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PubMed1993

Structural basis of geriatric voiding dysfunction. II. Aging detrusor: normal versus impaired contractility.

Little information on the structural norm of the aging detrusor is currently available. To gain insight into the pathophysiology of geriatric voiding dysfunction, detrusor biopsies were examined by electron microscopy to identify structural correlates of specific, urodynamically defined abnormalities of vesical function in 35 elderly subjects. Prospective urodynamic grouping of the subjects and segregation of the detrusor specimens by ultrastructural features were done independently and blindly. One structural pattern so identified, the dense band pattern, matched the urodynamic group with neither detrusor overactivity nor bladder outlet obstruction. This neither group included 11 women and 2 men 65 to 91 years old (mean age 76 years). Except for 2 patients with minimal stress incontinence, all were symptom-free. None of the patients had diabetes or a neurological deficit. Urodynamically, 10 patients had impaired and 3 had normal detrusor contractility. The dense band structural pattern was characterized by overall normal configuration of muscle cells and cell junctions, sarcolemma (muscle cell membrane) dominated by dense bands with depleted caveolae in interposed zones and slight widening of spaces between muscle cells with little-collagen content. Specimens from the 10 subjects with impaired contractility displayed, in addition, widespread degeneration of muscle cells and axons. The remaining 3 specimens, without degeneration, matched the subjects with normal contractility, who were continent and symptom-free. It is proposed that the dense band pattern represents the structural norm of aging detrusor, heralds a process of muscle cell de-differentiation in the detrusor accompanying natural aging, and may affect exchange and storage of ions involved in the excitation-contraction coupling mechanism of muscle cells through depletion of caveolae. Widespread degeneration of muscle cells and axons, superimposed on the dense band pattern, is proposed as the structural correlate of impaired detrusor contractility in the aging detrusor.

Aged↗
PubMed2002

Effect of muscarinic antagonists on micturition pressure measured by cystometry in normal, conscious rats.

OBJECTIVES: To establish an in vivo model to screen new muscarinic antagonists for the treatment of overactive urinary bladder and to calculate the respective ID(50) values. METHODS: The conscious rat cystometry model was modified to determine a complete dose-response curve in each animal. Spontaneous micturition was induced by infusion of room-temperature saline into rat bladders at a constant rate of 12 mL/hr. Cumulative doses of muscarinic antagonists administered in the femoral vein caused dose-dependent inhibition of the urinary bladder contraction measured as the micturition pressure. In addition, the in vitro pK(B) values for atropine, PNU-200577 (DD01), tolterodine, oxybutynin, and terodiline were determined in carbachol-contracted rat bladder strips. RESULTS: The rank order of the in vivo ID(50) values were atropine (14 +/- 4 nmol/kg), PNU-200577 (22 +/- 12 nmol/kg), tolterodine (94 +/- 20 nmol/kg), oxybutynin (175 +/- 89 nmol/kg), darifenacin (236 +/- 144 nmol/kg), desethyloxybutynin (313 +/- 209 nmol/kg), propiverine (4561 +/- 2079 nmol/kg), and terodiline (18,339 +/- 5348 nmol/kg). Tolterodine and PNU-200577 caused a parallel shift of the in vitro concentration-response curve to the right and did not alter the maximal contraction. The ID(50) values correlated significantly with the in vitro rat pK(B) and human bladder pA(2) values. CONCLUSIONS: The present results suggest that the rat cystometry model can be used in in vivo screening for new muscarinic antagonists.

Animals↗
PubMed2006

Lower urinary tract disease: what are we trying to treat and in whom?

The diseases of the lower urinary tract are traditionally divided into abnormalities of storage and abnormalities of emptying. The targets for therapy were the organs most responsible for influencing storage and emptying. Modern understanding places the symptomatic status of the patient as the overriding criterion for treatment. It also accommodates a broader understanding of multiple and overlapping systems. Symptoms of voiding dysfunction have been clearly shown to be associated with symptoms of other genitourinary disease, for example, erectile dysfunction (ED). Treatment of voiding dysfunction has also been shown to have effects (adverse or beneficial) in these other domains. Thus, the symptoms of lower urinary tract disease (LUTD) that have to be considered now as targets relevant to these therapies include ED, ejaculatory dysfunction, sexual desire, sexual pain disorders and female sexual dysfunction. The anatomic, neural and endocrine systems that support these symptomatic functions and dysfunctions span the range from the urogenital smooth muscle to the hypothalamus, the bladder sensory output to the micturition centre and growth factors to androgens. Potentially important targets also include vascular and spinal structures, sex hormones and nitric oxide as well as the obvious genes, enzymes and receptors. The epidemiological studies prove the convergence of LUTD when viewed through the lens of the current patient-related outcomes and problem constructs. This convergence serves as a clear guidance to include wide ranging outcome instruments in all future studies with compounds being investigated for the treatment of LUTD. Out of these will come evidence of expected and unexpected collateral effects. The convergence should open the possibility to a different business model for developing therapeutic concepts. The blockbuster drug for a monolithic indication may be supplemented by agents with single or multiple pathway activity with smaller parallel targets. Using an approach based on patient reported outcomes to therapeutic targets not only widens the range of conditions, but also the patient types who can be considered as having LUTD.

Depression↗
PubMed2006

Molecular mechanisms of detrusor and corporal myocyte contraction: identifying targets for pharmacotherapy of bladder and erectile dysfunction.

The Post-Genomic age presents many new challenges and opportunities for the improved understanding, diagnosis and treatment of human disease. The long-term goal is to identify molecular correlates of disease processes, and use this information to develop novel and more effective therapeutics. A major hurdle in this regard is ensuring that the molecular targets of interest are indeed relevant to the physiology and/or pathophysiology of the processes being studied, and, moreover, to determine if they are specific to the tissue/organ being investigated. As a first step in this direction, we have reviewed the literature pertaining to bladder and erectile physiology/pharmacology and dysfunction and attempted to summarize some of the critical molecular mechanisms regulating detrusor and corporal myocyte tone. Because of the vast amount of published data, we have limited the scope of this review to consideration of the calcium-mobilizing and calcium-sensitizing pathways in these cells. Despite obvious differences in phenotypic characteristics of the detrusor and corporal myocyte, there are some common molecular changes that may contribute to, for example, the increased myocyte contractility characteristic of bladder and erectile dysfunction (i.e. increased Rho kinase activity and decreased K(+) channel function). Of course, there are also some important distinctions in the pathways that modulate contractility in these two cell types (i.e. the contribution of ryanodine-sensitive calcium stores and the nitric oxide/cGMP pathways). This report highlights some of these similarities and distinctions in the hope that it will encourage scientific discourse and research activity in this area, eventually leading to an improved quality of life for those millions of individuals that are afflicted with bladder and erectile dysfunction.

Animals↗
PubMed2006

Integrated control of lower urinary tract--clinical perspective.

The neural mechanisms that determine social bladder control are reviewed, with a particular emphasis on the role played by sensation in the process. Much has been learnt about the neural control of the bladder from studying patients with neurological disease and those disorders that are known to disrupt bladder storage are described. Possible approaches to treatment of the resulting incontinence are reviewed and it is acknowledged that in the future, the optimal treatment for incontinence may be determined by its precise underlying pathophysiology in each instance, for example, suprapontine causes requiring different medication to spinal causes. Although the main emphasis of urological research and development so far has been the treatment of incontinence, effective therapy for other bladder disorders such an impaired emptying or bladder pain could have an important impact on the bladder symptoms of many patients.

Animals↗
PubMed2006

Diagnosis and management of dysfunctional voiding.

PURPOSE OF REVIEW: This review will focus on the diagnosis and management of voiding dysfunction in neurologically and anatomically normal children. The discussion will highlight recent developments and research in the clinical approach as well as the etiology and classification of these disorders. RECENT FINDINGS: Voiding dysfunction in children encompasses a wide spectrum of clinical entities, recently classified collectively as dysfunctional elimination syndromes. Voiding dysfunction typically presents after toilet training and may originate from behavioral issues that arise around this time in childhood development. The spectrum of disorders includes urge syndrome, dysfunctional voiding with an uncoordination between the detrusor and urinary sphincter, and enuresis. Clinical symptoms may vary from mild incontinence to severe disorders with endpoints of irreversible bladder dysfunction with vesicoureteral reflux, urinary tract infection and resulting nephropathy. Diagnosis relies heavily on a good history and physical examination, but also includes radiologic and urodynamic evaluation. Treatment generally consists of medical therapy, primarily with anticholinergics as well as behavioral therapy to modify learned voiding patterns that contribute to the voiding dysfunction. SUMMARY: This overview of voiding dysfunction in children outlines the established approaches to its diagnosis and treatment and highlights the most recent developments in the field.

Biofeedback, Psychology↗
PubMed2006

Characterization and restoration of altered inhibitory and excitatory control of micturition reflex in experimental autoimmune encephalomyelitis in rats.

Multiple sclerosis (MS) is characterized by inflammatory lesions throughout the central nervous system. Spinal cord inflammation correlates with many neurological defecits. Most MS patients suffer from micturition dysfunction with urinary incontinence and difficulty in emptying the bladder. In experimental autoimmune encephalomyelitis (EAE) induced in female Lewis rats, a model of MS, we investigated at distinct clinical severity scores the micturition reflex by cystometrograms. All rats presenting symptomatic EAE suffered from micturition reflex alterations with either detrusor areflexia or hyperactivity. During pre-symptomatic EAE, a majority of rats presented with detrusor areflexia, whereas at onset of clinical EAE, detrusor hyperactivity was predominant. During progression of EAE, detrusor areflexia and hyperactivity were equally expressed. Bladder hyperactivity was suppressed by activation of glycine and GABA receptors in the lumbosacral spinal cord with an order of potency: glycine > GABA(B) > GABA(A). Detrusor areflexia was transformed into detrusor hyperactivity by blocking glycine and GABA receptors. Spinalization abolished bladder activity in rats presenting detrusor hyperactivity and failed to induce activity in detrusor areflexia. Altogether, the results reveal an exaggerated descending excitatory control in both detrusor reflex alterations. In detrusor areflexia, a strong segmental inhibition dominates this excitatory control. As in treatment of MS, electrical stimulation of sacral roots reduced detrusor hyperactivity in EAE. Blockade of glycine receptors in the lumbosacral spinal cord suppressed the stimulation-induced inhibitory effect. Our data help to better understand bladder dysfunction and treatment mechanisms to suppress detrusor hyperactivity in MS.

Animals↗
PubMed1998

Drug treatment of urinary incontinence.

Urinary incontinence is usually classified into four types: stress, urge, reflex and overflow incontinence. The first three types of incontinence are due to urine storage dysfunction and the latter is due to urine emptying dysfunction. To improve urine storage dysfunction treatment should be aimed at decreasing detrusor overactivity, increasing bladder capacity and/or increasing outlet resistance, whereas to improve emptying dysfunction, increasing detrusor contractility and/or decreasing outlet resistance are required. This review summarizes the various drugs currently in clinical use and new drugs under investigation.

Journal Article↗
PubMed2002

Modulation of bladder alpha1-adrenergic receptor subtype expression by bladder outlet obstruction.

PURPOSE: alpha1-Adrenergic receptor (alpha1AR) antagonists are effective for relieving obstructive and irritative symptoms in patients with bladder outlet obstruction. While the alpha1aAR is responsible for prostate smooth muscle relaxation and outlet obstruction relief, to our knowledge the mechanisms underlying the relief of irritative symptoms remain to be determined. Therefore, we investigated mechanisms by which bladder alpha1AR subtypes may be involved in this process. MATERIALS AND METHODS: We studied 42 rats, including 6 unoperated controls, 17 sham operated controls and 19 obstructed animals. Animals were characterized for baseline voiding pattern, followed by surgical intervention or sham surgery to establish obstruction (1.09 mm. restricted opening). After 6 weeks to enable the development of detrusor hypertrophy, voiding behavior was reexamined, the animals were sacrificed and bladder tissue was immediately placed in liquid nitrogen. alpha1AR subtype messenger (m)RNA was quantitated using quantitative competitive reverse transcriptase-polymerase chain reaction and protein expression was determined using radioligand binding with the alpha1AR antagonist [125iodine]2-(-[4-hydroxyphenyl]-ethyl-aminomethyl)tetralone (saturation analysis for total alpha1AR density and competition analysis with BMY7378 and 5-methylurapidel to determine alpha1AR subtypes). RESULTS: In this model 6-week surgical obstruction produced a 6.3-fold increase in bladder weight versus sham operation (p <0.001), concurrent with increased voiding frequency versus before obstruction (p <0.004). Although bladder alpha1AR density did not increase overall with obstruction, striking changes in alpha1AR subtype expression occurred. In control animals 70% of alpha1AR mRNA was the alpha1a subtype, 5% were alpha1b and 25% were alpha1d, whereas in obstructed animals bladder alpha1AR expression changed to 23% alpha1a, 2% alpha1b and 75% alpha1d. Changes in alpha1AR mRNA expression were of similar magnitude throughout the bladder dome, mid body and base. Parallel changes were also evident at the protein level with 100% alpha1aAR expression in control animals changing to new onset alpha1dAR expression (mean plus or minus standard error of mean 36% +/- 7%) in animals with a 5-fold or greater increase in bladder weight. CONCLUSIONS: Our findings indicate a remarkable increase in bladder alpha1dAR mRNA and protein expression after 6 weeks of obstruction and resultant detrusor hypertrophy. This finding is potentially important since alpha1dARs have 10 to 100-fold higher affinity for the endogenous neurotransmitter norepinephrine than the alpha1a or alpha1bAR subtypes. These findings imply that targeting alpha1d may provide a new therapeutic approach for controlling bladder irritative symptoms and possibly detrusor overactivity associated with bladder outlet obstruction.

Animals↗
PubMed2004

[Hypnotherapy in the treatment of refractory nocturnal enuresis].

BACKGROUND: Nocturnal enuresis represents a practical, social and emotional problem. The present study illustrates the advantage of using hypnosis as a therapy in chronic cases. MATERIAL: Twelve boys, median age 12 years (range 8-16), eight with primary nocturnal enuresis and four with primary nocturnal and diurnal enuresis, reported at referral a median of 0 (range 0-3) dry nights per week. All patients had a family history of enuresis and had used enuresis alarm and Desmopressin; 50% used Imipramin. Eight had been referred to psychological or psychiatric services for treatment. METHODS: All patients had undergone a somatic assessment by a paediatrician, a paediatric surgeon, or an urologist. After a preliminary assessment of motivation, they underwent hypnotherapy with a median of six sessions (range 2-8), followed by median one month with self-hypnosis exercises. RESULTS: At follow-up after three months and one year, nine out of 12 patients had respectively 6-7/7, and 7/7 dry nights per week. Three patients had nocturnal enuresis at follow-up; two of them were referred to a paediatric surgeon for their overactive urine bladder and one was referred to his local psychiatric clinic because of ongoing family conflicts. INTERPRETATION: Hypnotherapy had lasting effects for boys with chronic and complex forms of nocturnal enuresis. We suggest that hypnotherapy should be included in the therapeutic guidelines.

Child↗
PubMedDate not supplied

[Detrusor pseudohyperactivity syndrome in children with constipation].

THE AIM OF THE STUDY: was the evaluation of dependencies occurring between constipation and observed nocturia, pressing tenesmus and daytime urinary incontinence. MATERIAL AND METHODS: the studies were conducted in 51 children aged between 3 and 17 years including 25 girls and 26 boys hospitalized in the Clinical Department because of nocturia, pressing tenesmus and daytime urinary incontinence. In all children a complex diagnostic work up of the urinary system and the lower segment of alimentary tract was performed. Results of the examinations were compared to the control group. RESULTS: analysis of the results of the conducted examinations indicates that the overblown rectal ampulla, through the pressure exerted on the urinary bladder, seemingly decreases its volume causing the occurrence of pressing tenesmus, nocturia and daytime urinary incontinence. This process leads to the formation of detrusor hyperactivity syndrome characterized by: chronic constipation, increase of miction frequency and simultaneous decrease of volume of each portion of urine, nocturia and/or daytime urinary incontinence. CONCLUSIONS: chronic constipation disturbs the functional-morphological equilibrium between the end segment of alimentary tract and the urinary bladder. By influencing the process of filling and accumulation of urine in the bladder they lead to the formation of detrusor hyperactivity syndrome.

Adolescent↗
PubMed2001

Recent clinical studies of new pharmacologic agents and their efficacy in the treatment of incontinence.

Two agents for the control of overactive bladder-tolterodine (TOL) and extended-release oxybutynin (Oxy-XL)-have been evaluated in a number of studies for their efficacy in urge incontinence. Studies have demonstrated that TOL achieved a 20% reduction in the frequency of voiding and a 45% reduction in urge incontinent episodes. Efficacy was comparable between TOL and immediate-release oxybutinin (Oxy-IR), the standard anticholinergic comparator. There is a delay of some weeks in achieving relief with TOL, but thereafter there is a continued decrease in the total number of both micturitions and incontinent episodes in 24 hours. Trials demonstrated that there were no safety concerns at all with TOL. In particular, there was a lower incidence of dry mouth with TOL than with Oxy-IR. Dose-ranging studies established that TOL produced the lowest incidence of side effects while maintaining efficacy. In a long-term, community-use study of Oxy-XL, there was a very low incidence of central nervous system side effects, including mental acuity and memory. Among elderly nursing home patients, Oxy-XL achieved a 90% reduction in weekly urge incontinence episodes and an 86% decrease in pad use. Oxy-XL was shown to cause a significantly lower reduction in salivary output than Oxy-IR and TOL. In a recent head-to-head comparison study, there were significant differences found between Oxy-XL and TOL. Other studies have shown that the administration of Oxy-XL results in a significantly lower production of the metabolites responsible for anticholinergic side effect, particularly dry mouth, than with the standard release form, owing largely to the elimination of a first-pass effect. A long-acting form of TOL resulted in a 53% reduction in incontinent episodes. Both these anticholinergic agents have been shown to have excellent efficacy and tolerability. But the future of OAB therapy lies in targeting other mechanisms responsible for incontinence.

Journal Article↗