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PubMed2006

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↗
PubMed1997

Stimulation of bladder activity by volume, L-dopa and capsaicin in normal conscious rats--effects of spinal alpha 1-adrenoceptor blockade.

To study possible differences in alpha 1-adrenoceptor involvement in the spinal mechanisms mediating bladder activity induced by volume (bladder filling), central (L-dopa), and peripheral (capsaicin) stimulation, we investigated if these types of bladder activity were modified by intrathecal (i.t.) or intra-arterial (i.a.) administration of the alpha 1-adrenoceptor antagonist, indoramin. Indoramin is selective for the alpha 1A-adrenoceptor subtype, whereas most clinically used alpha 1-adrenoceptor antagonists, including doxazosin, have no subtype selectivity. The drug effects were studied by continuous cystometry in normal, conscious rats and rats with bladder activity evoked by intraperitoneal L-dopa (50 mg/kg after carbidopa pretreatment), or by intravesical capsaicin (30 microM). I.t. indoramin (50 nmol) significantly decreased micturition pressure, and increased bladder capacity and micturition volume. Dribbling incontinence due to urinary retention was observed in one of ten rats. L-dopa-stimulated bladder overactivity was significantly attenuated by i.t. or i.a. indoramin (50 nmol). Similar effects of i.t. and i.a. doxazosin (50 nmol) have been reported previously. Intravesical capsaicin (30 microM) caused bladder activity, which was attenuated by i.t. indoramin (50 nmol), but not by i.t. doxazosin (50 nmol). I.a. indoramin did not reduce capsaicin-induced bladder activity; doxazosin was moderately effective. The results suggest that the bulbospinal micturition reflex evoked by bladder filling and L-dopa involves a descending pathway where transmission is partly mediated by spinal alpha 1-adrenoceptors. Bladder overactivity evoked by intravesical capsaicin, which elicits a vesicospinal-vesical reflex, was not affected by i.t. doxazosin in a dose that attenuates activity mediated through the bulbo-spinal pathway. This suggests less involvement of spinal alpha 1-adrenoceptors in the vesico-spinal-vesical than in the bulbo-spinal voiding reflex.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed2006

Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate.

1 We have systematically reviewed the presence, functional responses and regulation of alpha(1)-, alpha(2)- and beta-adrenoceptors in the bladder, urethra and prostate, with special emphasis on human tissues and receptor subtypes. 2 Alpha(1)-adrenoceptors are only poorly expressed and play a limited functional role in the detrusor. Alpha(1)-adrenoceptors, particularly their alpha(1A)-subtype, show a more pronounced expression and promote contraction of the bladder neck, urethra and prostate to enhance bladder outlet resistance, particularly in elderly men with enlarged prostates. Alpha(1)-adrenoceptor agonists are important in the treatment of symptoms of benign prostatic hyperplasia, but their beneficial effects may involve receptors within and outside the prostate. 3 Alpha(2)-adrenoceptors, mainly their alpha(2A)-subtype, are expressed in bladder, urethra and prostate. They mediate pre-junctional inhibition of neurotransmitter release and also a weak contractile effect in the urethra of some species, but not humans. Their overall post-junctional function in the lower urinary tract remains largely unclear. 4 Beta-adrenoceptors mediate relaxation of smooth muscle in the bladder, urethra and prostate. The available tools have limited the unequivocal identification of receptor subtypes at the protein and functional levels, but it appears that the beta(3)- and beta(2)-subtypes are important in the human bladder and urethra, respectively. Beta(3)-adrenoceptor agonists are promising drug candidates for the treatment of the overactive bladder. 5 We propose that the overall function of adrenoceptors in the lower urinary tract is to promote urinary continence. Further elucidation of the functional roles of their subtypes will help a better understanding of voiding dysfunction and its treatment.

Adrenergic Agonists↗
PubMed1993

The ice-water test--a simple and valuable supplement to routine cystometry.

The results of cystometrograms and ice-water tests (IWTs) were retrospectively evaluated in 557 patients with overactive bladders, lower motor neuron lesions or pure stress incontinence. The IWT was considered positive when, following ice-water instillation, the fluid was expelled from the bladder within 1 min. The test was considered false negative when no fluid escaped despite a sustained detrusor contraction of the same magnitude as the micturition contraction. Ninety-seven percent of patients with complete and 91% of those with incomplete upper motor neuron lesions had a positive or a false negative IWT. About 75% of the patients with multiple sclerosis, Parkinson's disease or previous cerebrovascular accident had a positive IWT. All patients with lower motor neuron lesions or pure stress incontinence had a negative IWT. There was a significant correlation between a positive IWT and an abnormal sensation of bladder filling and inability to inhibit micturition voluntarily, as well as between a negative IWT and the occurrence of phasic detrusor contractions during cystometry. The study shows that the IWT is a sensitive test for differentiating upper from lower motor neuron lesions. It is also a useful parameter for functional subdivision of overactive bladders. In patients with voiding dysfunction in the absence of lower urinary tract inflammation, a positive test is an indicator of a silent or overt neurological disorder.

Adolescent↗
PubMed2005

Urodynamic effects of oxybutynin and tolterodine in conscious and anesthetized rats under different cystometrographic conditions.

BACKGROUND: Antimuscarinic agents are the most popular treatment for overactive bladder and their efficacy in man is well documented, producing decreased urinary frequency and an increase in bladder capacity. During cystometry in rats, however, the main effect reported after acute treatment with antimuscarinics is a decrease in peak micturition pressure together with little or no effect on bladder capacity. In the present experiments we studied the effects, in rats, of the two most widely used antimuscarinic drugs, namely oxybutynin and tolterodine, utilising several different cystometrographic conditions. The aim was to determine the experimental conditions required to reproduce the clinical pharmacological effects of antimuscarinic agents, as seen in humans, in particular their ability to increase bladder capacity. RESULTS: Intravenous or oral administration of tolterodine or oxybutynin in conscious rats utilized 1 day after catheter implantation and with saline infusion at constant rate of 0.1 ml/min, gave a dose-dependent decrease of micturition pressure (MP) with no significant change in bladder volume capacity (BVC). When the saline infusion rate into the bladder was decreased to 0.025 ml/min, the effect of oral oxybutynin was similar to that obtained with the higher infusion rate. Also, experiments were performed in rats in which bladders were infused with suramin (3 and 10 microM) in order to block the non-adrenergic, non-cholinergic component of bladder contraction. Under these conditions, oral administration of oxybutynin significantly reduced MP (as observed previously), but again BVC was not significantly changed. In conscious rats with bladders infused with diluted acetic acid, both tolterodine and oxybutynin administered at the same doses as in animals infused with saline, reduced MP, although the reduction appeared less marked, with no effect on BVC. In conscious rats utilized 5 days after catheter implantation, a situation where inflammation due to surgery is reduced, the effect of tolterodine (i.v.) and oxybutynin (p.o.) on MP was smaller and similar, respectively, to that observed in rats utilized 1 day after catheter implantation, but the increase of BVC was not statistically significant. In anesthetized rats, i.v. administration of oxybutynin again induced a significant decrease in MP, although it was of questionable relevance. Both BVC and threshold pressure were not significantly reduced. The number and amplitude of high frequency oscillations in MP were unmodified by treatment. Finally, in conscious obstructed rats, intravenous oxybutynin did not modify frequency and amplitude of non-voiding contractions or bladder capacity and micturition volume. CONCLUSION: Despite the different experimental conditions used, the only effect on cystometrographic parameters of oxybutynin and tolterodine in anesthetized and conscious rats was a decrease in MP, whereas BVC was hardly and non-significantly affected. Therefore, it is difficult to reproduce in rats the cystometrographic increase in BVC as observed in humans after chronic administration of antimuscarinic agents, whereas the acute effects seem more similar.

Animals↗
PubMed2004

Darifenacin: a novel M3 muscarinic selective receptor antagonist for the treatment of overactive bladder.

Darifenacin is a novel M3 muscarinic selective receptor antagonist for once-daily treatment of overactive bladder (OAB), a highly prevalent, chronic and debilitating disease defined by urinary urgency with or without urge incontinence, usually with increased frequency of micturition and nocturia. In vitro, darifenacin is a potent and specific muscarinic receptor antagonist with </= 59-fold higher selectivity for muscarinic M3 receptors relative to other muscarinic receptor subtypes. This profile may, therefore, confer clinical efficacy in the treatment of OAB, with a lower propensity for adverse effects and safety issues related to blockade of other muscarinic receptor subtypes. Indeed, consistent with its low relative affinity for M1 and M2 receptors, no effects on cognitive function and heart-rate variability, respectively, have been observed with darifenacin. Subsequent large-scale clinical trials have confirmed that darifenacin (at doses of 7.5 and 15 mg/day) results in central nervous system and cardiac adverse events comparable to placebo, and provides early and meaningful improvement across a range of OAB symptoms including incontinence episodes, urgency and urinary frequency. On the basis of such findings, darifenacin would appear to meet the current need for an effective OAB pharmacotherapy that is efficacious, well-tolerated and, more importantly, minimises the risk of safety-related adverse effects.

Benzofurans↗
PubMed2005

Overactive bladder in the elderly: a guide to pharmacological management.

Overactive bladder (OAB) is a common condition characterised by the symptoms of urinary frequency and urgency, with or without urge incontinence and nocturia. The prevalence of OAB increases markedly with age in both men and women. OAB can have a detrimental effect on physical functioning and psychological well-being, as well as significantly reducing quality of life. Antimuscarinic therapy -- with or without behavioural therapy -- represents the most common treatment for patients with OAB. Several antimuscarinic agents are currently available for the treatment of OAB in adults, including oxybutynin, tolterodine, trospium chloride, darifenacin and solifenacin. The antimuscarinics all appear to exert their clinical effect through inhibition of the bladder muscarinic receptors, but they vary both in structure and in their functional profile. While efficacy has been demonstrated in adult populations (including patients >65 years of age), few studies have been reported specifically in a geriatric population, and antimuscarinics are often underutilised in the elderly despite the marked increase in the prevalence of OAB in this age group. One explanation for this apparent underuse of an effective treatment option may be concerns about the frequency of anticholinergic adverse events, such as dry mouth; the likelihood of detrimental CNS effects, including cognitive impairment and sleep disturbances; and the potential for harmful interactions with existing pharmacotherapy. When selecting an antimuscarinic agent for the management of an elderly patient presenting with OAB, in addition to considering evidence of clinical efficacy and tolerability, issues of safety specific to an older population should be borne in mind. In particular, the likelihood of detrimental CNS effects should be considered, including cognitive impairment and sleep disturbances, secondary to anticholinergic load. Oxybutynin and tolterodine have both been associated with cognitive adverse events and effects on sleep architecture and quality. In contrast, trospium chloride and darifenacin do not appear to be associated with cognitive adverse events and trospium chloride does not negatively affect sleep architecture or quality. Biotransformation by the cytochrome P450 (CYP450) system is an important step in the activation or elimination of a large number of drugs, including oxybutynin, tolterodine, darifenacin and solifenacin, raising the possibility of clinically relevant and potentially serious drug interactions. In elderly patients, such interactions are of particular relevance given the potential for declining activity of certain members of the CYP450 family combined with decreased hepatic blood flow, which can reduce first-pass metabolism and thus the bioavailability of drugs metabolised via this route. Of the antimuscarinic agents used to treat OAB, only trospium chloride is not extensively metabolised in the liver by the CYP450 system and is excreted largely as the active parent compound in the urine. This paper provides an overview of the pathophysiology of OAB and reviews current approaches to achieving a differential diagnosis and selecting appropriate treatment for the older patient. The pharmacology and clinical effects of current medication for the treatment of OAB symptoms in patients defined by the OAB pharmacology literature as 'elderly' are also reviewed.

Aged↗
PubMed2002

Modulation of viscero-somatic H-reflex during bladder filling: a possible tool in the differential diagnosis of neurogenic voiding dysfunctions.

OBJECTIVE: Despite evidence that the activation of visceral afferents modulates spinal motoneurone activity in humans, the circuits responsible for this modulation remain unclear. The aim of the present study was to assess the effect of urinary bladder filling on the excitability of somatic spinal motoneurones in patients affected by overactive bladder secondary to neurogenic and non-neurogenic causes in both patients with bladder underactivity and normal subjects by means of a urodynamic evaluation. METHODS: In order to evaluate the influence of bladder filling on somatic reflexes, we studied the H-reflex evoked by electrical stimuli applied to the tibial nerve at the popliteal fossa and recorded from the soleus muscle. The H-reflex was tested in the following conditions: (1). empty bladder; (2). medium bladder filling; (3). maximum bladder filling; (4). five minutes after bladder emptying. The H-reflex amplitude at empty bladder was considered as the control value. RESULTS: In healthy subjects, we observed a progressive reduction in the H-reflex amplitude during bladder filling. In spinal cord-injured patients affected by a neurogenic overactive bladder, bladder filling failed to inhibit the H-reflex amplitude; a decrease in the H-reflex amplitude similar to that displayed by normal subjects was observed in patients with a non-neurogenic overactive bladder. By contrast, H-reflex behavior was unmodified in neurogenic underactive bladder patients and was similar to normal subjects in psychogenic underactive patients. CONCLUSIONS: As behavior of the H-reflex varies during bladder filling in neurogenic and non-neurogenic overactive bladder patients as well as in neurogenic and non-neurogenic underactive bladder patients, H-reflex modulation may be considered a useful tool in the differential diagnosis of voiding dysfunctions.

Adult↗
PubMed2003

[Overactive bladder--which diagnosis investigations are necessary before initiating primary treatment?].

The symptom complex of frequency and urgency with or without urge incontinence is termed overactive bladder (OAB) according to the new definition by the International Continence Society. The background for this change in definition is the great economic and social importance of the disease, the rising costs in medicine, and the tendency to develop the simplest possible therapeutic strategies. Therapy consists of the administration of an anticholinergic/spasmolytic drug for at least 3 months. Although a great percentage of patients with OAB can be clinically identified, the required exclusion of "local pathologic and metabolic factors" calls for a minimal diagnostic program to come to fairly exact findings. This includes a detailed case history with standardized and evaluated questionnaires, a bladder diary, detailed clinical examination, urine analysis consisting of microscopic and microbiologic examination, uroflowmetry including measurement of residual urine, and examination of the kidneys and the upper urinary tract (determination of creatine and sonography). Minimally invasive tests to improve validity regarding obstruction and detrusor overactivity are being developed. These tests are intended to make an invasive pressure-flow study unnecessary. However, using the above-described minimal diagnostic program, one has to take into account that patients suffering from complaints without underlying idiopathic detrusor overactivity and with urgency/urge incontinence due to bladder outlet obstruction are referred for primary therapy with anticholinergic/antispastic drugs. In cases of neurologic signs, pathologic urinary findings, reduced urinary flow rate with residual urine, and problems of the upper urinary tract, further diagnostic studies are necessary. In any case, such patients need not undergo primary therapy on the basis of a clinical diagnosis. An ex iuvantibus therapy with anticholinergic drugs--even if limited to 3 months--is not acceptable if the diagnostic minimal program is not used.

Bacteriuria↗
PubMed2003

Pharmacological effects of KRP-197 on the human isolated urinary bladder.

KRP-197, 4-(2-methylimidazol-l-yl)-2,2-diphenylbutyramide, is a newly synthesized antimuscarinic drug, developed for the treatment for overactive bladder. For evaluation of pharmacological characteristics of KRP-197, we investigated whether it influenced both prejunctional and postjunctional muscarinic receptors on the isolated human detrusor smooth muscles as compared with the effects of atropine, oxybutynin, and propiverine. Using the muscle bath technique, we investigated the effects of various antimuscarinic drugs on the contractions induced by carbachol, KCl, CaCl(2), and electrical field stimulation. Furthermore, using high-performance liquid chromatography with a microdialysis technique, we measured the acetylcholine release from the muscle strips during electrical field stimulation. The effects of various antimuscarinic drugs on acetylcholine releases were also evaluated. Pretreatment with various antimuscarinic drugs caused parallel shifts to the right in carbachol-induced concentration-response curves. The rank order of pA(2) values was KRP-197 > or = atropine > oxybutynin > propiverine. Atropine and KRP-197 did not cause significant inhibition of KCl- and CaCl(2)-induced contractions. All drugs caused concentration-dependent inhibitions in electrical field stimulation-induced contractions. Pretreatment with atropine and propiverine did not cause significant changes in electrical field stimulation-induced acetylcholine release. However, KRP-197, and oxybutynin caused significant decreases in acetylcholine release. The present study demonstrates that KRP-197 has an inhibitory effect on postjunctional muscarinic receptors as well as on prejunctional muscarinic receptors to modulate acetylcholine release in human detrusor smooth muscles. The findings suggest the usefulness of KRP-197 as a therapeutic drug for an overactive bladder with symptoms of frequency, urgency, and urge incontinence.

Aged↗
PubMed2005

[The effect of botulinum toxin injection into the bladder for overactive bladder: two case].

Two cases of intractable overactive bladder which were treated by intradetrusor botulinum-A toxin (BTX-A) are presented. Case 1: A 53-year-old woman suffered from adhesive arachinoiditis. She had severe detrusor hyperreflexia and urge urinary incontinence despite a high dose of anticholinergic medication. Under cystoscopic control, a total of 300 units of BTX-A were injected into the detrusor muscle at 30 sites (10 units per ml per site), sparing the trigone area using a 27G flexible injection needle. This procedure was done under both caudal anesthesia with 10 ml 1% lidocaine and bladder mucosa anesthesia by instilling 40 ml 2% lidocaine. At a 12-week followup she was completely continent. Case 2: A 63-year-old man with intractable detrusor overactivity of idiopathic origin was treated using the above technique. Urge urinary incontinence decreased 4 weeks after the BTX-A injections. However, postvoid residual urine volume was increased, and intermittent self-catheterization was needed. Intradetrusor BTX-A dramatically increases the bladder capacity and decreases the frequency of urge urinary incontinence. However, this treatment caused urinary retention in Case 2. We believe that the dosage amount of BTX-A should be changed case by case.

Botulinum Toxins, Type A↗
PubMed2003

[Physiology and evaluation of overactive bladder].

Detrusor overactivity is a urodynamic observation characterized by involuntary detrusor contractions during the filling phase which may be spontaneous or provoked. There are certain patterns of detrusor overactivity. Phasic detrusor overactivity is defined by a characteristic wave form and may or may not lead to urinary incontinence. Terminal detrusor overactivity is defined as a single involuntary detrusor contraction occurring at cystometric capacity, which cannot be suppressed. Neurogenic detrusor overactivity is qualified as neurogenic when it is a relevant neurological condition (old term is "detrusor hyperreflexia"), idiopathic detrusor overactivity when there is no defined cause (this term replaces "detrusor instability"). In neurogenic patients, detrusor overactivity is secondary to various pathophysiologic factors: interruption of inhibitor pathways issued from cerebral regions, activation de novo of vesical C reflex mediated by unmyelinated capsaicin fibers, and ultrastructural modifications of bladder urothelium. Bladder overactivity treatment is necessary to avoid renal complications and improve quality of life of neurogenic patients.

Humans↗
PubMed2005

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↗