Urinary Bladder Hyperactivity Research Articles

Spinal neuron-glia-immune interaction in cross-organ sensitization

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), historically considered as regional gastrointestinal disorders with heightened colonic sensitivity, are increasingly recognized to have concurrent dysfunction of other visceral and somatic organs, such as urinary bladder hyperactivity, leg pain, and skin hypersensitivity. The interorgan sensory cross talk is, at large, termed "cross-organ sensitization." These organs, anatomically distant from one another, physiologically interlock through projecting their sensory information into dorsal root ganglia (DRG) and then the spinal cord for integrative processing. The fundamental question of how sensitization of colonic afferent neurons conveys nociceptive information to activate primary afferents that innervate distant organs remains ambiguous. In DRG, primary afferent neurons are surrounded by satellite glial cells (SGCs) and macrophage accumulation in response to signals of injury to form a neuron-glia-macrophage triad. Astrocytes and microglia are major resident nonneuronal cells in the spinal cord to interact, physically and chemically, with sensory synapses. Cumulative evidence gathered so far indicate the indispensable roles of paracrine/autocrine interactions among neurons, glial cells, and immune cells in sensory cross-activation. Dichotomizing afferents, sensory convergency in the spinal cord, spinal nerve comingling, and extensive sprouting of central axons of primary afferents each has significant roles in the process of cross-organ sensitization; however, more results are required to explain their functional contributions. DRG that are located outside the blood-brain barrier and reside upstream in the cascade of sensory flow from one organ to the other in cross-organ sensitization could be safer therapeutic targets to produce less central adverse effects.

Alternative Methods for Testing Botulinum Toxin: Current Status and Future Perspectives.

Botulinum toxins are neurotoxic modular proteins composed of a heavy chain and a light chain connected by a disulfide bond and are produced by Clostridium botulinum. Although lethally toxic, botulinum toxin in low doses is clinically effective in numerous medical conditions, including muscle spasticity, strabismus, hyperactive urinary bladder, excessive sweating, and migraine. Globally, several companies are now producing products containing botulinum toxin for medical and cosmetic purposes, including the reduction of facial wrinkles. To test the efficacy and toxicity of botulinum toxin, animal tests have been solely and widely used, resulting in the inevitable sacrifice of hundreds of animals. Hence, alternative methods are urgently required to replace animals in botulinum toxin testing. Here, the various alternative methods developed to test the toxicity and efficacy of botulinum toxins have been briefly reviewed and future perspectives have been detailed.

Аденілатна система еритроцитів щурів з гіперактивним сечовим міхуром за умов його корекції лікарськими засобами гормональної енерготропної дії

Аденілатна система еритроцитів щурів з гіперактивним сечовим міхуром за умов його корекції лікарськими засобами гормональної енерготропної дії

Human T-Lymphotropic Virus, Associated Myelopathy and Leukemia: A Review

Human T Lymphotronic Virus type 1 was the first retrovirus discovered associated with fatal diseases in humans and said to have emerged following zoonotic transmission from simian populations. Their primary target is adult CD4 T-cells and most infected individuals are asymptomatic. However, a significant number may develop persistent infection and progress to an aggressive lymphoproliferative disease, known as Adult T-cell Leukemia/Lymphoma-ATLL. Some may develop a debilitating neuro-inflammatory disease called Tropical Spastic Paraparesis-TSP, predominantly involving the lower limbs, with or without hyperactive urinary bladder. Unprotected sexual intercourse and breastfeeding account for the highest number of cases and is also transmitted by uncheck blood transfusion or sharing of contaminated sharps. ATLL and TSP are life-threatening diseases initially restricted to Middle East and some parts of Africa, but recently, cases are being reported in many parts of the world. Unfortunately, even though the antiretroviral therapy have greatly improved and significantly reduced HIV progression to AIDS, such great break through is not worthy benefit for HTLV infected individuals. Thus, they are identified as severe human diseases of public health concern. This review is an overview and contains update about the biology of the virus, its interaction with the host, HAM/TSP and ATLL; their epidemiology and clinical presentations.

Addition of Neostigmine and Atropine to Conventional Management of Postdural Puncture Headache: A Randomized Controlled Trial.

Postdural puncture headache (PDPH) lacks a standard evidence-based treatment. A patient treated with neostigmine for severe PDPH prompted this study. This randomized, controlled, double-blind study compared neostigmine and atropine (n = 41) versus a saline placebo (n = 44) for treating PDPH in addition to conservative management of 85 patients with hydration and analgesics. The primary outcome was a visual analog scale score of ≤3 at 6, 12, 24, 36, 48, and 72 hours after intervention. Secondary outcomes were the need for an epidural blood patch, neck stiffness, nausea, and vomiting. Patients received either neostigmine 20 μg/kg and atropine 10 μg/kg or an equal volume of saline. Visual analog scale scores were significantly better (P< .001) with neostigmine/atropine than with saline treatment at all time intervals after intervention. No patients in the neostigmine/atropine group needed epidural blood patch compared with 7 (15.9%) in the placebo group (P< .001). Patients required no >2 doses of neostigmine/atropine. There were no between-group differences in neck stiffness, nausea, or vomiting. Complications including abdominal cramps, muscle twitches, and urinary bladder hyperactivity occurred only in the neostigmine/atropine group (P< .001). Neostigmine/atropine was effective in treating PDPH after only 2 doses. Neostigmine can pass the choroid plexus but not the blood-brain barrier. The central effects of both drugs influence both cerebrospinal fluid secretion and cerebral vascular tone, which are the primary pathophysiological changes in PDPH. The results are consistent with previous studies and clinical reports of neostigmine activity.

Main risk factors symptoms of manifestation of urinary incontinence in childbearing age women with overactive bladder syndrome

Since many factors can affect the manifestation of urinary disorders in a particular woman at different periods of life, some of them can cause urinary incontinence, affect the choice of method and the success of treatment. Syndrome of a hyperactive bladder is, in addition to medical, a serious socio-economic problem and leads to social disadaptation of the individual. The aim of research was to identify predictors (provoking, contributing factors or risk factors) of hyperactive urinary bladder syndrome in pregnant women of different age groups in early stages of pregnancy. A total of 75 pregnant women with a hyperactive bladder syndrome (the main group) and 60 practically healthy pregnant women with no incontinence (control group) at the gestation period of 12 weeks were examined. It was determined that in the general group of women with hyperactive urinary bladder the working, with satisfactory and unsatisfactory economic conditions prevailed. Among occupational hazards, 61,3% of pregnant women noted permanent physical activity, forced delay in urination (44%), prolonged orthostatic body position (20,0%), and significant physical activity (29,3 %). It was found that among pregnant women more extragenital pathology, almost all women smoke (93,3%) and drink alcohol often enough (89,3 %), besides the length of smoking is much larger, compared with the swearing smokers of practically healthy women. It was found that in the hyperactive bladder group, unsatisfactory family relationships (58,7%) predominate, resulting in more single women. The overwhelming majority of women with hyperactive urinary bladder begin their sexual life up to 14 years old and have more than 4 sexual partners, which, in combination with contraception in the form of interrupted sexual intercourse, leads to an increase in the third and fourth degree of vaginal purity, as well as the appearance of more bacterial vaginosis and diseases in women with hyperactive urinary bladder, sexually transmitted infections. It was established that in the main group all the indicators of anesthetic history prevail in comparison with the main group. In the general group, the majority of pregnant women associated with the emergence of hyperactive bladder with pregnancy and childbirth (40%), a large weight of the fetus (18,3%); 14,7% of women were considered to be the reason for motility disorders, which were postponed during the lunar and gestational periods; 13.7% of urinary incontinence appeared after a change in sexual partner, and also after sexual intercourse (13,3%). The results of the research indicate that a survey of diseases such as hyperactive bladder syndrome requires a comprehensive approach by carefully collecting the socioeconomic status, style and quality of life, extragenital diseases, family, obstetric-gynecological and hereditary history, as well as sexual function women in the reproductive period.

Взаємозв’язок між станом детрузора і тонусом товстої кишки та їхнім сфінктерним апаратом у жінок з гіперактивним сечовим міхуром

The objective: increase the effectiveness of diagnosis and treatment of women with a hyperactive bladder, combined neurogenic pathology of the lower urinary tract and distal colon. Patients and methods. The study included 73 women. In assessing the symptoms of clinical manifestations and EMG and UFS data, two groups of patients were identified: the first group – women with increased tone of the neuro-muscular structures of the hyperkinetic type; the second group - women with an increased tone of the neuromuscular structures of the hypokinetic type. In the first group, 37 women were examined, whose mean age was 44.5±2.3 years, and the duration of the disease was 16.7±1.6 months. The second group included 36 women, whose average age was 43.4±2.1 years, and the average duration of the disease was 19.7±1.5 months. Results. The performed treatment showed clinically high efficiency of electrostimulation application depending on the state of the tone of the neuromuscular structures of the lower urinary tract and the distal part of the large intestine, which is confirmed by the data of UFS and EMG. Conclusion. The obtained data allowed to develop and optimize methods of treatment of women with hyperactive urinary bladder with a combined neurogenic pathology of the lower urinary tract and distal division of the large intestine. Key words: neurogenic disorders in urination, intestine neurogenic dysfunction, detrusor, uroflowmetry, electromyography.

Treatment of patients with hyperactive urinary bladder with hyperkinetic detrusor tone and combined neurogenic pathology of the distal colon

The objective : to improve the efficiency of treatment of patients with overactive bladder detrusor tone hyperkinetic and combined neurogenic disorders of the distal colon. Patients and methods. Complex diagnostics and treatment was performed by 70 patients with hyperactive bladder with hyperkinetic tone of detrusor and distal colon. Of these 33 men, mean age 42.7±2.2 years old with duration of illness 13.4±1.2 months and 37 women, mean age 44.5±2.3 years, and disease duration – 16 , 7±1.6 months. All the patients in order to diagnose and monitor the effectiveness of treatment to start, after the first, third, sixth and courses conducted urofloumetrichnoe electromyographic examination of the bladder and the distal colon and sphincter apparatus. Conservative therapy included conducting stimulation by stimulation. Results . Evaluation results of the effectiveness of treatment of patients with overactive bladder detrusor hyperkinetic tone and combined neurogenic pathology distal colon efficacy analysis was performed using modifications of the dynamics complaints data questionnaires uroflowmetry, electromyography. Conclusion . The data obtained allowed us to develop and optimize the treatment of patients with overactive bladder with detrusor hyperactivity tone and combined neurogenic disorders of the distal colon.

Dynamics of changes in the parameters of electromyography in the treatment of hyperactive urinary bladder with hyperkinetic tone of the detrusor and the distal part of the colon

Dynamics of changes in the parameters of electromyography in the treatment of hyperactive urinary bladder with hyperkinetic tone of the detrusor and the distal part of the colon

THERAPY OF HYPERACTIVE URINARY BLADDER: EXPANSION OF HORIZONS

Hyperactive urinary bladder (HUB) is one of the most frequent disturbances of the urination. Hyperactive urinary bladder (HUB) is a syndrome characterized by presence of imperative uriesthesia accompanied and not accompanied by urgent urinary incontinence usually in combination with frequent urination and nocturia with proved lack of infection and other evident pathologic changes. Pharmacotherapy is a priority method of HUB therapy. The major group of drugs is m-cholinblockers (tolterodine, oxybutinine, trospium chloride, solifenacin). Solifenacin is a modern and effective drug for therapy of HUB that has limitations on indications such as closed- ngle glaucoma, retention of urine, grave gastrointestinal diseases, myasthenia gravis. Mirabegron is the first β3-adrenoreceptor antagonist for therapy of HUB that proved its effectiveness in patients ho previously received therapy by m-cholinolytics. Mirabegron can be used at glaucoma and myasthenia, it doesn’t cause acute urine retention.

The medical rehabilitation of the children presenting with the hyperactive urinary bladder

The present article is focused on the modern technologies for the medical rehabilitation of the children presenting with the hyperactive urinary bladder (UB) designed to promote the act of urination in the children at all levels of bladder innervation.

Effect of Ovariectomy on External Urethral Sphincter Activity in Anesthetized Female Rats

The postmenopausal hypoestrogen condition is associated with various lower urinary tract dysfunctions, including frequency, urgency, stress urinary incontinence and recurrent urinary infection. We determined whether hypoestrogen induced lower urinary tract dysfunction after ovariectomy is also associated with an alteration in external urethral sphincter activity. Bilateral ovariectomy was performed in female Sprague-Dawley® rats and sham operated rats served as controls. Transvesical cystometry and external urethral sphincter electromyogram activity were monitored 4, 6 and 12 weeks after sham operation or bilateral ovariectomy and at 6 weeks in bilaterally ovariectomized rats treated with estrogen. The micturition reflex was elicited in sham operated and bilaterally ovariectomized, urethane anesthetized animals. Post-void residual urine increased and voiding efficiency decreased in rats with 4 to 12 weeks of bilateral ovariectomy. The silent period of external urethral sphincter electromyogram activity was shortened significantly and progressively at increased times after bilateral ovariectomy. These effects were prevented by estradiol treatment. As evidenced by shortening of the external urethral sphincter electromyogram silent period in ovariectomized rats, the disruption of coordination between the external urethral sphincter and the detrusor muscle could decrease urine outflow and in turn voiding efficiency. Estrogen replacement reverses these changes, suggesting that the central pathways responsible for detrusor-sphincter coordination are modulated by gonadal hormones.

Effects of β3-Adrenergic Receptor Activation on Rat Urinary Bladder Hyperactivity Induced by Ovariectomy

Voiding dysfunctions, including increased voiding frequency, urgency, or incontinence, are prevalent in the postmenopausal population. Beta(3)-adrenergic receptor (beta(3)AR) agonists, which relax bladder smooth muscle, are being developed to treat these conditions. We utilized the rat ovariectomy (OVX) model to investigate the effect of ovarian hormone depletion on bladder function and the potential for beta(3)AR agonists to treat bladder hyperactivity in this setting. OVX increased voiding frequency and decreased bladder capacity by approximately 25% in awake rats and induced irregular cystometrograms in urethane-anesthetized rats. Reverse transcription-polymerase chain reaction revealed three betaARs subtypes (beta(1,2,3)) in bladder tissue, and immunostaining indicated beta(3)AR localization in urothelium and detrusor. Receptor expression was not different in OVX and SHAM rats. The beta(3)AR agonist selectivity of BRL37344 [(+/-)-(R(*),R(*))-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid sodium hydrate], TAK-677 [(3-((2R)-(((2R)-(3-chlorophenyl)-2-hydroxyethyl)amino)propyl)-1H-indol-7-yloxy)acetic acid], and FK175 [acetic acid, 2-[[(8S)-8-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]oxy], ethyl ester, hydrochloride] was confirmed by examining the relative potency for elevation of cAMP in CHOK1 cells overexpressing the various rat betaARs. Intravenous injection of each of the beta(3)AR agonists (0.1-500 microg/kg) in anesthetized rats decreased voiding frequency, bladder pressure, and amplitude of bladder contractions. In bladder strips, beta(3)AR agonists (10(-12)-10(-4) M) decreased baseline tone and reduced spontaneous contractions. BRL37344 (5 mg/kg) and TAK-677 (5 mg/kg) injected intraperitoneally in awake rats decreased voiding frequency by 40 to 70%. These effects were not altered by OVX. The results indicate that OVX-induced bladder dysfunction, including decreased bladder capacity and increased voiding frequency, is not associated with changes in beta(3)AR expression or the bladder inhibitory effects of beta(3)AR agonists. This suggests that beta(3)AR agonists should prove effective for the treatment of overactive bladder symptoms in the postmenopausal population.

ATP released from the urothelium contributes to bladder hyperactivity induced by acetic acid in the rat

Event Abstract Back to Event ATP released from the urothelium contributes to bladder hyperactivity induced by acetic acid in the rat Jose E. Marinhas1*, D. Monteiro1, N. Silva1, M. Faria1, M. Duarte-Araujo1, M. Silva-Ramos1, 2 and P. Correia-de-Sa1 1 Instituto de Ciencias Biomedicas Abel Salazar - Universidade do Porto (ICBAS-UP), Laboratorio de Farmacologia e Neurobiologia, Unidade Multidisciplinar de Investigacao Biomedica (UMIB), Portugal 2 CHP - HGSA, Serv. Urologia, Portugal The bladder epithelium releases ATP in response to mechanical stimuli (and to chemical irritants), which may activate suburothelial sensory nerve fibers. Although the pathogenic mechanisms of bladder overactivity (OAB) are not fully understood, atropine-resistant purinergic reactivity increases in these patients (e.g. interstitial cystitis). Therefore, we aimed at investigating ATP release from the urothelium and the effects of this purine on bladder pressure and pelvic nerve activity in a in vivo rat model of hyperactive urinary bladder. Irritative cystometry (produced by the infusion of acetic acid, AA, 0.2-1% v/v) has been used to investigate new therapies from OAB.AA (0.2-1%, for 15 min) concentration-dependently decreased the time (ICI, 67 to 81% of control) and the pressure threshold (PTh, 58 to 85% of control) for appearance of the micturition reflex. Using the luciferin- luciferase luminescence assay (Enliten ATP kit, Promega, USA), we showed that urinary ATP increased (52±7%, n=5) following the micturition reflex. The concentration of urinary ATP was significantly (P<0.05) enhanced in the presence of AA (1%, 297±25%, n=3), while the activity of urinary lactate dehydrogenase (LDH) remained unchanged. Increases in the voiding frequency caused by AA (0.2%) were enhanced by intravesical infusion of the P2X1 and P2X3 agonist, alpha,beta-methyleneATP (30 μM), and of the ecto- ATPase inhibitor, ARL67156 (200 μM). PPADS, applied either by intravesical infusion (30 μM) or by intravenous bolus (17 μmol/Kg), reduced AA-induced bladder hyperactivity. However, in contrast to alpha,beta-methyleneATP (30 μM), PPADS also decreased the contraction amplitude. Blockade of ADP- sensitive P2Y1 receptors with MRS2179 (1 μmol/Kg, i.v.) increased the voiding frequency secondary to AA (0.2 %), but it was devoid of effect on the contraction amplitude.Although there is extensive literature indicating that many different types of purinoceptors are present in the lower urinary tract, the pathophysiological role of these receptors in OAB is still uncertain. Our results showed that ATP released from the urothelium play a role on bladder hyperactivity induced by intravesical infusion of acetic acid and that different subtypes of P2 purinoceptors regulate afferent nerve activity (P2X2/3 and P2Y1) and smooth muscle contractions (probably P2X2).Work supported by FCT, Soc. Port. Urologia and Univ. Porto / Caixa Geral de Depósitos. Conference: 11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009. Presentation Type: Poster Presentation Topic: Neuronal Communication Citation: Marinhas JE, Monteiro D, Silva N, Faria M, Duarte-Araujo M, Silva-Ramos M and Correia-de-Sa P (2009). ATP released from the urothelium contributes to bladder hyperactivity induced by acetic acid in the rat. Front. Neurosci. Conference Abstract: 11th Meeting of the Portuguese Society for Neuroscience. doi: 10.3389/conf.neuro.01.2009.11.148 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 12 Aug 2009; Published Online: 12 Aug 2009. * Correspondence: Jose E Marinhas, Instituto de Ciencias Biomedicas Abel Salazar - Universidade do Porto (ICBAS-UP), Laboratorio de Farmacologia e Neurobiologia, Unidade Multidisciplinar de Investigacao Biomedica (UMIB), Porto, Portugal, josemarinhas@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jose E Marinhas D. Monteiro N. Silva M. Faria M. Duarte-Araujo M. Silva-Ramos P. Correia-de-Sa Google Jose E Marinhas D. Monteiro N. Silva M. Faria M. Duarte-Araujo M. Silva-Ramos P. Correia-de-Sa Google Scholar Jose E Marinhas D. Monteiro N. Silva M. Faria M. Duarte-Araujo M. Silva-Ramos P. Correia-de-Sa PubMed Jose E Marinhas D. Monteiro N. Silva M. Faria M. Duarte-Araujo M. Silva-Ramos P. Correia-de-Sa Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

OP-068 New method for urinary bladder hyperactivity induced by acetic acid in conscious rats(The 97th Annual Meeting of the Japanese Urological Association)

OP-068 New method for urinary bladder hyperactivity induced by acetic acid in conscious rats(The 97th Annual Meeting of the Japanese Urological Association)

A new method for producing urinary bladder hyperactivity using a non-invasive transient intravesical infusion of acetic acid in conscious rats

Introduction Animal models that closely resemble the pathophysiology of human overactive bladder are important for evaluating novel therapeutics to treat the disorder. We established a non-invasive hyperactive bladder model that is sensitive to anti-muscarinic drugs and without bladder inflammation. Methods Acetic acid solution was infused into the bladder for 5 min via the urethral orifice without any surgical procedures under isoflurane anaesthesia. After washing the bladder with saline, voiding frequency (VF) and total urine volume were determined for 9 h under conscious conditions. Results Infusion of a 0.5% acetic acid solution caused a significant increase in VF, without influencing total urine volume or inducing significant histopathological inflammatory alterations in the bladder urothelium. Oral administration of oxybutynin (3 and 10 mg/kg) significantly ameliorated increases in VF induced by 0.5% acetic acid. Infusion of 0.75% acetic acid induced intensive urinary inflammation and a decrease in total urine volume as well as an increase in VF. Oral treatment with oxybutynin (10 mg/kg) did not significantly improve the increased VF due to 0.75% acetic acid. Acetic acid (0.5%) infusion evoked bladder hyper-responsiveness whether applied at night or during the day. However, VF was increased more by the nighttime application of acetic acid, while there were no significant differences in basal levels of VF between daytime and nighttime. Discussion In this study, the non-invasive rat urinary hyperactive bladder model indicated minimizes the secondary effects of experimental procedures such as surgical operations and anesthesia on bladder function and is sensitive to oxybutynin. Thus, the model may be useful for investigating novel therapeutics for OAB treatment.

Rho-Kinase Inhibition Suppresses Potassium Chloride-Induced Bladder Hyperactivity in a Rat Model

The molecular mechanisms by which potassium induces urinary bladder hyperactivity are not clear. In the present study, we tested our hypothesis that potassium chloride (KCl)-induced bladder hyperactivity might be mediated through a calcium-sensitizing RhoA-Rho-kinase pathway in an in vivo animal model using urodynamic parameters. Two groups of adult male rats (n = 8) were anesthetized, their bladder exteriorized, and a saline-filled Intracath fixed into the bladder dome. This Intracath was connected to a pressure transducer and an infusion pump. Continuous filling cystometrograms were performed by infusing warm saline (0.04 mL/min) to obtain baseline data on each rat. The number of contractions per unit time (intercontractile intervals in seconds), pressure threshold, and peak pressure during micturition were recorded. To create bladder hyperactivity, protamine sulfate (30 mg/mL) followed by KCl (500 mM) was infused intravesically, and a continuous filling cystometrogram was again recorded. Y-27632, a specific RhoA-Rho-kinase inhibitor, was administered either intra-arterially (group 1) or intravesically (group 2) to each rat, and an additional continuous filling cystometrogram was recorded with KCl (500 mM) to observe the effects of Rho-kinase inhibition on bladder contractility. Intravesical KCl infusion after protamine exposure resulted in significantly greater contractions and decreased the intercontractile interval (P <0.05). Y-27632 administration attenuated the effect of KCl on the contractions and intercontractile interval and decreased the mean pressure threshold. Suppression of KCl-induced bladder contractility by the Rho-kinase inhibitor Y-27632 confirmed the involvement of this novel calcium-sensitizing RhoA-Rho-kinase pathway in mediating these smooth muscle contractions.

Different brain effects during chronic and acute sacral neuromodulation in urge incontinent patients with implanted neurostimulators

To compare changes in regional cerebral blood flow (rCBF), using positron emission tomography (PET), during chronic and acute sacral neuromodulation (SN). SN is an effective long-term treatment for chronic urge incontinence due to urinary bladder hyperactivity, as sensory nerves, spinal and supraspinal structures are probably responsible for the action of SN. It is not known which brain areas are involved, and the optimum benefit of SN is not immediate, suggesting that induced plasticity of the brain is necessary. Brain activity was measured in two groups: 12 urge incontinent patients (11 women and one man; mean age 52 years) in whom an implanted unilateral S3 nerve neurostimulator had been effective for >6 months (mean time after implantation 4.5 years); and eight urge incontinent patients (seven women and one man; mean age 49 years) in whom the neurostimulator was activated for the first time in the PET scanner. During SN in chronically implanted patients, there were significant decreases in rCBF in the middle part of the cingulate gyrus, the ventromedial orbitofrontal cortex, midbrain and adjacent midline thalamus, and rCBF increases in the dorsolateral prefrontal cortex. During acute SN in newly implanted patients, there were significant decreases in rCBF the medial cerebellum, and increases in the right postcentral gyrus cortex, the right insular cortex and the ventromedial orbitofrontal cortex. Group analysis between chronic and newly implanted patients showed significant differences in the associative sensory cortex, premotor cortex and the cerebellum, all three involved in learning behaviour. These findings suggests that chronic SN influences, presumably via the spinal cord, brain areas previously implicated in detrusor hyperactivity, awareness of bladder filling, the urge to void and the timing of micturition. Furthermore, SN affects areas involved in alertness and awareness. Acute SN modulates predominantly areas involved in sensorimotor learning, which might become less active during the course of chronic SN.

A rat model for studying effects of sacral neuromodulation on the contractile activity of a chronically inflamed bladder.

To develop an animal model in which the effects of electrical stimulation of the sacral nerves (sacral neuromodulation) on a chronic hyperactive urinary bladder can be studied. In female rats the urinary bladder was instilled with mustard oil (0.4%); after 10 days the animals were anaesthetized with intraperitoneal urethane, the bladder catheterized and connected to a pressure transducer. Stimulating electrodes were placed into the sacral foramina bilaterally. The intensity and duration of sacral electrical stimulation was varied systematically to determine the effects of the sacral neuromodulation on bladder contractions. The main effect of the neuromodulation was an increase in the interval between contractions, i.e. during and for some time after the stimulation the contractions were completely abolished. The duration of the pause increased with the intensity and duration of stimulation. After the contractions had reappeared the frequency of contractions was reduced for a long period. In animals with chronic cystitis the effects of neuromodulation tended to be stronger (the pauses were longer) than in control animals with an intact bladder, but only in one test (increase of pause length with stimulus duration) was the difference statistically significant. The results show that this animal model is suitable for studying the effects and mechanisms of sacral neuromodulation on a chronic hyperactive urinary bladder.

Effects of ZD6169, a K ATP channel opener, on bladder hyperactivity and spinal c- fos expression evoked by bladder irritation in rats

Cystometrographic recording and immunocytochemical techniques were used to examine the effects of ZD6169, an ATP-sensitive K +-channel opener, and capsaicin, an afferent neurotoxin, on urinary bladder hyperactivity and immediate early gene expression in the spinal cord induced by acetic acid (0.25%) irritation of the bladder. Chemical irritation of the bladder of the rat increased the frequency of voiding reflexes by 8 fold and increased c- fos expression in neurons in the dorsal commissure (DCM), sacral parasympathetic nucleus (SPN) as well as the medial and lateral dorsal horn (MDH, LDH) of L 6 and S 1 segments of the spinal cord. Pretreatment with ZD6169 (30 nM) for 1 h reduced the effect of acetic acid on voiding frequency as reflected by an increase in the intercontraction interval (ICI, 137±48% increase, P<0.05). ZD6169 also decreased the number of Fos positive neurons in the L 6 spinal cord, in the DCM (62.1±7.1% decrease), SPN (48.8±7%), MDH (50±7.3%) and LDH regions (38.8±10.5%). Similar reductions were noted in the S 1 spinal cord: 65.1±10.8% in DCM, 53.8±11% in SPN, 56±10.4% in MDH and 25.3±18.1% in LDH. Capsaicin pretreatment (125 mg/kg, s.c., 4 days prior to the experiments) also reduced bladder hyperactivity (550% increase in ICI) and decreased the numbers of acetic acid-induced Fos positive neurons 78.8±6.3% in DCM, 73±7.8% in MDH, 59.2±16% in LDH and 45.2±17% in SPN of L 6 segment of the spinal cord. These results suggest that ZD6169 can influence bladder hyperactivity by suppressing the firing of capsaicin-sensitive C-fiber bladder afferents which are known to modulate the micturition reflex.