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At least 811 records · Page 45Linked to original sources

PubMed2006

Enhancement of rat bladder contraction by artificial sweeteners via increased extracellular Ca2+ influx.

INTRODUCTION: Consumption of carbonated soft drinks has been shown to be independently associated with the development of overactive bladder symptoms (OR 1.62, 95% CI 1.18, 2.22) [Dallosso, H.M., McGrother, C.W., Matthews, R.J., Donaldson, M.M.K., 2003. The association of diet and other lifestyle factors with overactive bladder and stress incontinence: a longitudinal study in women. BJU Int. 92, 69-77]. We evaluated the effects of three artificial sweeteners, acesulfame K, aspartame and sodium saccharin, on the contractile response of isolated rat detrusor muscle strips. METHODS: Strips of detrusor muscle were placed in an organ bath and stimulated with electrical field stimulation (EFS) in the absence and presence of atropine, and with alpha,beta methylene ATP, potassium, calcium and carbachol. RESULTS: Sweeteners 10(-7) M to 10(-2) M enhanced the contractile response to 10 Hz EFS compared to control (p<0.01). The atropine-resistant response to EFS was marginally increased by acesulfame K 10(-6) M, aspartame 10(-7) M and sodium saccharin 10(-7) M. Acesulfame K 10(-6) M increased the maximum contractile response to alpha,beta methylene ATP by 35% (+/-9.6%) (p<0.05) and to KCl by 12% (+/-3.1%) (p<0.01). Sodium saccharin also increased the response to KCl by 37% (+/-15.2%) (p<0.05). These sweeteners shifted the calcium concentration-response curves to the left. Acesulfame K 10(-6) M increased the log EC(50) from -2.79 (+/-0.037) to -3.03 (+/-0.048, p<0.01) and sodium saccharin 10(-7) M from -2.74 (+/-0.03) to 2.86 (+/-0.031, p<0.05). The sweeteners had no significant effect on the contractile response to carbachol but they did increase the amplitude of spontaneous bladder contractions. DISCUSSION: These results suggest that low concentrations of artificial sweeteners enhanced detrusor muscle contraction via modulation of L-type Ca(+2) channels.

Adenosine Triphosphate↗

PubMed2006

Bladder dysfunction in patients with cauda equina lesions.

AIMS: Data on lower urinary tract (LUT) function obtained in larger, systematically studied populations of patients with cauda equina lesions are limited. We report urinary function in 65 patients with chronic lesions. METHODS: A urinary function questionnaire was used, and neurological examination, quantitative electromyography (EMG) of the external anal sphincter (EAS) muscles, EMG assessment of the sacral reflex, and conventional urodynamic measurements were performed. RESULTS: Severe LUT dysfunction was found in 14%/15%, moderate in 27%/46%, and mild in 46%/39% men/women. Urinary symptoms interfered with daily life in 88%/92% and sexual life in 72%/67% of sexually active men/women. Symptoms of disturbed bladder emptying were the most common (95%/92% men/women), followed by urinary incontinence (56%/71%) and symptoms of overactive bladder (40%/56%). Perianal sensation was abnormal in 96%, EMG of the EAS muscle in 88%, and sacral reflex in 84% of patients. In 40%/17% men/women, a postvoid residual (>100 ml) was found. On filling cystometry overactive bladder was found in 21%/0%, reduced detrusor capacity in 9%/15%, and during voiding phase an acontractile detrusor or detrusor underactivity were found in 59%/85% men/women. Using multiple linear regression analysis, perianal sensory loss (P=0.0001) and female gender (P<0.02) had a significant positive effect on urinary incontinence score. CONCLUSIONS: Our study demonstrated significant LUT dysfunction, which disturbed the life of the majority of patients with chronic lesions of the cauda equina. Due to poor correlation between patients' symptoms and urodynamic findings cystometric surveillance is proposed in all patients with significant cauda equina lesions.

Adult↗

PubMed2007

Autoantibody-mediated bladder dysfunction in type 1 diabetes.

Bladder dysfunction is a common complication of diabetic autonomic neuropathy; however, its cause remains uncertain. We have recently identified a novel IgG autoantibody (Ab) in patients with type 1 diabetes that acts as an agonist at the dihydropyridine (DHP) site of L-type voltage-gated calcium channels (VGCC), disrupting neuronal regulation of visceral smooth muscle. In the present study, passive transfer to mice of IgG from patients with type 1 diabetes was used to investigate the role of anti-VGCC Abs in mediating diabetic bladder dysfunction. Injection of mice with diabetic immunoglobulin (IgG) with anti-VGCC activity induced features of an overactive bladder, including phasic detrusor contractions and a loss of bladder wall compliance. The bladder overactivity is mimicked by the DHP agonist Bay K8644, reversed by the DHP antagonist nicardipine, but is insensitive to the motor nerve blocker tetrodotoxin, indicating that the anti-VGCC Ab acts at the level of the bladder detrusor itself. This study reports the first evidence of Ab-mediated bladder dysfunction in type 1 diabetes, which may be part of a wider spectrum of smooth muscle and cardiac abnormalities.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2003

Effects of ATP-sensitive K+ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction.

AIMS: To compare in vivo the efficacy, potency, and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs), YM934 and (-)-cromakalim to a muscarinic antagonist, tolterodine in a novel partial outlet obstructed pig model. METHODS: Partially obstructed female Landrace pigs were implanted with telemetry transmitters to allow the continuous measurement of intravesical, abdominal and arterial pressures. A subcutaneous port catheter was used to adjust bladder volume. Bladder and arterial pressure were simultaneously monitored under isoflurane anesthesia before and after increasing i.v. doses of test compounds. RESULTS: Under anesthesia, voiding was completely inhibited, but spontaneous, nonvoiding bladder contractions were observed with mean amplitude of 16 +/- 1 cm H(2)O, duration of 35 +/- 2 seconds, and intercontraction interval of 43 +/- 4 seconds (n = 25). YM934 and (-)-cromakalim both caused dose-dependent decreases in bladder contraction area under the curve (AUC) with effective doses to inhibit AUC by 35% of 3.6 and 14.9 nmol/kg, i.v., respectively. However, concomitant reductions in mean arterial pressure of 12 and 13% were also observed. Tolterodine did not inhibit spontaneous bladder contractions at doses up to 100 nmol/kg, i.v. corresponding to plasma concentrations up to 41 ng/mL. CONCLUSIONS: The superior efficacy of KCOs to inhibit spontaneous bladder contractions relative to tolterodine support the hypothesis that KCOs may provide an alternate therapeutic mechanism to treat symptoms of overactive bladder if bladder-vascular selectivity can be sufficiently improved. The minimally invasive model described herein appears useful in the preclinical evaluation of potential therapeutics targeted to treat the overactive bladder.

Adenosine Triphosphate↗

PubMed2002

M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland.

The antimuscarinic profile of the experimental drug solifenacin/YM905 [(+)-(1 S,3' R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate] for the treatment of overactive bladder was compared with the commonly prescribed agent oxybutynin. In radioligand binding assays, p K(i) values of solifenacin for M(1), M(2), and M(3) receptors were 7.6, 6.9, and 8.0, respectively. These values for oxybutynin were 8.6 (M(1)), 7.7 (M(2)), and 8.9 (M(3)). Solifenacin and oxybutynin antagonized the contractile effect of carbachol (CCh) on isolated guinea pig urinary bladder smooth muscle (detrusor), displaying the negative logarithm of antagonist apparent affinity constant (p K(b) value) of 7.1 for solifenacin and 7.4 for oxybutynin. To study the tissue selectivity between bladders and salivary glands, guinea pig detrusor and mouse submandibular gland cells were stimulated with CCh and monitored for intracellular Ca2+, as determined by Fura 2 fluorescence. Ca2+ mobilization of detrusor cells was inhibited equipotently by solifenacin (p K(i)=8.4) and oxybutynin (p K(i)=8.6), whereas that of the gland cells was antagonized less potently by solifenacin (p K(b)=7.4) than by oxybutynin (p K(b)=8.8), although the M(3) subtype mediated both cell responses. In anesthetized rats, solifenacin (63-2100 nmol kg(-1) or 0.03-1 mg kg(-1)) dose-dependently inhibited CCh-stimulated increases in urinary bladder pressure, while its inhibitory effects on salivation and bradycardia were apparent only at a dose of 2100 nmol kg(-1). In contrast, oxybutynin within a dose range of 77-770 nmol kg(-1) (0.03-0.3 mg kg(-1)) inhibited responses of the bladder and salivary gland slightly more potently than that of the heart. In addition, inhibitory effects of darifenacin indicated a major role of M(3) receptors in the bladder and salivary gland. Therefore, M(3) receptor antagonism by solifenacin could be bladder-selective. This selectivity remains to be elucidated and may provide new approaches to the pharmacotherapy of overactive bladder.

Animals↗

PubMed1990

[A case of neurogenic bladder due to arachnoid cyst of the middle cranial fossa].

A 6-year-old girl, with urinary incontinence for the past 3 years, showed an overactive bladder and detrusor-sphincter dyssynergia (DSD) in urodynamic study. An epileptic focus in the right occipital area, as well as a large arachnoid cyst in the left middle cranial fossa was revealed by EEG and intracranial CT. After surgery for the arachnoid cyst, urinary incontinence was improved with disappearance of the epileptic focus in EEG, and an alteration of overactive bladder into normolactive one and improvement of DSD were observed in urodynamic study. It was considered that the urinary incontinence of this case might be associated with the ectopic epileptic focus due to the arachnoid cyst.

Arachnoid↗

PubMed2005

Understanding detrusor sphincter dyssynergia--significance of chronology.

OBJECTIVES: To evaluate in patients with spinal cord injury (SCI) and detrusor sphincter dyssynergia (DSD) whether the onset of external urethral sphincter (EUS) contractions precedes or follows the onset of bladder contractions and to address the issue of potential therapeutic approaches based on the understanding of DSD chronology. METHODS: A retrospective review of video-urodynamic recordings of patients with SCI that demonstrated both untreated neurogenic overactive bladder and DSD, from January 2002 to December 2003, was performed. Delay A was defined as the period between the onset of an EUS pressure increase and the onset of a bladder pressure increase and delay B as the period between the onset of a urethral sphincter pressure increase and the moment at which the bladder pressure increase reached 10 cm H2O greater than the baseline value. RESULTS: Twenty patients with traumatic SCI matched all inclusion criteria. Delay A was positive (EUS contracted first) in 16 (80%) of 20 patients. The mean time for delay A was 2.2 seconds. A positive association was found among a positive delay A, the completeness of the spinal lesion, and continuous DSD type. Delay B was positive in all 20 patients (100%). The mean time for delay B was 7.6 seconds. CONCLUSIONS: In most patients with SCI and DSD, the EUS contraction started before the onset of the bladder contraction. Additionally, in all patients with SCI, the EUS contraction started before the critical part of the bladder contraction. A pathophysiologic hypothesis for such chronology is discussed. A potential therapeutic application would be to use urethral sphincter activity to trigger inhibition of bladder contractions (conditional neuromodulation) and treat the neurogenic overactive bladder.

Humans↗

PubMed2002

(-)-(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. I. In vitro characterization.

Alterations in the myogenic activity of the bladder smooth muscle are thought to serve as a basis for the involuntary detrusor contractions associated with the overactive bladder. Activation of ATP-sensitive K(+) (K(ATP)) channels has been recognized as a potentially viable mechanism to modulate membrane excitability in bladder smooth muscle. In this study, we describe the preclinical pharmacology 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 1,4-dihydropyridine K(ATP) channel opener (KCO) that demonstrates enhanced bladder selectivity for the suppression of unstable bladder contractions in vivo relative to other reference KCOs. A-278637 activated K(ATP) channels in bladder smooth muscle cells in a glyburide (glibenclamide)-sensitive manner as assessed by fluorescence membrane potential assays using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (EC(50) = 102 nM) and by whole cell patch clamp. Spontaneous (myogenic) phasic activity of pig bladder strips was suppressed (IC(50) = 23 nM) in a glyburide-sensitive manner by A-278637. A-278637 also inhibited carbachol- and electrical field-stimulated contractions of bladder strips, although the respective potencies were 8- and 13-fold lower compared with inhibition of spontaneous phasic activity. As shown in the accompanying article [Brune ME, Fey TA, Brioni JD, Sullivan JP, Williams M, Carroll WA, Coghlan MJ, and Gopalakrishnan M (2002) J Pharmacol Exp Ther 303:387-394], A-278637 suppressed myogenic contractions in vivo in a model of bladder instability with superior selectivity compared with other KCOs, WAY-133537 [(R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)cyclobut-1-enylamino]-3-ethyl-benzonitrile] and ZD6169 [(S)-N-(4-benzoylphenyl)3,3,3-trifluro-2hydroxy-2-methyl-priopionamide]. A-278637 did not interact with other ion channels, including L-type calcium channels or other neurotransmitter receptor systems. The pharmacological profile of A-278637 represents an attractive basis for further investigations of selective K(ATP) channel openers for the treatment of overactive bladder via myogenic etiology.

ATP-Binding Cassette Transporters↗

PubMed2005

Effect of botulinum toxin on detrusor overactivity induced by intravesical adenosine triphosphate and capsaicin in a rat model.

OBJECTIVES: To assess the effects of intravesical injection of botulinum toxin type A (BTX) on a model of detrusor overactivity induced by intravesical infusions of adenosine triphosphate (ATP) and capsaicin. BTX has recently been used clinically to treat overactive bladder syndromes without a precise knowledge of the mechanism of action. METHODS: Twelve Sprague-Dawley rats underwent BTX injections. Six received 1.0 U and 6 received 0.5 U. BTX injections were done at bladder tube placement. Ten rats received saline injections as controls. After 48 hours of recovery, all 22 animals underwent awake, conscious cystometrography (CMG), performed using both saline and ATP (20 mM) intravesical infusion at 0.074 mL/min. In another 4 rats, capsaicin (100 microM) was infused intravesically before and after the BTX injections. The CMG parameters calculated included bladder contraction pressures and contraction frequencies (contractions per minute or Herz). RESULTS: Intravesical saline CMG produced a contraction frequency of 0.78 +/- 0.10 Hz. Intravesical ATP doubled this voiding frequency to 1.45 +/- 0.18 Hz (P = 0.003). BTX treatment at 1.0 U reduced the frequency to 0.91 +/- 0.13 Hz (P = 0.02). BTX injection significantly decreased the bladder contraction pressure during saline and ATP CMG. However, 0.5 U BTX did not decrease ATP-induced overactivity; therefore, in the capsaicin experiments, 1.0 U BTX was used. Although BTX tended to reverse detrusor overactivity secondary to intravesical capsaicin, this difference was not statistically significant. CONCLUSIONS: Intravesical infusion of either ATP or capsaicin can induce detrusor overactivity. BTX was more effective in blocking the effect of ATP than of capsaicin, although BTX injection did show a trend in reducing the contraction frequencies and amplitudes induced by capsaicin. The clinical utility of using BTX to treat overactive bladder syndromes and bladder hypersensory states, especially those that may be caused by an augmentation of the purinergic pathway, should be studied further.

Adenosine Triphosphate↗

PubMed2005

Assessment of cognitive function of the elderly population: effects of darifenacin.

PURPOSE: Overactive bladder is common in the elderly population, which is susceptible to cognitive disorders and drug induced cognitive impairment. Existing overactive bladder treatments may cause adverse events, such as cognitive impairment, due to antagonism of the M1 receptor in the central nervous system. In this study we evaluated the effect of darifenacin, an M3 selective antagonist, on cognitive function in elderly volunteers without clinical dementia. MATERIALS AND METHODS: This double-blind, 3-period crossover study randomized 129 volunteers 65 years or older with no/mild cognitive impairment to receive 3 of 5 treatments, namely darifenacin controlled release (3.75, 7.5 or 15 mg once daily), darifenacin immediate-release (5 mg 3 times daily) or matching placebo for 14 days. Each treatment period was separated by 7 days of washout. Cognitive function tests were completed at baseline and at treatment end. RESULTS: For the primary end points of memory scanning sensitivity, speed of choice reaction time and word recognition sensitivity, there were no statistically significant differences for darifenacin vs placebo. There were no statistically significant differences in secondary variables except memory scanning speed, which increased in all groups relative to baseline, but improvement was greater with placebo than with 3.75 mg darifenacin. Darifenacin treatment was not associated with changes in alertness, contentment or calmness, which are likely to be clinically relevant. Darifenacin was well tolerated. CONCLUSIONS: : In elderly volunteers 2 weeks of treatment with darifenacin had no effect on cognitive function compared with baseline and it was not significantly different from placebo. This may be related to its M3 receptor selectivity with negligible M1 receptor antagonism.

Aged↗

PubMed2004

In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats.

Solifenacin succinate [YM905; (+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate] is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. The aim of the present study was to evaluate the in vitro and in vivo bladder selectivity profile of solifenacin over salivary gland in the same animal species, and to compare the results with those obtained for tolterodine, oxybutynin, darifenacin and atropine. Solifenacin and the other antimuscarinic drugs inhibited carbachol-induced increases in intracellular Ca(2+) levels in bladder smooth muscle cells and salivary gland cells isolated from rats in a concentration-dependent manner. The inhibitory effect of solifenacin for bladder smooth muscle cells (pK(i)=8.12) was 3.6-fold more potent than that for salivary gland cells (pK(i)=7.57). In contrast, the inhibitory effects of the other antimuscarinic drugs for bladder smooth muscle cells were 1.7- to 2.2-fold more potent than those for salivary gland cells. In anesthetized rats, solifenacin dose-dependently inhibited carbachol-induced intravesical pressure elevation and salivary secretion, and exhibited functional selectivity (3.7- to 6.5-fold) for urinary bladder over salivary gland. Tolterodine was also 2.2- to 2.4-fold more selective in inhibition of bladder response. In contrast, oxybutynin, darifenacin and atropine did not show functional selectivity for urinary bladder. These results indicate that solifenacin exerts greater selectivity for urinary bladder over salivary gland than tolterodine, oxybutynin, darifenacin and atropine, and may consequently provide symptomatic benefit in the treatment of overactive bladder with less dry mouth than currently used antimuscarinic drugs.

Animals↗

PubMed2006

Pain during ice water test distinguishes clinical bladder hypersensitivity from overactivity disorders.

BACKGROUND: The Bladder cooling reflex (BCR) i.e. uninhibited detrusor contractions evoked by intravesical instillation of cold saline, is a segmental reflex believed to be triggered by menthol sensitive cold receptors in the bladder wall, with the afferent signals transmitted by C fibres. The BCR is a neonatal reflex that becomes suppressed by descending signals from higher centres at approximately the time when the child gains full voluntary control of voiding. It re-emerges in adults with neurogenic detrusor overactivity as a consequence of loss of central descending inhibition, resulting from conditions such as spinal cord injury or multiple sclerosis. We have recently shown an increase of nerve fibres expressing the cool and menthol receptor TRPM8 in both overactive (IDO) and painful bladder syndrome (PBS), but its functional significance is unknown. We have therefore studied the bladder cooling reflex and associated sensory symptoms in patients with PBS and overactivity disorders. METHODS: The BCR, elicited by ice water test (IWT) was performed in patients with painful bladder syndrome (PBS, n = 17), idiopathic detrusor overactivity (IDO, n = 22), neurogenic detrusor overactivity (NDO, n = 4) and stress urinary incontinence (as controls, n = 21). The IWT was performed by intravesical instillation of cold saline (0 - 4 degrees C). A positive IWT was defined as presence of uninhibited detrusor contraction evoked by cold saline, associated with urgency or with fluid expulsion. Patients were asked to report and rate any pain and cold sensation during the test. RESULTS: A positive IWT was observed in IDO (6/22, 27.3%) and NDO (4/4, 100%) patients, but was negative in all control and PBS patients. Thirteen (76.5%) PBS patients reported pain during the IWT, with significantly higher pain scores during ice water instillation compared to the baseline (P = 0.0002), or equivalent amount of bladder filling (100 mls) with saline at room temperature (P = 0.015). None of the control or overactive (NDO/IDO) patients reported any pain during the IWT. CONCLUSION: The BCR in DO may reflect loss of central inhibition, which appears necessary to elicit this reflex; the pain elicited in PBS suggests afferent sensitisation, hence sensory symptoms are evoked but not reflex detrusor contractions. The ice water test may be a useful and simple marker for clinical trials in PBS, particularly for novel selective TRPM8 antagonists.

Adult↗

PubMed2004

Effects of NSAIDs on bladder function in normal and cystitis rats: a comparison study of aspirin, indomethacin, and ketoprofen.

To clarify the potential usefulness of non-steroidal anti-inflammatory drugs, NSAIDs, for patients with overactive bladder, we examined the effect of NSAIDs on urodynamic parameters in normal and cystitis rats and compared their ulcerogenic activity in the gastrointestinal mucosa. Cystometry was performed after administration of the conventional NSAIDs, aspirin, indomethacin, or ketoprofen. Prostaglandin levels were measured in the bladder of cystitis rats pretreated with NSAIDs. Furthermore, the ulcerogenic responses were examined. NSAIDs increased bladder capacity without any effect on micturition pressure in normal rats in the following rank order of potency: ketoprofen > or = indomethacin > or = aspirin. In cystitis rats, bladder capacity was increased and micturition frequency was decreased. The levels of prostaglandin were significantly increased in cystitis rats. All NSAIDs inhibited the increment of prostaglandin levels at doses equal to that effective in the improvement of bladder functions. When administered intraduodenally, both ketoprofen and indomethacin induced lesions in the gastrointestinal mucosa. However, aspirin had no significant effect. We demonstrate that NSAIDs are effective in animal models of disease, most likely by suppressing by prostaglandin synthesis. Since aspirin, in contrast to ketoprofen or indomethacin, did not cause any gastrointestinal lesions, aspirin might be the NSAIDs treatment of choice for overactive bladder.

Animals↗

PubMed2006

[Urological applications of botulinum toxins].

Botulinum toxins (BT) are one of the most powerful poisons in nature. They are responsible for human botulism and constitute a potential chemical weapon, but can also be used as a therapeutic agent. Sphincter, bladder and prostatic injections have been described in urological indications as varied as detrusor-sphincter dyssynergia and neurogenic detrusor hyperactivity, idiopathic overactive bladder symptoms, interstitial cystitis, obstructive voiding disorders related to benign prostatic hyperplasia or chronic prostatitis, and recurrent urethral stricture. This review of the literature presents the results and level of evicence in support of the use of BT in urological indications. Detrusor injections of BT-A constitute an alternative conservative treatment that is effective in the short term (6-12 months) after failure of anticholinergic agents to treat neurogenic detrusor hyperactivity (level 1b). Sphincter injections are effective in the short-term treatment of neurogenic detrusor-sphincter dyssynergia (level 1c). The efficacy observed during preliminary clinical trials of detrusor injections of BT-A for idiopathic overactive bladder symptoms or interstitial cystitis (level 4) and prostatic injections for obstruction related to BPH (level 1c) justifies the major interest raised by this new therapeutic approach. However, these preliminary results must be confirmed by comparative studies on a sufficient number of patients with long-term follow-up before considering the use of this technique in routine clinical practice.

Botulinum Toxins↗

PubMed2003

Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies.

Although patients with multiple sclerosis (MS) are likely to have problems with bladder, bowel and sexual function, these problems have often been neglected in the past. Bladder dysfunction produces symptoms of urgency, frequency and urge incontinence (due to bladder overactivity and incomplete emptying), and is found in up to 75% of patients with MS. The mainstay of drug treatment for neurogenic bladder overactivity is anticholinergic medication, although intravesical treatments have also been proposed, such as the vanilloids and botulinum toxin, as well as sublingual cannibanoids. There has been much progress with pro-erectile agents in recent years, notably the use of sildenafil citrate, which has been shown to be particularly efficacious in these patients. Other agents include apomorphine hydrochloride and newer phosphodiesterase 5 inhibitors; however, the efficacy of these drugs in patients with MS remains to be proven. Research in female sexual dysfunction is also progressing, although this aspect of patient well being has only recently been addressed; the reported development of a classification system for the condition is likely to help categorise future treatments. Unlike bladder and sexual dysfunction, there have been rather limited advances in the treatment of faecal incontinence and constipation specifically for patients with MS, despite a prevalence of up to 50%. This review highlights the strategies for these types dysfunction commonly seen in patients with MS, with report of recent pharmacological developments.

Constipation↗

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↗

PubMed2002

Beta3-adrenoceptors in human detrusor muscle.

The detrusor muscle contains beta-adrenoceptors (beta-AR), and 2 subtypes-beta1-AR and beta2-AR-have been identified in most species. Although beta2-AR has an important role in muscle relaxation via activation of adenylate cyclase, evidence suggests that a third subtype, beta3-AR, which is implicated in metabolic functions of endogenous catecholamines, mediates relaxation of human detrusor muscle. There is a predominant expression of beta3-AR messenger RNA (mRNA) in human bladder tissue, with 97% of total beta-AR mRNA being represented by the beta3-AR subtype and only 1.5% and 1.4% by the beta1-AR and beta2-AR subtypes, respectively. Functionally, selective beta3-AR agonists relax human isolated detrusor, whereas selective beta1-AR/beta2-AR agonists do not. Isoproterenol-induced relaxation is inhibited by selective beta3-AR antagonists but not by selective beta1-AR or beta2-AR antagonists. In animal models, beta3-AR agonists increase bladder capacity and have only weak cardiovascular side effects. Although this evidence points toward the clinical utility of beta3-AR agonists as therapy for overactive bladder, clinical trials of beta3-AR agonists identified in animal models as antiobesity agents indicate side effects of tremor and tachycardia. Development of compounds with high selectivity for the human beta3-AR, identified by screening techniques using cell lines transfected with the human beta1-AR, beta2-AR, and beta3-AR genes, may mitigate such problems. Together with the preliminary finding that 49% (21 of 43) of patients with idiopathic detrusor instability have a tryptophan 64 arginine mutation of the beta3-AR gene, which may be a useful genetic marker, evidence points toward beta3-AR being a therapeutic target for treatment of overactive bladder disorder.

Adrenergic Agonists↗

PubMed2004

[Changes in muscarinic receptors of the aging bladder].

The prevalence of the overactive bladder syndrome (OAB) increases with age. Unfortunately, treatment of the condition is still unsatisfactory. Since muscarinic receptor antagonists are the only effective drug treatment to date, it is logical to assume that muscarinic receptors play an important role in the pathogenesis of OAB. Muscarinic receptors are involved in both the normal and overactive detrusor contraction, and age-dependent changes in muscarinic receptor functions have been found in both animals and human detrusors. In animals as well as humans, two components of detrusor contraction have been demonstrated, the dominating one mediated by muscarinic receptors and the other by ATP (atropine-resistant component). The muscarinic receptor-mediated component decreases with age, and the ATP (purinergic) part increases. However, the clinical consequence of this is unclear, since no major age-dependent changes in the efficacy of antimuscarinic agents in the treatment of OAB have been demonstrated.

Aged↗