Volume Threshold For Micturition Research Articles

First in Human Subjects Testing of the UroMonitor: A Catheter-free Wireless Ambulatory Bladder Pressure Monitor.

Urodynamics is the standard method of diagnosing bladder dysfunction, but involves catheters and retrograde bladder filling. With these artificial conditions, urodynamics cannot always reproduce patient complaints. We have developed a wireless, catheter-free intravesical pressure sensor, the UroMonitor, which enables catheter-free telemetric ambulatory bladder monitoring. The purpose of this study was twofold: to evaluate accuracy of UroMonitor pressure data, and assess safety and feasibility of use in humans. Eleven adult female patients undergoing urodynamics for overactive bladder symptoms were enrolled. After baseline urodynamics, the UroMonitor was transurethrally inserted into the bladder and position was confirmed cystoscopically. A second urodynamics was then performed with the UroMonitor simultaneously transmitting bladder pressure. Following removal of urodynamics catheters, the UroMonitor transmitted bladder pressure during ambulation and voiding in private. Visual analogue pain scales (0-5) were used to assess patient discomfort. The UroMonitor did not significantly alter capacity, sensation, or flow during urodynamics. The UroMonitor was also easily inserted and removed in all subjects. The UroMonitor reproduced bladder pressure, capturing 98% (85/87) of voiding and nonvoiding urodynamic events. All subjects voided with only the UroMonitor in place with low post-void residual volume. Median ambulatory pain score with the UroMonitor was rated 0 (0-2). There were no post-procedural infections or changes to voiding behavior. The UroMonitor is the first device to enable catheter-free telemetric ambulatory bladder pressure monitoring in humans. The UroMonitor appears safe and well tolerated, does not impede lower urinary tract function, and can reliably identify bladder events compared to urodynamics.

MP03-07 THE LACK OF MECHANOSENSITIVE TREK-1 CHANNEL MIMICS THE DEVELOPMENT OF AGING-RELATED BLADDER PHENOTYPES IN MICE

You have accessJournal of UrologyCME1 Apr 2023MP03-07 THE LACK OF MECHANOSENSITIVE TREK-1 CHANNEL MIMICS THE DEVELOPMENT OF AGING-RELATED BLADDER PHENOTYPES IN MICE Alison Xiaoqiao Xie, Nao Iguchi, and Anna Malykhina Alison Xiaoqiao XieAlison Xiaoqiao Xie More articles by this author , Nao IguchiNao Iguchi More articles by this author , and Anna MalykhinaAnna Malykhina More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003214.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Previous animal and human studies have confirmed that the potassium channel subfamily K member 2 (TREK-1), a member of two-pore domain mechanosensitive K+ channels (K2P), acts as a mechanosensor in the urinary bladder. We reported that TREK-1 is a predominantly expressed K2P channel in the human detrusor, and its expression and function are altered in patients with idiopathic detrusor overactivity (DO). TREK-1 expression in the peripheral organs and in the nervous system also declines during aging. This study aimed to investigate the role of TREK-1-related mechanosensitivity in the detrusor in aging mice. METHODS: Bladder histology, detrusor contractility, and voiding function were investigated in adult (3, 6, 9 and 12 months old) TREK-1 KO mice of both sexes and age-matched wildtype controls. Bladder weight, detrusor smooth muscle (DSM) thickness, and collagen content were compared between the groups using paraffin-embedded bladder samples. Bladder strip assay was used to evaluate detrusor muscle contractility and nerve-induced bladder contractions. Voiding spot assay (VSA) and awake cystometry recordings were performed to assess micturition patterns in vivo. RESULTS: Increased bladder weight and bladder wall thickness were observed in TREK-1 KO mice of both sexes, starting as early as at 6-month-old. and threshold volume in cystometry recordings. In comparison to age- and sex-matched controls, bladder strips isolated from TREK-1 KO mice showed significantly decreased DSM contractility including contractile responses to electric field stimulation and cholinergic receptor activation. Interestingly, while the peak forces of evoked DSM contractions decreased with aging in control mice, TREK-1 KO animals at 6-12 month-old displayed DSM contractility that was lower than in 12-month-old control animals. Increased numbers of non-voiding contractions were observed in both sexes of TREK-1 KO mice, whereas the bladder capacity, intermicturition interval, and micturition threshold volume were significantly increased in comparison to age-matched controls. CONCLUSIONS: In summary, the lack of TREK-1 expression in adult mice significantly increased a number of functional changes typically observed in underactive bladders with detrusor overactivity, including increases in bladder size, weight, capacity, and a significant decrease in DSM contractility. Our findings suggest that decreased TREK-1 expression may mimic the development of age-related voiding phenotypes in mice. Source of Funding: DK095817 (Malykhina), DK116648 (Malykhina) and Department of Surgery Academic Enrichment Fund (Xie) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e23 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alison Xiaoqiao Xie More articles by this author Nao Iguchi More articles by this author Anna Malykhina More articles by this author Expand All Advertisement PDF downloadLoading ...

Prolonged Inhibitory Effects of Repeated Tibial Nerve Stimulation on the Micturition Reflex in Decorticated Rats

ObjectiveThis study aimed to determine whether a short-term repeated stimulation of tibial nerve afferents induces a prolonged modulation effect on the micturition reflex in a decorticated rat model. Material and MethodsFifteen female Sprague-Dawley rats (250–350 g) were fully decorticated and paralyzed in the study. Tibial nerve stimulation (TNS) was delivered by inserting two pairs of needle electrodes close to the nerves at the level of the medial malleolus. Constant flow cystometries (0.07 mL/min) at approximately ten-minute intervals were performed, and the micturition threshold volume (MTV) was recorded and used as a dependent variable. After four to five stable recordings, the tibial nerves of both sides were stimulated continuously for five minutes at 10 Hz and at an intensity of three times the threshold for α-motor axons. Six same stimulations were applied repeatedly, with an interval of five minutes between each stimulation. Mean MTV was calculated on the basis of several cystometries in each half-hour period before, during, and after the six repeated TNS. ResultsDuring the experiment, all the animals survived in good condition with relatively stable micturition reflexes, and a significant increase in MTV was detected after TNS. The strongest effect (mean = 178%) was observed during the first 30 minutes after six repeated stimulations. This obvious threshold increase remained for at least five hours. ConclusionsA prolonged poststimulation modulatory effect on the micturition reflex was induced by short-term repeated TNS in decorticated rats. This study provides a theoretical explanation for the clinical benefit of TNS in patients with overactive bladder and suggests decorticated rats as a promising model for further investigation of the neurophysiological mechanisms underlying the bladder inhibitory response induced by TNS.

Role of hyperpolarization-activated cyclic nucleotide-gated channels in aging bladder phenotype

ObjectiveTo assess the functional role of Hyperpolarization-activated cyclic nucleotide-gated gated channel (HCN) subtypes in the aging bladder phenotype characterized by diminished bladder volume sensation (BVS) with or without the detrusor instability (DI). MethodsExpression of HCN subtypes was examined by quantitative RT-PCR and Western blot in aged male Fisher 344 rats (n = 15) and young rats (n = 15). Nocturnal urination and awake cystometry (CMG) were assessed in presence and absence of a steady state HCN channel blockade achieved with daily oral gavage of vehicle or Ivabradine (HCN blocker) 6 mg/kg for 7 days. ResultsThe association of BVS with the age-related downregulation (~30%) of cAMP sensitive HCN1, HCN2 subtypes, and (~50%) upregulation of cAMP insensitive HCN3 subtype is evinced by the doubling in the mean urine volume of nocturnal voids (0.82 ± 0.22 mL vs 0.41 ± 0.12 mL; n = 10; p < 0.05) predicting an age-related rise in the micturition volume threshold (p < 0.0001) in CMG, which is raised further by Ivabradine treatment (p < 0.0005). Ivabradine also doubled non-voiding contractions (NVC) and maximum voiding pressure (MVP) in young and aged rats, respectively (p < 0.0001) to abolish the age-related, innate two -fold elevation in NVC not accompanied with MVP rise in untreated aged rats (p < 0.005). ConclusionThe age-related HCN downregulation is mechanistically linked to the exhibition of aging bladder phenotype with the manifestation of DI following steady state blockade of HCN channels in Ivabradine treated young rats. The amplification of MVP in aged rats mediated by FDA approved Ivabradine hints at potential repurposing opportunity in detrusor underactivity.

PD27-07 BEDSIDE TO BENCHTOP RESEARCH UNCOVERS THE FUNCTIONAL ROLE OF HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED GATED (HCN) CHANNELS IN AGING BLADDER PHENOTYPE

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Basic Research & Pathophysiology (PD27)1 Sep 2021PD27-07 BEDSIDE TO BENCHTOP RESEARCH UNCOVERS THE FUNCTIONAL ROLE OF HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED GATED (HCN) CHANNELS IN AGING BLADDER PHENOTYPE Nishant Singh, Irina Zabbarova, Anthony Kanai, Christopher Chermansky, Naoki Yoshimura, and Pradeep Tyagi Nishant SinghNishant Singh More articles by this author , Irina ZabbarovaIrina Zabbarova More articles by this author , Anthony KanaiAnthony Kanai More articles by this author , Christopher ChermanskyChristopher Chermansky More articles by this author , Naoki YoshimuraNaoki Yoshimura More articles by this author , and Pradeep TyagiPradeep Tyagi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002020.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The aging bladder phenotype in detrusor overactivity, detrusor underactivity or detrusor hyperactivity with impaired contractility patients is characterized by detrusor instability with or without the loss of bladder volume sensitivity. Since separate studies reported age related downregulation of Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in mouse and human bladder, we examined the functional significance of age related reduction in HCN activity with multiple oral dosing of FDA approved HCN blocker, Ivabradine. METHODS: Aged male Fisher 344 rats (n=15) and young rats of both genders (n=15) were left untreated or treated daily with oral gavage of either vehicle or Ivabradine 6mg/kg (n=5) for 7 days prior to assessing nocturnal urination followed by awake cystometry on 7th day and quantitative RT-PCR and Western blot of HCN subtypes of untreated aged and young rats. RESULTS: Untreated aged aged rats (n=10) voided nearly double the volume of individual voids of young rats at night time (0.82±0.22 mL vs 0.41±0.12 mL, p<0.05), which was confirmed by a significant increase (p<0.05) in the micturition volume threshold (VT) in awake cystometry of aged rats. Increase in VT of aged rats coincided with a doubling of non-voiding contraction (NVC) frequency (p<0.05) while maximum voiding pressure (MVP) did not change with age. The age- related alterations in cystometry parameters correlated with the significant downregulation of cAMP sensitive HCN1and HCN2 subtype (40%) and the upregulation of cAMP insensitive HCN3 (60%) subtype. Ivabradine treatment significantly increased the VT (p<0.005), NVC frequency (p<0.001) and MVP (p<0.0001) in young and aged rats to different extents. CONCLUSIONS: A critical role for the altered bladder expression of HCN subtypes in the manifestation of aging bladder phenotype is supported by the dramatic changes in the bladder function following pharmacological blockade of HCN channels in young rats. The dramatic effect of Ivabradine on VT and MVP of aged rats in this bedside to benchtop research provides a basis for the therapeutic benefit of Ivabradine on detrusor underactivity of a male patient (Int Urol Nephrol, 40: 333, 2008). Source of Funding: NIA- AG062971 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e446-e446 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nishant Singh More articles by this author Irina Zabbarova More articles by this author Anthony Kanai More articles by this author Christopher Chermansky More articles by this author Naoki Yoshimura More articles by this author Pradeep Tyagi More articles by this author Expand All Advertisement Loading ...

Effect of Electroacupuncture on Bladder Dysfunction via Regulation of MLC and MLCK Phosphorylation in a Rat Model of Type 2 Diabetes Mellitus

Previous studies observed have reported that electroacupuncture (EA) is effective in relieving diabetic bladder dysfunction (DBD); however, little is known about the mechanism. Therefore, we explored the effects and mechanisms of EA on DBD in streptozotocin–high-fat diet- (STZ–HFD-) induced diabetic rats. The Sprague-Dawley male rats were divided randomly into four groups: normal group, diabetes mellitus group (DM group), DM with EA treatment group (EA group), and DM with sham EA treatment group (sham EA group). After 8 weeks of EA treatment, the body weight, serum glucose, bladder weight, and cystometrogram were evaluated. The bladder wall thickness was examined by abdominal ultrasound imaging. After the transabdominal ultrasound measurements, hematoxylin-eosin (HE) staining was used to observe the bladder mucosa layer. The bladder detrusor smooth muscle cells (SMCs) and fibroblasts were observed under transmission electron microscopy (TEM). The phospho-myosin light chain (p-MLC), phospho-myosin light chain kinase (p-MLCK), and phospho-myosin phosphatase target subunit 1 (p-MYPT1) levels in the bladder were examined using Western blot. The bladder weight, serum glucose, bladder wall thickness, volume threshold for micturition, and postvoid residual (PVR) volume in the diabetic rats were significantly higher than those in the control animals. EA treatment significantly reduced the bladder weight, bladder wall thickness, volume threshold for micturition, and PVR volume in diabetic rats. EA caused a significant increase in the MLC dephosphorylation and MLCK phosphorylation levels in the group compared to the sham EA and model groups. EA reduced the infiltration of inflammatory cells in the bladder mucosa layer of diabetic rats. In addition, EA repaired the damaged bladder detrusor muscle of diabetic rats by reducing mitochondrial damage of the SMCs and fibroblasts. Therefore, EA could reduce the bladder hypertrophy to ameliorate DBD by reversing the impairment in the mucosa layer and detrusor SMCs, which might be mainly mediated by the regulation of p-MLC and p-MLCK levels.

Repeat periods of electrical stimulation prolong the modulation of the micturition reflex in the rat.

The aim of this study was to determine if the duration of the micturition reflex modulation could be prolonged by repeated periods of afferent stimulation in the decorticated rat. Eighteen female Sprague-Dawley rats were used for the study, 10 for intravesical electrical stimulation (IVES), and 8 for Ano-genital pudendal afferents stimulation. Repeated constant flow cystometries were performed with body-warm saline (0.06-0.1 mL/min) at about 10 min interval. The selected afferents were stimulated continuously for 5 min at maximal intensity. The same stimulation was repeated six times with a pause of 5 min between the stimulations. The mean threshold volume of cystometries performed during one hour before and each hour after the stimulation were compared. After six periods of IVES, the micturition threshold volume decreased to its lowest value (62% of control) during the first hour and remained at 80% 4 h later (n = 10, P < 0.01). Ano-genital afferent stimulation produced a corresponding increase in the micturition threshold volume. The long-lasting poststimulation effect was again observed for more than 5 h. During the first hour the mean threshold volume increased to 211% of controls and it remained at about this level for the entire observation period (n = 8, P < 0.01). Repeated short periods of stimulation prolonged the modulatory effect well beyond the stimulation period. The findings provide experimental evidence supporting the clinical application of IVES and ano-genital stimulation for treatment of neurogenic urinary bladder dysfunction.

Integrin-Linked Kinase Improves Functional Recovery of Diabetic Cystopathy and Mesenchymal Stem Cell Survival and Engraftment in Rats.

Diabetic cystopathy (DCP), characterized by peripheral neuropathy-associated bladder dysfunction, is a common urinary complication in patients with diabetes (~80%). Bone marrow mesenchymal stem cell (BMMSC) transplantation, a new and emerging regenerative therapy, provides a curative option for DCP. However, the application of this therapy is limited by the low survival rate and engraftment of transplanted stem cells. This study was undertaken to determine whether integrin-linked kinase (ILK) overexpression would improve stem cell survival and engraftment after BMMSC transplantation. Diabetes was induced in rats by injection of streptozotocin. ILK expression was detected by qRT-PCR and Western blot. Bladder function was measured by urodynamic analyses. Smooth-muscle regeneration and vascularization were evaluated by immunohistochemistry staining. ILK overexpression by adenovirus promotes proliferation of BMMSCs in vitro. ILK overexpression enhanced the ability of BMMSCs to decrease the volume threshold for micturition and residual urine in the rats with diabetes. The contractile response of bladder strips, tissue structure of bladder and smooth-muscle regeneration/vascularization were also improved in the rats receiving ILK-modified BMMSCs. Our data highlight the clinical potential of transplantation of gene-modified BMMSCs in the treatment of DCP, thereby serving as a rapid and effective first-line strategy to cure the bladder dysfunction resulting from long-term diabetes.

Possible role of the major pelvic ganglion in the modulation of non-voiding activity in rats.

The existence of a motor-sensory system contributing to bladder sensation is now becoming widely accepted. Although it is clear that the motor component of this system appears to be generated within the bladder wall, recent observations suggest that the mechanisms involved in its modulation may lie outside the wall. The present study was undertaken to gain more insights into the peripheral modulation of non-voiding activity and the role of the major pelvic ganglion. Male Sprague-Dawley rats anesthetized with urethane were used. The bladder was filled till 60% of the micturition threshold volume. The baseline pressure and the superimposed non-voiding activity were observed before and after consecutive bilateral transections of the hypogastric and pelvic nerves and bilateral ablation of the major pelvic ganglia. Hypogastric and pelvic nerve transection didn't significantly change the baseline pressure and superimposed non-voiding activity. Removal of the major pelvic ganglia resulted into an increased baseline pressure when compared with the control and increased amplitude of the non-voiding contractions when compared with both the decentralized condition (both hypogastric and pelvic nerves transected) and the control. The frequency of the non-voiding contractions wasn't affected. Non-voiding activity during the urine storage phase seems to be modulated at the level of the major pelvic ganglion. This suggests the possibility of local circuits between the bladder and the peripheral ganglia that may be responsible for an inhibitory component influencing non-voiding activity.

Influence of Intravesical Lower pH on the Micturition Reflex Threshold in the Rat

Aims: To investigate whether intravesical lower pH induces a micturition threshold reflex change of anaesthetized rats. Methods: Thirteen female rats, anaesthetized by a-chloralose and paralyzed by pancurone bromide were used for the experiments. The micturition threshold volume was determined by repeated cystometry. Simultaneously bladder afferent activities in four and efferent activities in seven rats were recorded from the exposed pelvic nerve to the bladder. Results: Cystometry with acidic saline at pH 3 and 4 induced a significant decrease in micturition threshold volume. The mean value of these groups of test showed that bladder compliance, micturition threshold pressure and maximal micturition contraction pressure were decreased significantly comparing with the controls. There were no changes in all other parameters recorded from afferent and efferent, e.g. afferent threshold volume, afferent or efferent activity at the micturition threshold and their peak activity at the micturition contraction. Conclusions: Acidic solution provoked sensitivity but reduced the force of the contractility to the urinary bladder. The effect was presented without a detectable change in the firing properties of bladder Ad mechanoreceptor afferents. It is proposed that proton sensitive bladder receptors with unmyelinated afferent were stimulated by the acidic solution and that the micturition reflex was facilitated by afferent inflow from such receptors. The findings were clinically important in choosing the medium for urodynamic examination.

Mechanisms of Pelvic Organ Crosstalk: 1. Peripheral Modulation of Bladder Inhibition by Colorectal Distention in Rats

Bladder activity can be inhibited by afferent input from the colorectum (inhibitory rectovesical reflex). We evaluated the functional response of the rat bladder to nonnoxious and noxious colorectal distention, and investigated the mechanical and pharmacological peripheral modulation of this response. In 70 female Sprague-Dawley® rats we evaluated the effect of nonnoxious (20 mm Hg) and noxious (40 and 60 mm Hg) colorectal distention on the micturition volume threshold and on bladder activity in a filled bladder. We also studied the effect of rectal balloon size (1.5 vs 3.5 cm long), and rectal administration of 2% lidocaine jelly or 1 mM allyl isothiocyanate solution on the inhibitory rectovesical reflex. Colorectal distention at 60 mm Hg increased the micturition volume threshold (mean ± SE 0.640 ± 0.056 vs 0.448 ± 0.035 ml in controls, p <0.001). Bladder contraction frequency was significantly decreased by 40 and 60 mm Hg colorectal distention vs controls (mean 0.62 ± 0.06 and 0.33 ± 0.05 per minute, respectively, vs 0.77 ± 0.03, each p <0.001). These effects were reversible and pressure dependent (p <0.001), and more pronounced using a large rectal balloon (mean 40 vs 60 mm Hg colorectal distention 0.35 ± 0.12 vs 0.07 ± 0.04 per minute, p = 0.004). We noted no significant graded inhibition of bladder contraction amplitude or duration. The inhibitory rectovesical reflex was reversibly abolished by intrarectal lidocaine administration. Intrarectal allyl isothiocyanate administration significantly increased the effect of noxious colorectal distention on bladder contraction frequency. Only noxious levels of colorectal distention initiated the inhibitory rectovesical reflex. The effect increased with rectal balloon size and with intrarectal administration of allyl isothiocyanate. It was reversibly abolished by lidocaine. Results suggest that spinal interneurons are the mechanism behind the inhibitory rectovesical reflex.

Transcutaneous Electrical Nerve Stimulation (TENS) Improves the Diabetic Cytopathy (DCP) via Up-Regulation of CGRP and cAMP

The objective of this study was to investigate the effects and mechanism of Transcutaneous Electrical Nerve Stimulation (TENS) on the diabetic cytopathy (DCP) in the diabetic bladder. A total of 45 rats were randomly divided into diabetes mellitus (DM)/TENS group (n = 15), DM group (n = 15) and control group (n = 15). The rats in the DM/TENS and TENS groups were electronically stimulated (stimulating parameters: intensity-31 V, frequency-31 Hz, and duration of stimulation of 15 min) for three weeks. Bladder histology, urodynamics and contractile responses to field stimulation and carbachol were determined. The expression of calcitonin gene-related peptide (CGRP) was analyzed by RT-PCR and Western blotting. The results showed that contractile responses of the DM rats were ameliorated after 3 weeks of TENS. Furthermore, TENS significantly increased bladder wet weight, volume threshold for micturition and reduced PVR, V% and cAMP content of the bladder. The mRNA and protein levels of CGRP in dorsal root ganglion (DRG) in the DM/TENS group were higher than those in the DM group. TENS also significantly up-regulated the cAMP content in the bladder body and base compared with diabetic rats. We conclude that TENS can significantly improve the urine contractility and ameliorate the feeling of bladder fullness in DM rats possibly via up-regulation of cAMP and CGRP in DRG.

Cause of Residual Urine in Bladder Outlet Obstruction: An Experimental Study in the Rat

We explored the role of bladder mechanoreceptors in post-void residual urine in rats with bladder outlet obstruction. Partial bladder outlet obstruction was induced by a urethral ligature in 11 adult female Sprague-Dawley® rats. Nine sham operated rats served as controls. The outcome was evaluated in acute experiments using α-chloralose anesthesia 6 weeks later. Bladders were catheterized for infusion, pressure recording and intravesical electrical stimulation. Bladder efferent activity was recorded from a thin pelvic nerve branch close to the bladder. Micturition contractions were triggered at different bladder volumes by a brief train of electrical stimulation of bladder afferents while monitoring post-stimulus efferent activity and reflex bladder contractions. The degree of obstruction was assessed by bladder wet weight at the end of the experiment. Bladder weight, micturition threshold volume, anatomical bladder capacity and peak contraction force were significantly increased in obstructed rats. In sham operated controls a triggered micturition reflex was sustained by afferent feedback from the bladder until the bladder was empty. In contrast, reflex discharges failed with substantial volume remaining in the bladder in obstructed rats. The minimal micturition reflex volume correlated positively with bladder weight, micturition threshold volume and maximal bladder capacity (r ≥0.74). In rats with partial bladder outlet obstruction the micturition reflex failed before the bladder was empty due to a decreased afferent drive from bladder mechanoreceptors. Similar changes may contribute to post-void residual urine in humans with bladder outlet obstruction.

Bladder mechanoreceptor changes after artificial bladder outlet obstruction in the anesthetized rat

Experimental animal models of bladder outlet obstruction (BOO) have reproduced several features of BOO in man, i.e., detrusor hypertrophy, instability, frequency, and residual urine. This study was focused on the mechanisms underlying the development of residual urine in patient with benign prostatic hyperplasia (BPH) by examining changes in tension sensitivity of bladder mechanoreceptors in rat model. Female adult Sprague-Dawley rats including 12 BOO and 17 sham operated rats were used in this study. Cystometrograms together with the bladder afferent activity were recorded. Tension sensitivity of the afferents was determined by plotting the normalized afferent response against the contraction evoked bladder pressure at different volumes. Degree of obstruction was assessed by the wet weight of the bladder at the end of the experiment. The bladder weight, maximal bladder capacity, micturition threshold volume, peak contraction force, and volume at peak contraction force were all significantly increased in obstructed animals. The threshold volume for afferent activation was increased (mean 0.60 ml compared to 0.15 ml in controls; P < 0.001), positively correlated with the bladder weight (r = 0.74). The tension sensitivity of the bladder mechanoreceptors and the slope of their normalized pressure-response functions were significantly lower at the comparable volumes in the obstructed animals. Rats with BOO had bladder mechanoreceptors with higher threshold volumes and lower tension sensitivity. Such changes would result in a weaker afferent drive of the micturition reflex. Similar changes may contribute to the development of residual urine and retention in patients with BOO.

Selective Pharmacological Blockade of the TRPV1 Receptor Suppresses Sensory Reflexes of the Rodent Bladder

We investigated the pharmacological effect of TRPV1 antagonists in anesthetized rodent models of bladder function. The TRPV1 antagonists JNJ17203212 and JYL1421 were evaluated in the anesthetized rat volume induced micturition reflex model. JNJ17203212 was further evaluated in this model in capsaicin (Sigma) desensitized rats, and in rat capsaicin and mouse citric acid models of irritant induced detrusor overactivity. Systemic JNJ17203212 and JYL1421 administration in the anesthetized rat volume induced micturition reflex model resulted in an increased micturition threshold volume. JNJ17203212 also decreased bladder contraction amplitude but JYL1421 had no effect. Capsaicin desensitization significantly increased baseline micturition threshold volume and decreased bladder contraction amplitude in the volume induced micturition reflex model compared to those in sham treated controls and JNJ17203212 produced no further effect after capsaicin desensitization. JNJ17203212 was also effective in 2 models of irritant induced detrusor overactivity, preventing the decrease in micturition threshold volume and the increase in bladder contraction amplitude observed with intravesical instillation of 10 microM capsaicin, and the decreased voiding interval induced by intravesical citric acid. The TRPV1 antagonists JNJ17203212 and JYL1421 increased the threshold for activation of the micturition reflex in the anesthetized rat volume induced micturition reflex model. This effect appeared to be mediated by capsaicin sensitive afferents. JNJ17203212 also inhibited detrusor overactivity induced by intravesical capsaicin and intravesical citric acid. These data extend our understanding of the role of TRPV1 in sensory modulation of the micturition reflex under nonirritant and inflammatory conditions.

Gating of the micturition reflex by tonic activation of bladder cold receptors in the cat

To determine whether C afferents can modify the gating of the Adelta micturition reflex in order to identify the neuronal site of interaction of the two afferent systems. Adult female cats, anaesthetized with alpha-chloralose, had their bladder and urethra catherized through a slit in the proximal urethra. Micturition threshold volume was assessed by cystometry and bladder efferent activity recorded simultaneously. The bladder was filled at a slow rate (1.2-3.5 ml/min) with either body-warm saline (control) or menthol solution (0.06 mM) or by cold saline (4 degrees C). Of 14 trial sessions in 5 animals, the threshold volume of the Adelta micturition reflex was consistently reduced by menthol infusions from a control median (md) value of 16.8 to 10.2 ml (P < 0.01). The threshold pressure was also somewhat decreased from md 0.7 to 0.5 kPa (P < 0.05), while the peak pressure or pressure slope did no differ in two situations. Similar results were obtained with slow cold infusions into the bladder (nine sessions in three animals). The threshold volume decreased from md 19.8 to 17.4 ml (P < 0.05). The bladder reflex response to slow menthol or cold infusions had the typical features of an Adelta micturition reflex in that the efferent activity was largely abolished by the bladder Adelta mechanoreceptor unloading. Gradual tonic activation of bladder cold receptors lowers the threshold volume of the ordinary Adelta micturition, pointing to a segmental spinal mechanism for the gating of the micturition reflex.

Bladder inhibition or excitation by electrical perianal stimulation in a cat model of chronic spinal cord injury

To test the hypothesis that perianal electrical stimulation (PES) in chronic spinal cord-injured (SCI) cats could induce frequency-dependent inhibitory or excitatory reflex bladder responses. The experiments were conducted > or =4-5 weeks after spinal cord transection at the T9-T10 level. PES was applied via a pair of hook electrodes to the perianal skin area in three awake female cats with chronic SCI. A double-lumen balloon catheter was inserted through the urethra into the bladder to monitor bladder pressure and infuse saline (2-4 mL/min). Under isovolumetric conditions PES at 3-10 Hz significantly inhibited large-amplitude reflex bladder activity induced by bladder distension above the micturition volume threshold. However, PES at 20-50 Hz induced large-amplitude bladder contractions when the bladder volume was below the micturition volume threshold. Inhibitory PES (7 Hz) significantly increased the mean (sem) bladder capacity by 40 (10)% when it was applied continuously during cystometrography. The optimum excitatory PES (30 Hz) induced large-amplitude (>25 cmH(2)O), long-duration (>20 s) bladder contractions at a wide range of bladder volumes (10-90% of bladder capacity). This study showed that activation of pudendal afferent fibres by PES could induce frequency-dependent reflex bladder responses in awake cats with chronic SCI, indicating that a possible noninvasive treatment based on PES could be developed to restore both continence and micturition function for patients with SCI.

The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception

In micturition control, the roles of ionotropic glutamate (iGlu) receptors NMDA and AMPA are well established, whereas little is known about the function of metabotropic glutamate (mGlu) receptors. Since antagonists for mGlu5 receptors are efficacious in animal models of inflammatory and neuropathic pain, we examined whether mGlu5 receptors play a role in the voiding reflex and bladder nociception and, if so, via centrally or peripherally localized receptors. The mGlu5 receptor antagonist MPEP dose-dependently increased the micturition threshold (MT) volume in the volume-induced micturition reflex (VIMR) model in anesthetized rats. Following doses of 5.2, 15.5 and 51.7 μmol/kg of MPEP (intraduodenal), the MT was increased by 24.7 ± 5.0%, 97.2 ± 12.5% ( P < 0.01) and 128.0 ± 28.3% ( P < 0.01) from the baseline, respectively ( n = 4–5; compared with 0.8 ± 9.1% in the vehicle group). Infusing MPEP (0.3, 1 mM) directly into the bladder also raised MT. However, the efficacious plasma concentrations of MPEP following intravesical dosing were similar to that after intraduodenal dosing (EC 50 of 0.11 and 0.27 μM, respectively, P > 0.05). MPEP also dose-dependently attenuated the visceromotor responses (VMR, total number of abdominal EMG spikes during phasic bladder distension) in anesthetized rats. The VMR was decreased to 1332.4 ± 353.9 from control of 2886.5 ± 692.2 spikes/distension ( n = 6, P < 0.01) following MPEP (10 μmol/kg, iv). Utilizing the isolated mouse bladder/pelvic nerve preparation, we found that neither MPEP (up to 3 μM) nor MTEP (up to 10 μM) affected afferent discharge in response to bladder distension ( n = 4–6). In contrast, MPEP attenuated the responses of the mesenteric nerves to distension of the mouse jejunum in vitro. These data suggest that mGlu5 receptors play facilitatory roles in the processing of afferent input from the urinary bladder, and that central rather than peripheral mGlu5 receptors appear to be responsible.

Inhibitory and excitatory perigenital-to-bladder spinal reflexes in the cat

This study revealed that in awake chronic spinal cord-injured (SCI) cats reflexes from perigenital skin area to the bladder can be either inhibitory or excitatory. Electrical perigenital stimulation at frequencies between 5 and 7 Hz significantly inhibited large-amplitude rhythmic reflex bladder activity, whereas frequencies between 20 and 40 Hz induced large-amplitude bladder contractions even at low bladder volumes when reflex bladder activity was absent. Both inhibitory and excitatory effects were enhanced as the stimulation intensity increased (5-30 V, 0.2-ms pulse width). During cystometrograms, the inhibitory stimulation (7 Hz) significantly increased the micturition volume threshold 35 +/- 13% above the control volume, while the excitatory stimulation (30 Hz) significantly reduced the threshold 21 +/- 3%. Mechanical perigenital stimulation applied by repeated light stroking of the perigenital skin with a cotton swab only induced an excitatory effect on the bladder. Both electrical and mechanical perigenital stimuli induced large-amplitude (>30 cm H(2)O) bladder contractions that were relatively consistent over a range of bladder volumes (10-90% of the capacity). However, the excitatory electrical stimulation only induced bladder contractions lasting on average 42.2 +/- 3.9 s, but the mechanical stimulation induced bladder contractions that lasted as long as the stimulation continued (2-3 min). Excitatory electrical or mechanical perigenital stimulation also induced poststimulus voiding. The ability to either inhibit or excite the bladder by noninvasive methods could significantly transform the current clinical management of bladder function after SCI.

Effects of coffee and caffeine on bladder dysfunction in streptozotocin-induced diabetic rats1

To explore the effects and mechanisms of caffeine and coffee on bladder dysfunction in streptozotocin-induced diabetic rats. Sprague-Dawley male rats were divided randomly into 4 groups: control, diabetes mellitus (DM), DM with coffee treatment, and DM with caffeine treatment. The diabetic rat was induced by intraperitoneal injection of streptozotocin (60 mg/kg). After 7 weeks of treatment with coffee and caffeine, cystometrogram, contractile responses to electrical field stimulation (EFS) and acetylcholine (ACh), and cyclic AMP (cAMP) concentration of the bladder body and base were measured. The bladder weight, volume threshold for micturition and post-void residual volume (PVR) in the diabetic rats were significantly higher compared to those in the control animals. Coffee or caffeine treatment significantly reduced the bladder weight, bladder capacity and PVR in the diabetic rats. DM caused significant decreases in cAMP concentration of the bladder and coffee and caffeine caused upregulation of cAMP content in the diabetic bladder. In addition, coffee and caffeine tended to normalize the altered detrusor contractile responses to EFS and ACh in the diabetic rats. These results indicate that caffeine and coffee may have beneficial effects on bladder dysfunction in the early stage of diabetes by increasing cAMP content in the lower urinary tract, recovering the micturition reflex and improving the detrusor contractility.