Voiding Cycle Research Articles

Integration of spectroscopy and imaging to optimize evaluation of voiding dysfunction

Voiding dysfunction occurs due to the interplay of anatomic, physiologic and functional elements. Hence, integration of new imaging and spectroscopy modalities offers the potential for improving patient assessment by enabling the causal structural defects, formal staging of pelvic floor dysfunction and underlying physiologic mechanisms to be better defined. The purpose of this review is to outline the limitations of current imaging, and highlight the advantages of newer technologies in the evaluation of patients with voiding dysfunction due to loss of structural integrity of the pelvic floor. The everyday action of voiding belies the complex interplay of neural control of the voiding cycle, precise function of healthy organ systems and hemodynamic changes in the microcirculation required for the bladder to fill and empty normally. Brain mediated control initiates voluntary voiding, and integrity of the spinal cord is required to transmit neural signaling to the bladder. A spino-bulbo-spinal reflex is integral to voluntary voiding while urine storage is dependent on lumbosacral spinal reflexes (27). The bladder microcirculation is uniquely adapted to maintain perfusion as the organ's size and wall thickness alter as it fills and empties, and to preferentially perfuse the detrusor muscle prior to bladder contraction. The structure of the pelvic floor is integral to continence; with incontinence in various forms a consequence of the effects of damage, structural weakness or organ prolapse. Urinary incontinence due to loss of pelvic floor integrity is a complex condition. With aging and the effects of illness and injury the normal supportive function of the pelvic floor muscles, ligaments and fascia becomes compromised. Progressive reduction or traumatic loss of soft tissue support results in pelvic organ prolapse (POP), which is a prevalent and debilitating disorder (25). POP is part of the spectrum of abnormalities occurring with pelvic floor dysfunction (35). POP is defined as abnormal symptomatic displacement of the pelvic organs from their normal anatomic position; herniation of some or all of the pelvic viscera occurs, including the urethra, bladder, vaginal vault, cervix, small bowel,

S-Nitrosoglutathione protects the spinal bladder: novel therapeutic approach to post-spinal cord injury bladder remodeling.

Bladder and renal dysfunction are secondary events of the inflammatory processes induced by spinal cord injury (SCI). S-Nitrosoglutathione (GSNO), an endogenous nitrosylating agent is pleiotropic and has anti-inflammatory property. Hence, GSNO ameliorates inflammatory sequelae observed in bladder and renal tissues after SCI. Thus, we postulate that GSNO will improve the recovery of micturition dysfunction by quenching the bladder tissue inflammation associated with SCI. Contusion-based mild SCI was induced in female Sprague-Dawley rats. Sham operated rats served as the controls. SCI rats were gavaged daily with GSNO (50 µg/kg) or vehicle. Bladder function was assessed by urodynamics at 2 and 14 days following SCI. Urine protein concentration and osmolality were measured. Bladder and kidney tissues were analyzed by histology and immunofluorescence for a variety of endpoints related to inflammation. Two days after SCI, urodynamics demonstrated a hyperreflexive bladder with overflow and no clear micturition events. By Day 14, vehicle animals regained a semblance of a voiding cycle but with no definite intercontraction intervals. GSNO-treated SCI-rats showed nearly normal cystometrograms. Vehicle-treated SCI rats had increased bladder wet weight, proteinuria, and urine osmolality at Day 14, which was reversed by GSNO treatment. In addition, the SCI-induced increase in immune cell infiltration, collagen deposition, iNOS, and ICAM-1 expression and apoptosis were attenuated by GSNO. These results indicate that oral administration of GSNO hastens the recovery of bladder function after mild contusion-induced SCI through dampening the inflammation sequelae. These findings also suggest that GSNO-mediated redox modulation may be a novel therapeutic target for the treatment of mild SCI-induced renal and bladder dysfunction.

Comparison of ambulatory versus video urodynamics in patients with spinal cord injury

To compare the data obtained through video urodynamics (VUD) with those obtained through one voiding cycle ambulatory urodynamics monitoring (AUM) in patients with spinal cord injury (SCI). A comparative study was conducted in 69 patients with SCI (mean age±s.d. 44±16.9 years), 51 men and 18 women, who were subjected to AUM and VUD. A lack of agreement was observed between the two tests with respect to the cystometric capacity (CC) (ml) (275±197.2 AUM versus 416±198.3 VUD), filling pressure (cm H2O) (4±5.3 AUM versus 9±12.5 VUD), bladder compliance (ml cm(-1) H2O) (116±114.9 AUM versus 161±179.4 VUD), maximum detrusor contraction pressure (cm H2O) (87±65.2 AUM versus 47±35.0 VUD), post-void residual (ml) (206±201.5 AUM versus 308±237.7 VUD) and stress urinary incontinence (kappa index: -0.052). Only the CC obtained in the AUM was in agreement with the mean bladder volume gathered from the frequency-volume chart. Agreement was observed with respect to the presence of neurogenic detrusor overactivity (kappa index: 0.307) and bladder outlet obstruction index (cm H2O) (17±48.0 AUM versus 15±18.7 VUD). There was no clear association between AUM parameters and bladder neck morphology, the presence of radiological detrusor-external sphincter dyssynergy or vesicoureteral reflux observed in the VUD. The differences between both methods discourage the use of AUM with just one voiding cycle in the evaluation of patients with SCI.

Changes in the Function and Expression of T-Type and N-Type Calcium Channels in the Rat Bladder after Bladder Outlet Obstruction

We evaluated possible changes in the function and expression of T-type and N-type Ca(2+) channels in the bladder of rats with bladder outlet obstruction. Female Sprague Dawley® rats were divided into a group with bladder outlet obstruction created by partial urethral ligation and a sham operated group. Six weeks postoperatively we determined the mRNA expression of T-type and N-type Ca(2+) channels in the bladder, dorsal root ganglion and spinal cord. We also cystometrically investigated expression by intravenous administration of the T-Ca blocker RQ-00311610 or the N-type Ca(2+) channel blocker ω-conotoxin GVIA. We then performed in vitro functional studies of detrusor strips using these blockers. mRNA expression of T-type Ca(2+) channels in the bladder detrusor and mucosa layers, and the spinal cord dorsal horn, and N-type Ca(2+) channels in the whole bladder and detrusor layer, and the spinal cord dorsal horn was greater in the obstructed group than the sham operated group. In obstructed rats bladder capacity and voided volume increased after RQ-00311610 administration but the number of nonvoiding contractions decreased after ω-conotoxin GVIA administration. Detrusor strips from obstructed rats showed weaker contractile responses to electrical field stimulation, particularly in regard to the purinergic component. ω-Conotoxin GVIA suppressed electrical field stimulation induced contractions only in the detrusor of obstructed rats, especially the cholinergic component. Blocking T-type Ca(2+) channels increased bladder capacity while N-type Ca(2+) channel blockade inhibited nonvoiding contractions in rats with bladder outlet obstruction. Decreased bladder efferent neurotransmission occurred after bladder outlet obstruction, predominantly in its purinergic component and detrusor contractions via cholinergic neurotransmission were activated in a compensatory manner, probably via N-type Ca(2+) channel up-regulation.

Bidirectional electromigration failure

Pulsed bidirectional currents in copper interconnect can cause electromigration (EM) –induced cyclic void behaviour. Cycles of void nucleation, growth, shrinkage and healing may be seen in the time variation of a line’s resistance profile. In practice each cycle appears to create some net effect so that, eventually, the net effect of many cycles adds up to the failure criterion. We seek here to investigate whether the Stress Evolutional Model of Korhonen et al. [1] is capable of describing the net effect of a voiding cycle.

Chronic Cyclic Bladder Over Distention Up-Regulates Hypoxia Dependent Pathways

Bladder over distention secondary to anatomical or functional obstruction can eventually lead to pathological changes, including decreased elasticity and contractile dysfunction. We hypothesized that chronic bladder distention in a murine model would activate hypoxia dependent signaling pathways despite intermittent relief of distention. Female C57Bl/6 mice were oophorectomized at age 5 to 6 weeks and underwent urethral catheterization and 90-minute bladder distention. Acute and chronic time points were evaluated. Bladder tissue was harvested for hematoxylin and eosin, and immunohistochemical staining with the hypoxia markers Glut-1 (EMD Millipore, Merck, Darmstadt, Germany) and Hypoxyprobe™-1. Bladder tissue was also harvested for real-time polymerase chain reaction and oxidative stress measurement. Hypoxia polymerase chain reaction arrays were done to determine changes in gene expression. Oxidative stress was measured using F2-IsoP. Functional bladder changes were evaluated using voided urine blots. After acute distention and 5 consecutive distentions, bladders showed marked inflammatory changes on hematoxylin and eosin staining, and evidence of tissue hypoxia on immunohistochemistry. Quantitative real-time polymerase chain reaction revealed up-regulation of hypoxia and oxidative stress related genes, including Hif1a, Arnt2, Ctgf, Gpx1 and Hmox1. Measurements of oxidative stress with F2-IsoP did not change. Voided urine blots before and after bladder distention showed marked changes with an overactive voiding pattern. Chronic bladder distention is possible in the female mouse. It generates hypoxic injury, as characterized functionally by increased voiding patterns. This bladder injury model might more closely replicate bladder dysfunction in patients with poor bladder emptying due to neurological disease, including those noncompliant with intermittent catheterization.

Monitoring physiologic change in the bladder in health and disease. A new biomedical application of near-infrared spectroscopy

Biomedical applications of near-infrared spectroscopy (NIRS) utilize non-invasive optical technology to monitor alterations in tissue oxygenation and hemodynamics in real time via changes in concentration of the chromophores oxygenated and deoxygenated hemoglobin. Applications of NIRS to the bladder are novel and recent. Transcutaneous monitoring over the bladder as it fills and empties provides unique physiologic information, as hemodynamic variations in the organ's microcircu- lation and alterations in oxygen supply, demand and consumption in the detrusor muscle can be inferred. Such information, which is not available by other means, enhances investigation of patients with bladder dysfunction, offers new insights into causal pathology and hence potentially impact choice of pharmaceutical agents. Problem voiding is common, but the principal diagnostic test is invasive, and gives limited diagnostic and therapeutic information (pressure/flow). Continuous wave NIRS instruments are used for bladder monitoring. Initially NIR light was laser-generated; now miniaturized self-contained devices using light emitting diodes, spatial configuration of emitters to detector, and wireless capacity enhance research scope and clinical monitoring potential. NIRS bladder chromophore patterns during filling and voiding differ in health and disease. In addition to adding new knowledge re voiding dysfunction causation, data patterns characteristic of specific pathology have allowed construct of algorithms with comparable discriminant ability to current invasive diagnostic measures. Such data are physiologic because NIRS only detects change during events in the voiding cycle, pathologic changes mirror NIRS-derived effects of physiologic events (hypoxia/ischemia/fatigue) observed in other tissues (muscle/brain/spinal cord), and animal data and independent research corroborate the principal findings.

Usefulness of dynamic urethral resistance relation (DURR) measurement for differential diagnosis between static and dynamic urinary obstruction in male spinal cord injury patients

To study the validity of Dynamic Urethral Resistance Relation (DURR) for differential diagnosis between static and dynamic urinay obstruction in male spinal cord injury patients. A case-control study was conducted. The case group consisted of 24 male patients with spinal cord injury, aged under 40 years, with detrusor-periurethral sphincter dyssynergia and bladder outlet obstruction (BOO) according to the urethral resistance factor (URA). The control group consisted of 24 male patients with no neurological lesions, aged over 49 years, diagnosis of benign prostatic hyperplasia (BPH) and BOO according to Schäfer's minimum urethral opening pressure (Pmuo) and the URA. A pressure/flow study was performed in both groups, and the DURR was recorded graphically. Both groups showed significantly different DURR characteristics with respect to the number of spikes (higher in the case group), the intensity of the first three spikes and the maximum duration of the spikes (significantly longer in the case group). The patients in the case group had a DURR characterized by at least three spikes, located throughout the whole voiding cycle (pattern A). The patients in the control group had a DURR mainly characterized by a spike located at the start of micturition and a maximum second spike located at the end of micturition (pattern B). Pattern A showed a sensitivity with respect to the dynamic obstruction of 79% and a specificity of 100%. The sensitivity of pattern B with respect to the diagnosis of static obstruction was 71% and the specificity was 100%.

Real-Time Monitoring of Blood Flow and Intravesical Pressure in the Rat Bladder.

Because there is little information available about blood flow in the voiding cycle of the bladder, we performed a study in which we simultaneously monitored blood flow and intravesical pressure during the micturition cycle in a rat model. Approximately 300 g male Wistar rats were used in this study. Cystometric studies were performed according to our previous report, and simultaneously blood flow was monitored. Before the micturition reflex occurred, a significant increase in bladder blood flow was observed, and this increased blood flow continued during the micturition reflex. Under the maximum contraction pressure, blood flow rapidly decreased (within 10% compared to the max level). This low level of blood flow continued for more than half a minute. Our data indicated that the blood flow in the bladder was dynamically changed during voiding. This technique may represent a strong tool to investigate bladder function under drug administrations and/or pathophysiological conditions.

216 α1D-ADRENOCEPTOR BLOCKER IMPROVES VOIDING EFFICIENCY BY INCREASE IN SILENT PERIOD OF THE EXTERNAL URETHRAL SPHINCTER IN RATS WITH SPINAL CORD INJURY

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology1 Apr 2011216 α1D-ADRENOCEPTOR BLOCKER IMPROVES VOIDING EFFICIENCY BY INCREASE IN SILENT PERIOD OF THE EXTERNAL URETHRAL SPHINCTER IN RATS WITH SPINAL CORD INJURY Hirokazu Ishida, Hiroki Yamauchi, Hironobu Akino, and Osamu Yokoyama Hirokazu IshidaHirokazu Ishida Fukui, Japan More articles by this author , Hiroki YamauchiHiroki Yamauchi Fukui, Japan More articles by this author , Hironobu AkinoHironobu Akino Fukui, Japan More articles by this author , and Osamu YokoyamaOsamu Yokoyama Fukui, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.326AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES An ideal therapy for lower urinary tract dysfunction in spinal cord injury (SCI) patients would decrease bladder overactivity, thereby, promoting urine storage at low intravesical pressure, and promote efficient voiding at low pressure by decreasing detrusor-sphincter dyssynergia (DSD). In this study we investigated whether α1D-adrenoceptor blocker naftopidil improved voiding dysfunction of chronic SCI rats by monitoring cystometrogram CMG) and external-sphincter electromyogram (EUS-EMG) under unanesthesized state. METHODS The effects of intervenous α1D-adrenoceptor blocker naphtopidil were evaluated during cystometry in decebrated, unanesthetized female Sprague-Dawley rats with spinal cord chronically transected at the T8. Parameters measured included voided volume, residual volume, voiding efficiency, miction pressure, and EUS-EMG which consisted of more prominent tonic activity, shorter periods of bursting activity, and a reduction in the ratio of silent to active periods during bursting in SCI rats. RESULTS Compared to premedication control values, naftopidil ( 0.1, 1, and 3 mg/kg) dose-dependently decreased the number of non-voiding contractions (NVC) per voiding cycle (12.2±7.25 vs. 9±8.56, 6.5±6.74, 2.8±2.71 times, each p<0.05). However, voided volume and maximal pressure of voiding contraction were not significantly affected by naftopidil treatment. Naftopidil (0.1mg/kg, 1mg/kg) decreased residual volume (from 1.96±1.60ml to 1.43±1.60ml, 1.03±1.01ml, respectively; both p<0.05), and increased Voiding efficiency (from 28.5±29.0% to 44±25.8%, 53.4±36.9%, respectively; both p<0.05 ).Compared to control values at EUS-EMG, naftopidil (0.1mg/kg, 1mg/kg, and 3mg/kg) significantly increased burst period (2.46±1.51 sec vs. 8.51±1.45, 11.0±1.05, 9.8±1.50 sec, respectively) and silent period (0.036±0.02 vs. 0.061±0.02, 0.074±0.01, 0.1±0.04 sec). CONCLUSIONS These results suggest that α1D-adrenoceptor blocker reduces NVC and urethral resistance associated with DSD, resulting in improvement voiding efficiency in SCI rats. This report is the first to evaluate the effects of α1D-adrenoceptor blocker on EUS-EMG in SCI models. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e89 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hirokazu Ishida Fukui, Japan More articles by this author Hiroki Yamauchi Fukui, Japan More articles by this author Hironobu Akino Fukui, Japan More articles by this author Osamu Yokoyama Fukui, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Olfactory Mucosal Transplantation After Spinal Cord Injury Improves Voiding Efficiency by Suppressing Detrusor-Sphincter Dyssynergia in Rats

Several recent studies showed that olfactory mucosal transplantation after spinal cord injury promotes extensive regeneration of the injured spinal cord. We examined the efficacy of olfactory mucosal transplantation for bladder dysfunction after spinal cord injury in rats. In adult female rats the Th9-10 spinal cord was completely transected, followed by olfactory mucosal transplantation or gelatin sponge filling as the control. Each group was examined by cystometrogram and external urethral sphincter electromyogram. Calcitonin gene-related peptide and growth associated protein 43 double positive expression in the L6/S1 dorsal horn was evaluated by immunohistochemistry. Transplant sites were examined by immunohistochemistry with antibodies against neurofilament M and neuronal class III beta-tubulin. On cystometrogram voiding efficiency was significantly higher in the transplantation group than in controls. On external urethral sphincter electromyogram with simultaneous cystometrogram the transplantation group showed a larger ratio of interburst silent periods to burst activity duration and a greater number of high frequency oscillations. In the transplantation group calcitonin gene-related peptide and growth associated protein 43 double positive expression in the L6/S1 dorsal horn was less dense than in controls. The transplantation group showed strong neurofilament M and neuronal class III beta-tubulin expression at the transplant site. Olfactory mucosal transplantation after spinal cord injury weakened external urethral sphincter excessive bursting and increased the urethral opening to improve voiding efficiency. Olfactory mucosal transplantation may modify emergence of the spinal micturition reflex after spinal cord injury. Transplantation resulted in new axons growing at the transplant site, implying the possible existence of interneuron bridging across the injured spinal cord.

Voiding effects mediated by α2-adrenoceptors in the anaesthetized male rat

To study the role of α(2)-adrenoceptors (α(2)-AR) in micturition of anaesthetized male rats, with specific focus on the effects on the electrical activity (by electromyography, EMG) of the rhabdosphincter, and actual urinary flow rate, as the effects mediated by α(2)-ARs on sphincter activity and urethral pressures have not been established. Adult anaesthetized male Noble rats were used; intravesical pressure, rhabdosphincter EMG and urinary flow rate from the distal urethra were recorded. After baseline recordings, an α(2)-AR agonist (dexmedetomidine, DEX) or α(2)-AR antagonist (atipamezole), were injected intravenously. DEX treatment significantly decreased the maximum bladder pressure and urinary flow rate, and the amplitude of rhabdosphincter EMG was significantly reduced. Intraluminal pressure high-frequency oscillations, usually observed during rat voiding were abolished. The effects of DEX were fully reversed within 31 min. Atipamezole treatment significantly increased actual urinary flow rates and rhabdosphincter EMG amplitude, but the number of times flow was interrupted was increased during the voiding cycle, leading to increased overall micturition time. Stimulation and blockade of α(2)-ARs have a significant effect on lower urinary tract function. If the data from this rat model are also valid in humans, a study of the effects of atipamezole on urethral sphincter activity and urethral pressures in humans would be of interest, and might show therapeutic potential of the drug.

Sites of Pain From Interstitial Cystitis/Painful Bladder Syndrome

In interstitial cystitis/painful bladder syndrome multiple pain sites are common. We hypothesized that a careful and systematic description of the pain of interstitial cystitis/painful bladder syndrome might provide clues to its pathogenesis. Women with 12 months or greater of interstitial cystitis/painful bladder syndrome symptoms underwent a medical record review and interview. Each completed a questionnaire that included views of the female body and described up to 5 interstitial cystitis/painful bladder syndrome pains, noting 40 descriptors for each. Two-thirds of the 226 patients reported multiple pains. Pain could be consolidated at 4 sites, including suprapubic, urethral, genital and nongenitourinary. Most descriptors were similar and little evidence indicated that 1 pain influenced pain at another site. Another 3 patterns were evident, including 1) a suprapubic > urethral > genital > nongenitourinary ranking in site distribution and at each site proportions that were solitary, the worst and the most frequent pains, and pains that responded to bladder events, 2) site specific allodynia, and 3) for urethral and genital pains a wider spectrum of sensations, including burning, stinging and sharp. Patients with urethral (38%) or genital (27%) pain did not differ from those without such pain in 95% of 44 important characteristics. Suprapubic prominence and changes in the voiding cycle are features consistent with but do not prove that the bladder is the pain generator in interstitial cystitis/painful bladder syndrome and the pain sites described by patients are referred from it. The patients with interstitial cystitis/painful bladder syndrome who might have been diagnosed with vulvodynia or urethral syndrome did not differ from others in important patient variables.

Evaluation of Purinergic Mechanism for the Treatment of Voiding Dysfunction: A Study in Conscious Spinal Cord-injured Rats

To investigate the effect of a selective P2X(3-)P2X(2/3) purinergic receptor antagonist (a-317491) on detrusor hyperreflexia in conscious chronic spinal cord-injured female rats. Six chronic spinal cord-transected female Sprague-Dawley rats (290-336 g) were used in this study. Spinal transection at the T8-T9 segmental level was performed using aseptic techniques under halothane anesthesia. Fourteen to 16 weeks after spinal transection, A-317491, a selective P2X(3-)P2X(2/3) purinergic receptor antagonist, was administered intravenously in cystometry studies at increasing doses of 0.03, 0.1, 0.3, 1, 3, 10 and 30 micromol/kg at 40-50 minute intervals. Cystometrograms (CMGs) were performed before and after the administration of each dose of the drug. The continuous filling of CMGs revealed a large number of small-amplitude (> 8 cmH(2)O), non-voiding contractions (NVCs) (average, 9.7 per voiding cycle) preceding voiding contractions (mean amplitude, 31 cmH(2)O; duration, 2.5 minutes), which occurred at an interval of 539 seconds and at a pressure threshold of 5.7 cmH(2)O. When tested in a range of doses (0.03-30 micromol/kg, intravenous), A-317491 in doses between 1 and 30 micromol/kg significantly (p < 0.05) increased the interval between voids by 25%, reduced the number of NVCs by 42-62%, and increased the pressure threshold for voiding by 53-73%, but did not change the amplitude of the duration of the voiding contractions. The effects of the drug were apparent within 10 minutes following administration. These results indicate that purinergic mechanisms, presumably involving P2X(3) or P2X(2/3) receptors on bladder C-fiber afferent nerves, play an important role in the detrusor hyperreflexia that occurs after spinal cord injury in rats.

Time Dependent Changes in Diabetic Cystopathy in Rats Include Compensated and Decompensated Bladder Function

Diabetic bladder dysfunction is among the most common and bothersome complications of diabetes mellitus. While bladder filling and voiding problems have been reported, the precise functional changes in diabetic bladders remain unclear. We investigated time dependent changes in bladder function in streptozotocin induced diabetic rats. Cystometrograms and detrusor muscle contractility were examined in male age matched control and diabetic Sprague-Dawley rats (Harlan, Indianapolis, Indiana) 3, 6, 9, 12 and 20 weeks after diabetes induction with streptozotocin. Diabetes decreased average body weight and increased bladder weight, capacity and compliance. Peak detrusor leak pressure increased gradually from weeks 3 to 6 to 9 in diabetic rats (mean +/- SEM 47.3 +/- 2.5, 50.8 +/- 3.0 and 56.0 +/- 3.6 cm H(2)O) and in controls (36.9 +/- 1.4, 37.7 +/- 1.5 and 41.6 +/- 1.81 cm H(2)O, respectively). However, at 12 and 20 weeks diabetic rats deviated strongly from this trend with peak detrusor leak pressure decreasing vs controls (41.6 +/- 2.8 and 37.3 +/- 0.9 vs 45.2 +/- 1.7 and 49.6 +/- 1.4 cm H(2)O, respectively) and post-void resting pressures increasing from 9-week levels vs controls (interactions p <0.0001). In contractility studies increased contractile force responses of diabetic animals to carbamylcholine chloride, potassium chloride, adenosine 5'-triphosphate and electric field stimulation peaked at 6 or 9 weeks but at 12 to 20 weeks they generally reverted toward those of controls (carbamylcholine chloride and electrical field stimulation interactions p = 0.0022 and 0.01, respectively). Diabetic bladders may undergo a transition from a compensated to a decompensated state and transition in the streptozotocin rat model may begin 9 to 12 weeks after induction.

Transmitters contributing to the voiding contraction in female rats.

To assess in detail the contribution of acetylcholine and ATP to the different phases of the voiding contraction, urine flow and rhabdosphincter electromyographic (RB-EMG) activity in rats, using alpha,beta-methylene-ATP (desensitizing purinoceptors) and atropine (blocking muscarinic receptors). These agents and possibly other transmitters contribute to bladder emptying in rats, but how they contribute to the different phases of the micturition cycle, including the intraluminal pressure high-frequency oscillations (IPHFOs) is unclear. Adult anaesthetized female Sprague-Dawley rats were used; intravesical pressure, RB-EMG and urine flow from the distal urethra were recorded. After baseline recordings, alpha,beta-methylene-ATP (0.5 mg/kg), atropine (1 mg/kg), or both, were injected intravenously. Alpha,beta-Methylene-ATP significantly decreased the maximum bladder pressure during the first micturition phase, whereas atropine had little effect; the maximum bladder pressure during the second phase was also reduced. IPHFOs were apparent after both treatments. Atropine significantly reduced the maximum bladder pressure during the third phase. The maximum urinary flow rate was reduced by both alpha,beta-methylene-ATP and atropine; after exposure to both agents together, urinary flow was markedly reduced or stopped, and overflow incontinence developed. ATP contributes mainly to the initial and acetylcholine to the later phases of the voiding cycle in the rat. Neither agent abolished the IPHFOs; even after blocking the receptors for one transmitter and in the presence of IPHFOs, the bladder can still empty. However, if both receptors are blocked, overflow incontinence develops, suggesting that even if further transmitters are taking part in the voiding contraction, their physiological significance is questionable.

Dynamic pelvic-pudendal reflex plasticity mediated by glutamate in anesthetized rats

Reflex plasticity between pelvic afferent nerve (PAN) and pudendal efferent nerve (PEN), as well as external-urethral sphinctor (EUS) activity was examined in anesthetized rats. A progressive increase in the number of evoked action potentials per stimulus occurred in PEN and EUS activity when PAN was repetitively stimulated (1 Hz). This potentiation in pelvic-pudendal reflex (PPR) activity induced by repetitive stimulation was abolished by APV (D-2-amino-5-phosphonoraleric acid, i.t. 100 μM, 2–5 μl) and attenuated by the NBQX (2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline, i.t. 20 μM, 2–5 μl) but was not affected by the presence of bicuculline (i.t. 10 μM, 2–5 μl). The duration of contraction wave of intra-urethral pressure (IUP) elicited by a single electric shock was elongated by potentiated PPR, while the peak pressure was not affected. Both intrathecal application of glutamate (i.t. 0.1 mM, 2–5 μl) and NMDA (N-methyl-D-aspartic acid, i.t. 0.1 mM, 2–5 μl) induced spontaneous repetitive (0.31±0.02 Hz) burst discharges in PEN and EUSE and produced small contraction wave in IUP, which is similar to the high frequency oscillation phase during a voiding cycle of urinary bladder in rats. All these results demonstrate that repetitive stimulation of PAN can induce a distinct and long-lasting modulation in PPR activity and this change may be physiologically relevant in urinary continence.

Inter-observer agreement in the estimation of bladder pressure using a penile cuff.

Objective data are useful in quantifying a patient's lower urinary tract symptoms (LUTS). We are investigating the use of an inflatable penile cuff to obstruct flow progressively during voiding, and thereby determine the pressure p(cuff,int) at which flow is interrupted. The aim of this study was to determine the agreement between experienced observers in their estimates of p(cuff,int). We recorded 486 cuff inflation cycles during 142 voids from 42 subjects recruited from urology out-patient's and prostate assessment clinics. Each inflation cycle was assessed independently by three experienced observers, a total of 1,458 ratings. According to our standard assessment procedure, the observers (i) indicated whether the inflation should be analyzed, (ii) estimated p(cuff,int) for those inflation cycles judged suitable for analysis, and (iii) discarded measurements that were clearly inconsistent with others from the same voiding cycle. Overall, 689 of the 1,458 ratings (45%) were excluded, with just 4% of all ratings discarded for inconsistency. For 385 of the 486 inflation cycles (79%) there was complete agreement that the cycle should or should not be analyzed. Thereafter, for the 262 inflation cycles analyzed by two or three observers, the overall SD error in measurements of p(cuff,int) was 4.6 cm H(2)O. We conclude that there is good agreement between experienced observers in their interpretation of data from the cuff test. For practical purposes, there is no need for multiple observers in the clinical application of the cuff method.

Immunoneutralization of Nerve Growth Factor in Lumbosacral Spinal Cord Reduces Bladder Hyperreflexia in Spinal Cord Injured Rats.

We investigated the effects of intrathecal application of nerve growth factor (NGF) antibodies (Ab) on bladder hyperreflexia in chronic spinalized rats. In adult female rats an intrathecal catheter was implanted at the level of the L6 to S1 spinal cord, followed by complete transection of the Th8 to 9 spinal cord. At 10 days after spinalization the intrathecal catheter was connected to an osmotic pump for continuous delivery of vehicle or NGF Ab (10 microg daily) for 2 weeks. Awake cystometry was then performed. NGF levels in the L5 to S1 dorsal root ganglia, L6 spinal cord and bladder were also measured using enzyme-linked immunosorbent assay. The number of uninhibited bladder contractions per voiding cycle, maximal pressure of uninhibited bladder contraction and maximal voiding pressure were significantly decreased in NGF Ab treated versus vehicle treated spinalized rats. Intercontraction interval, baseline intravesical pressure, pressure threshold for voiding and voiding efficiency were not significantly changed by NGF Ab treatment. NGF levels in the bladder, L6 spinal cord and L5 to S1 dorsal root ganglia of vehicle treated spinalized rats was 1.6 to 4.8 times higher than in spinal cord intact rats. After intrathecal NGF Ab treatment NGF levels were significantly lower in the L6 to S1 dorsal root ganglia (30% to 35%) and L6 spinal cord (53%) but not in the bladder or L5 dorsal root ganglia compared with levels in vehicle treated spinalized rats. Increased levels of NGF in the bladder, spinal cord and dorsal root ganglia were associated with bladder hyperreflexia after spinal cord injury. Immuno-neutralization of NGF in the spinal cord suppressed NGF levels in the L6 to S1 dorsal root ganglia, which contain bladder afferent neurons, and also suppressed bladder hyperreflexia. Thus, suppression of NGF levels in afferent pathways could be useful for treating bladder hyperreflexia associated with spinal cord injury.

Effect of Oral Kohki Tea on Bladder Dysfunction Induced by Severe Partial Outlet Obstruction

Extracts of the leaves of Engelhardtia chrysolepis, a subtropical plant that grows wild in southern China, have been used medicinally in east Asia for hundreds of years. A standard extract named Kohki tea (Maruzen Pharmaceuticals, Onomichi City, Japan) is sold over the counter in Japan as a sweet tea shown to confer many beneficial effects on general health and well-being. The tea contains strong antioxidants, including several dihydroflavonol glycosides. The results of previous studies show that natural products with antioxidant activities provide protective effects on the bladder of rabbits with partial outlet obstruction. We determined in vivo and in vitro whether oral pretreatment of rabbits with Kohki tea protects the bladder from dysfunction induced by partial outlet obstruction. A total of 28 New Zealand White rabbits were separated into 4 groups of 7 each. Rabbits in groups 1 and 2 were treated by gavage with 100 mg./kg. Kohki tea daily in distilled water, while those in groups 3 and 4 were given distilled water. After 4 weeks of daily oral administration each rabbit was sedated, the bladder was catheterized and cystometry was performed at a filling rate of 1 ml. per minute. At the completion of cystometry the rabbits were immediately anesthetized. Moderate outlet obstruction was created in groups 1 and 3, and sham surgery was performed in groups 2 and 4. Treatment was continued for an additional 4 weeks, when each rabbit was sedated and cystometry was repeated. After cystometry the bladder was exposed through a midline incision, excised, weighed and 4 strips of bladder body were cut for contractility studies. The balance of the bladder was separated between smooth muscle and mucosa by blunt dissection, frozen in liquid nitrogen and stored at -70C for biochemical analyses. Partial outlet obstruction stimulated similar increases in the bladder weight of all obstructed rabbits. Partial outlet obstruction resulted in a significant decrease in bladder compliance in all obstructed animals. However, the bladder of obstructed rabbits given Kohki tea were significantly more compliant than those given water. Voiding pressures in the control group and the obstructed group given distilled water were approximately equal, while obstructed rabbits given Kohki tea showed significantly higher maximal voiding pressure. The contractile responses to all forms of stimulation were reduced by obstruction to a significantly greater degree in the rabbits not given tea than in those given tea. Sarcoplasmic reticulum Ca2+-adenosine triphosphatase enzyme activity of the bladder was significantly reduced in obstructed rabbits given vehicle but activity was not reduced in obstructed rabbits given Kohki tea. Kohki tea had a significant protective effect on bladder function, contractile responses and bladder biochemistry in rabbits with moderate to severe partial outlet obstruction.