Urodynamic variables were measured at the beginning and at the end of the treatment. Safety was evaluated on the basis of adverse events (AEs), vital signs and laboratory tests. RESULTS: TCl produced significant improvements in 'maximum cystometric bladder capacity' (median treatment effect = 52 ml, 95% confidence interval 32-71 ml, p<0.0001) and 'urinary volume at first unstable contraction' (median treatment effect = 48 ml, 95% confidence interval 28 to 68 ml, p = 0.0001). The patients' assessment of efficacy also showed significantly greater clinical improvement in the TCl group than in the placebo group (p < 0.0001). The patients recorded a 'cure' or a 'marked improvement' more often in the TCl group than in the placebo group (47.9% and 19.7%, respectively). TCl was well tolerated, with similar frequencies of AEs reported in both groups (TCl: 35.7%, placebo group: 38.9%). CONCLUSIONS: Trospium chloride (20 mg twice daily) is an effective and safe medication for the treatment of detrusor overactivity.

Benzilates↗
PubMed1977

Studies of enuresis. VIII. Detrusor and sphincter instability caused by overactivity of integral voiding reflexes.

Ninety-one children with nocturnal enuresis or enuresis plus daytime urgency incontinence were studied by cystometry. Seventy-two per cent of the girls and 62 per cent of the boys had evidence of bladder instability. Sixty-eight children in whom abnormalities were found on preliminary voiding urodynamics or voiding cystourethrography also underwent calibration and endoscopic examination under anesthesia. An atropine-suppression test was also performed preoperatively in some children with a markedly unstable bladder demonstrated on preoperative cystometry. In the majority of children tested suppression of bladder instability with atropine was demonstrable. Voluntary detrusor sphincter dyssynergia was demonstrated in a majority of the children with daytime urgency incontinence. Sixty-five per cent of the boys and 81 per cent of the girls were treated for urethral obstructive lesions suspected to be of functional urodynamic significance. Postoperative cystometry showed marked improvement in bladder stability in 57 per cent of the girls and 63 per cent of the boys treated for suspected urethral obstructive pathology. The anticholinergic suppression test was found to have no significant predictive value relative to the cause or surgical curability of bladder instability. The pathophysiologic significance of overactivity of integral voiding reflexes 6 through 11 is described.

Child↗
PubMed1996

Agents for the treatment of overactive detrusor. V. Synthesis and inhibitory activity on detrusor contraction of N-tert-butyl-4,4-diphenyl-2-cyclopentenylamine.

N-tert-Butyl-4,4-diphenyl-2-cyclopentenylamine ((+/-)-3) was designed to restrict the conformation of terodiline 1 and was synthesized in a 6-step approach starting with diphenylacetaldehyde (10) or in a 4-step approach starting with 2,2-diphenyl-4-pentenoic acid (17). Using di-p-toluoyltartaric acid as a resolving agent, the synthetic (+/-)-3 was resolved into its optically pure forms, (-)- and (+)-3. The (-)-enantiomer (-)-3.HCl (FK584) showed about ten times more potent inhibitory activity on urinary bladder rhythmic contraction in rats (ED30 = 0.18 mg/kg, i.v.) than terodiline (ED30 = 1.9 mg/kg, i.v.), while the (+)-enantiomer (+)-3.HCl showed no inhibitory activity at 1.0 mg/kg i.v. Compound (-)-3.HCl (FK584) has pharmacological properties similar to those of terodiline, as evaluated by in vitro assay and is currently in clinical development for the treatment of overactive detrusor.

Amines↗
PubMed2003

Intravesical oxybutynin: a local anesthetic effect on bladder C afferents.

PURPOSE: Intravesical oxybutynin is used to control bladder overactivity in patients who are refractory to or cannot tolerate oxybutynin given orally. Although it is clinically effective, the mode of action of intravesical oxybutynin remains unclear. We tested the influence of intravesical oxybutynin on single fiber pelvic nerve afferents from the rat bladder. MATERIALS AND METHODS: A total of 15 single afferent bladder units were identified. Based on conduction velocity they were grouped as Adelta or C fibers. The effect of repeat bladder filling was studied on the mechanosensitive properties of these units. Oxybutynin was than instilled and left in the bladder for 15 minutes. Unitary afferent activity was again analyzed 15, 60 and 90 minutes after the drug was removed. RESULTS: Repeat bladder filling did not change nerve activity in Adelta or C fibers. At 15 minutes after oxybutynin was washed out of the bladder C fiber afferents responded significantly less to intravesical pressure and volume compared with control filling. At 60 minutes C fibers partly regained mechanosensivity. After 90 minutes sensitivity still increased without achieving the response level before oxybutynin. No significant changes were noted in Adelta fibers during repeat bladder filling or after oxybutynin instillation. CONCLUSIONS: In this study we showed that intravesical oxybutynin has a direct anesthetic effect within the bladder wall. It temporarily desensitizes C fiber afferents, which could explain its clinical benefits in decreasing symptoms of bladder overactivity. No measurable effect was found on Adelta fibers.

Administration, Intravesical↗
PubMed2003

RNA synthesis in pons necessary for maintenance of bladder overactivity after cerebral infarction in rat.

PURPOSE: The maintenance of long lasting bladder overactivity caused by cerebral infarction is believed to require transcription in the pontine micturition center. Therefore, we examined the influence of the RNA synthesis inhibitor actinomycin D (Banyu Pharmaceutical Co., Ltd., Tokyo, Japan) on bladder overactivity induced by left middle cerebral artery occlusion. MATERIALS AND METHODS: Rats under halothane anesthesia were injected with actinomycin D or vehicle (mannitol) into the bilateral dorsal pontine tegmentum, followed by middle cerebral artery occlusion. Awake rats were cystometrically examined for 12 hours. The expression of c-fos and zif268 mRNA in the dorsal pontine tegmentum was monitored with real-time polymerase chain reaction. RESULTS: Injection of actinomycin D produced a significant decrease in bladder capacity in sham operated rats but bladder capacity returned to control levels before sham operation within 6 hours. In cerebral infarcted rats pretreated with vehicle bladder capacity was significantly decreased after middle cerebral artery occlusion and it remained consistently below half of pre-occlusion capacity. Actinomycin D blocked the decrease in bladder capacity in cerebral infarcted rats. In actinomycin D treated cerebral infarcted rats bladder capacity gradually recovered and returned to the control level before middle cerebral artery occlusion within 10 hours. Actinomycin D suppressed an increase in c-fos mRNA expression 1 hour after middle cerebral artery occlusion as well as in zif268 3 hours after occlusion. Administering actinomycin D 0.5 or 1 hour after middle cerebral artery occlusion also suppressed bladder overactivity until at least 10 hours after occlusion but injection 3 hours after occlusion did not. CONCLUSIONS: These results indicate that an RNA synthesis inhibitor can prevent a late stage of bladder overactivity. Transcription in the dorsal pontine tegmentum was found to be necessary to maintain the long lasting bladder overactivity caused by cerebral infarction.

Animals↗
PubMed2000

Randomized, double-blind study of electrical stimulation for urinary incontinence due to detrusor overactivity.

OBJECTIVES: To evaluate the usefulness of electrical stimulation for urinary incontinence due to detrusor overactivity in a randomized, double-blind manner. METHODS: Sixty-eight patients (29 men, 39 women, 70.0 +/- 11.2 years) were studied. Detrusor overactivity was urodynamically defined as involuntary detrusor contractions of more than 15 cm H(2)O during the filling phase. Ten-hertz square waves of 1-ms pulse duration were used. A vaginal electrode was used in the women and an anal or surface electrode in the men. The stimulation was given for 15 minutes twice daily for 4 weeks. The efficacy was evaluated on the basis of a frequency/volume chart and urodynamic study before and after treatment. RESULTS: Thirty-two patients in the active group and 28 in the sham group completed the study. The patient impressions were very good or good in 59% and 39% of the active and the sham group, respectively (P = 0.0354). On the cystometrogram, the bladder capacity at the first desire to void and the maximum desire to void increased significantly (P = 0.0104 and P = 0.0046, respectively) in the active group, but not in the sham group. Seven patients in the active group and 1 patient in the sham group were cured (P = 0.0324); 26 patients (81.3%) in the active group and 9 (32.1%) in the sham group improved (P = 0.0001). Of 17 patients in the active group, 13 remained cured or improved for an average of 8.4 months after completion of the 4-week treatment; in the sham group, 3 of 6 patients were cured or improved for an average of 4.7 months after completion of the 4-week treatment. CONCLUSIONS: Electrical stimulation was useful in treating urinary incontinence due to detrusor overactivity.

Adult↗
PubMed2000

Behavioral therapy for overactive bladder.

What is behavioral therapy? On the one hand there is no consensus in the literature as to the definition of the treatment or the optimal mode of delivery. On the other hand, it is possibly the "best" single treatment for urinary incontinence when viewed from a risk:benefit analysis. There is general agreement that within this framework wide variations exist in intensity of treatment, expertise required to deliver the treatment, and the subsequent cost of therapy. A definition of behavioral therapy should include at least the following techniques: first, education and explanation of normal lower urinary tract function; second, micturition charts and diaries; and finally, timed voiding/bladder training regimens. All of the behavioral methods are demonstrably effective, with improvement rates in incontinence episodes uniformly in excess of 50%. Our challenge is to define the critical parts of behavioral therapy and develop algorithms that can be delivered to the incontinent population in the most cost-effective manner.

Behavior Therapy↗
PubMed2004

A case for botulinum toxin-A in idiopathic bladder overactivity.

Botulinum toxin (BTX) has been shown to be an effective agent in suppressing detrusor overactivity due to neurogenic causes. Similar to results obtained with traditional agents to treat bladder overactivity (ie, antimuscarinic medications), the use of BTX has been extended to patients with idiopathic detrusor overactivity. This article briefly reviews the use of BTX to treat disorders of detrusor overactivity and, based on early clinical and laboratory results, establishes the case for its use as a therapeutic modality to treat idiopathic detrusor overactivity.

Botulinum Toxins, Type A↗