Biomedical subjects

Matthew O Fraser

Publications and source records attributed to Matthew O Fraser.

18 recordsLinked to original sources

PubMed2007

Activation of the external urethral sphincter central pattern generator by a 5-HT(1A) receptor agonist in rats with chronic spinal cord injury.

We recently demonstrated that treatment with the 5-HT(1A/7) receptor agonist [(R)-(+)-8-hydroxy-2-di-n-propylamino]tetralin (8-OH-DPAT) increases bladder capacity in chloralose-anesthetized female cats with chronic spinal cord injury. In the current study, we investigated the effects of 8-OH-DPAT on bladder capacity and external urethral sphincter (EUS) activity in urethane-anesthetized female rats (initial body mass 175-200 g) with chronic spinal cord injury (transsection at T10). Cystometric study took place 8-12 wk posttranssection. Intravesical pressure was monitored in urethane-anesthetized rats with a transvesical catheter, and EUS activity was assessed electromyographically. Spinal cord injury disrupts phasic activity of the EUS, resulting in decreased voiding efficiency and increased residual volume. 8-OH-DPAT induced a dose-dependent decrease in bladder capacity (the opposite of its effect in chronic spinal cord-injured cats) with an increase in micturition volume and decrease in residual volume resulting from improvement in voiding efficiency. The unexpected improvement in voiding efficiency can be explained by the 8-OH-DPAT-induced emergence of phasic EUS relaxation. Phasic EUS relaxation was also altered by 8-OH-DPAT in spinally intact rats, whereas the 5-HT(1A) receptor antagonist N-tert-butyl-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-2-phenylpropanamide (WAY-100635), on its own, was without effect. It remains to be determined when phasic relaxation is restored after spinal cord injury, and indeed whether it is ever truly lost or is only temporarily separated from excitatory input.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2006

Convergence of bladder and colon sensory innervation occurs at the primary afferent level.

Dichotomizing afferents are individual dorsal root ganglion (DRG) neurons that innervate two distinct structures thereby providing a form of afferent convergence that may be involved in pelvic organ cross-sensitization. To determine the distribution of dichotomizing afferents supplying the distal colon and bladder of the Sprague-Dawley rat and the C57Bl/6 mouse, we performed concurrent retrograde labeling of urinary bladder and distal colon afferents using cholera toxin subunit B (CTB) fluorescent conjugates. Animals were perfused 4-5 days after sub-serosal organ injections, and the T10-S2 DRG were removed, sectioned, and analyzed using confocal microscopy. In the rat, CTB-positive afferents retrogradely labeled from the bladder were nearly three times more numerous than those labeled from the distal colon, while in the mouse, each organ was equally represented. In both species, the majority of colon and bladder afferents projected from lumbosacral (LS) ganglia and secondarily from thoracolumbar (TL) ganglia. In the rat, 17% of the total CTB-positive neurons were retrogradely labeled from both organs with 11% localized in TL, 6% in LS, and 0.8% in thoracic (TH) ganglia. In the mouse, 21% of the total CTB-positive neurons were dually-labeled with 12% localized in LS, 4% in TH, and 4% in TL ganglia. These findings support the existence of dichotomizing pelvic afferents, which provide a pre-existing neuronal substrate for possible immediate and maintained pelvic organ cross-sensitization and ultimately may play a role in the overlap of pelvic pain disorders.

Afferent Pathways↗

PubMed2006

Colonic irritation in the rat sensitizes urinary bladder afferents to mechanical and chemical stimuli: an afferent origin of pelvic organ cross-sensitization.

Chronic pelvic pain (CPP) disorders frequently overlap. We have demonstrated that acute and chronic colonic irritation can lead to neurogenic cystitis. We hypothesize that acute colonic irritation can sensitize urinary bladder afferents to mechanical and chemical stimuli. Single-unit afferent activity was recorded from fine filaments of the pelvic nerve in urethane-anesthetized Sprague-Dawley female rats before and 1 h after intracolonic administration of trinitrobenzenesulfonic acid (TNBS). Only spontaneously active afferents with receptive fields in the bladder and conduction velocities <2.5 m/s (unmyelinated C-fibers) were studied. Mechanical sensitivity was tested by bladder distension (BD) during saline infusion, whereas chemical sensitivity was tested with intravesical capsaicin, bradykinin, or substance P. Colonic irritation increased the resting firing rate of bladder afferents twofold (1.0 +/- 0.2 vs. 0.49 +/- 0.2 impulses/s, P < 0.05). Moreover, at low-pressure BDs (10-20 mmHg), a greater percentage of afferents exhibited increased activity following TNBS (73 vs. 27%, P < 0.05). Although the magnitude of the afferent response to BD was unchanged at low pressures, the response was greatly enhanced at pressures 30 mmHg and above (2.36 +/- 0.56 vs. 8.55 +/- 0.73 impulses/s, P < 0.05). Responses to capsaicin, bradykinin, and substance P were also significantly enhanced following TNBS, and all responses were blocked by bladder denervation. In rats, colonic irritation sensitizes urinary bladder afferents to noxious mechanical and chemical stimuli. Interruption of the neural input to the bladder minimized this effect, suggesting a local afferent pathway from the colon. Thus, the overlap of CPP disorders may be a consequence of pelvic afferent cross-sensitization.

Action Potentials↗

PubMed2005

A model of neural cross-talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders.

BACKGROUND & AIMS: Irritable bowel syndrome, interstitial cystitis, and other chronic pelvic pain (CPP) disorders often occur concomitantly. Neural cross-talk may play a role in the overlap of CPP disorders via the convergence of pelvic afferents. We investigated the hypothesis that afferent irritation of one pelvic organ may adversely influence and sensitize another via neural interactions. METHODS: We measured pelvic organ smooth muscle and striated muscle reflexes during micturition and colorectal distention (CRD) in urethane-anesthetized rats. The effects of acute cystitis on distal colonic sensory thresholds to CRD and the effects of acute colonic irritation on micturition parameters were assessed. RESULTS: External urethral sphincter (EUS) electromyography (EMG) was typical for the rat, with phasic firing during micturition. External anal sphincter EMG also showed phasic firing during micturition in synchrony with EUS activity but, in addition, showed both tonic bursts and phasic firing independent of EUS activity. Before bladder irritation, graded CRDs to 40 cm H2O produced no notable changes in abdominal wall EMG activity. Following acute bladder irritation, dramatic increases in abdominal wall EMG activity in response to CRD were observed at much lower distention pressures, indicating colonic afferent sensitization. Analogously, following acute colonic irritation, bladder contraction frequency increased 66%, suggesting sensitization of lower urinary tract afferents. CONCLUSIONS: We report compelling evidence of bidirectional cross-sensitization of the colon and lower urinary tract in a novel experimental model. This cross-sensitization may account for the substantial overlap of CPP disorders; however, further studies are needed to fully characterize these pathways.

Animals↗

PubMed2005

New pharmacological treatments for urinary incontinence and overactive bladder.

Lower urinary tract dysfunction encompasses a number of different pathologies, and affects the lives of millions of patients worldwide. Although several pharmaceutical companies have been involved in urological drug discovery over the last several years, therapeutic options remain limited. The mainstay of treatment for overactive bladder and urinary incontinence for several years has been antimuscarinic agents. While additional antimuscarinic compounds are currently undergoing clinical development, next generation compounds aimed at novel targets and mechanisms of action are in clinical and preclinical development. This review highlights new compounds and approaches under clinical investigation by various pharmaceutical companies. These novel therapeutic strategies offer the promise of expanded treatment options for patients suffering from these disorders.

Animals↗

PubMed2004

Androgen and estrogen treatment, alone or in combination, differentially influences bone maturation and hypothalamic mechanisms that time puberty in the male rhesus monkey (Macaca mulatta).

In higher primates, the mechanisms that govern the ontogeny of gonadotropin-releasing hormone pulse generator activity and that, therefore, dictate the timing of the onset of puberty remain intriguingly elusive. Groups of three infant agonadal male monkeys were treated with sex steroids [17beta-estradiol (E(2)), testosterone (T), or dihydrotestosterone (DHT)] for the first year of life to advance bone age (BA). E(2) and T resulted in a significant advancement of BA, and a pubertal BA of 130 wk was attained at a mean chronological age of 64 and 67 wk, respectively. In contrast, DHT failed to advance BA during treatment but stimulated linear growth. All animals exhibited a pubertal resurgence in LH secretion, but the timing of this developmental event did not differ between treatment and control groups (the mean for all animals was 117.7 +/- 8.9 wk). Two of the three T-treated animals, however, displayed a pubertal LH resurgence at a remarkably young age (70 and 76 wk of age) that coincided with T withdrawal. During the period of steroid treatment, all three groups were significantly heavier than the controls. The rate of body weight gain was most rapid in the DHT-treated group. Steroid treatments also resulted in accelerated linear growth. Body weight gain and linear growth continued at the same rate as controls after withdrawal of treatment. These data indicate that attainment of a pubertal BA may be a necessary but not a sufficient factor to trigger the onset of puberty. The results not only are consistent with the view that androgen-induced skeletal maturation in males is mediated by estrogen receptor activity but also indicate that androgen receptor activity contributes to the pubertal growth spurt in males.

Androgens↗

PubMed2004

A model of intrinsic sphincteric deficiency in the rat: electrocauterization.

AIMS: Intrinsic sphincteric deficiency (ISD) denotes a malfunction of the distal urethral sphincter. Our objective was to produce a durable model of ISD in the rat. METHODS: Surrounding tissues lateral to the mid-urethra were cauterized to produce sphincteric injury in 24 adult female Sprague-Dawley rats. The rats were divided into four groups of six rats each and followed for 2, 4, 6, and 16 weeks. Sphincteric function was studied by using the vertical tilt table/intravesical pressure clamp model to measure leak point pressures (LPPs). Muscle and nerve damage were assessed with hematoxylin and eosin (H&E) and anti-protein gene product (PGP) 9.5 staining, respectively. As a control, 12 rats underwent a sham operation and subsequent LPP testing at 2, 4, 6, and 16 weeks. RESULTS: The mean LPPs of the rats 2, 4, 6, and 16 weeks after cauterization were 18.7 +/- 0.8 cm H2O, 27.6 +/- 1.6 cm H2O, 24.3 +/- 1.7 cm H2O, and 19.1 +/- 2.2 cm H2O, respectively. The mean LPPs of the rats 2, 4, 6, and 16 weeks after the sham operation were 49.8 +/- 1.3 cm H2O, 51.2 +/- 1.5 cm H2O, 51.6 +/- 2.0 cm H2O, and 49.7 +/- 0.6 cm H2O, respectively. When compared to time-matched control groups, the decreased LPPs in each cauterized group were significantly lower (P < 0.001). Histological analysis showed muscle damage and fewer nerves in all cauterized groups. CONCLUSIONS: Cauterization of tissues lateral to the mid-urethra decreased LPP without affecting bladder function. This electrocauterization model produced low LPPs that, after 2 weeks, were maintained for up to 16 weeks. Histology suggests that damage to striated muscle and nerves might have contributed to the change in LPP in this model for ISD.

Animals↗

PubMed2004

Induction of bladder sphincter dyssynergia by kappa-2 opioid receptor agonists in the female rat.

PURPOSE: The nonselective kappa opioid receptor agonist ethylketocyclazocine suppresses external urethral sphincter (EUS) reflexes in cats. We examined the role of spinal kappa-opioid receptor subtypes in the control of EUS function in rats using selective kappa-1 (U-50,488) or kappa-2 (GR-89,696) opiate receptor agonists. MATERIALS AND METHODS: Urethane anesthetized female rats were catheterized through the bladder dome for cystometry. EUS function was assessed electromyographically. Drugs were administered intrathecally or intravenously. RESULTS: Micturition in rats is accompanied at different times by tonic (continuous) EUS spike activity and by phasic bursts of spikes separated by pauses. GR-89,696 (0.05 to 5 microg intrathecally) caused a dose dependent decrease in the number of bursts per micturition without affecting spike frequency within individual bursts or during periods of tonic activity. It resulted in decreased voiding efficiency and at high doses dyssynergia and overflow incontinence. The nonselective opiate receptor antagonist naloxone (1 mg/kg intravenously) blocked GR-89,696 effects. U-50,488H (0.05 to 15 microg intrathecally) caused no change in cystometric parameters or in EUS-electromyography. CONCLUSIONS: Efficient voiding in rats depends on a spinal pattern generator causing EUS motor neuron firing to occur in bursts, resulting in rapid urethral contraction and relaxation. Intrathecal kappa-2-opiate receptor agonists suppress this pattern generator, decreasing the number of bursts occurring during each micturition without decreasing motor neuron spike frequency during individual bursts or during tonic spike activity associated with urethral closure. Resultant dyssynergia leads to decreased voiding efficiency. The relevance of kappa-2 opioid receptors should be explored in higher species, especially regarding spinal cord injury induced dyssynergia.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2004

Urodynamic and immunohistochemical evaluation of intravesical capsaicin delivery using thermosensitive hydrogel and liposomes.

PURPOSE: Aqueous insolubility of the vanilloids such as capsaicin is a major disincentive in their intravesical therapy of detrusor hyperreflexia. We sought to overcome the delivery of this hydrophobic neurotoxin by entrapping it in a lipid bilayer of positively charged multilamellar lipid vesicles (liposomes) or in a hydrophobic polymer matrix of thermosensitive hydrogel. MATERIALS AND METHODS: Liposomes, hydrogel and 30% ethanol/normal saline were prepared with or without 1 mM capsaicin (0.5 ml) and administered intravesically for 30 minutes to 7 groups of age matched, normal female adult Sprague-Dawley rats under halothane anesthesia. At 48 hours after intravesical instillation cystometric studies were performed using urethane anesthesia (0.04 ml per minute). The animals were subsequently sacrificed and whole bladders were harvested for histology and immunohistochemistry. RESULTS: In normal urethane anaesthetized rats capsaicin in 30% ethanol and liposomes completely blocked micturition reflexes. Capsaicin in hydrogel did not completely block the micturition reflex but it significantly decreased bladder contraction frequency compared with vehicle controls. The results of cystometry with capsaicin in liposomes and capsaicin in 30% ethanol correlated with a significant decrease in calcitonin gene-related peptide staining of afferent nerves in the bladder wall. Photographs taken after hematoxylin and eosin staining of the bladder treated with liposomes and hydrogel in the absence of capsaicin did not reveal any adverse histological changes. There were significant histological changes in bladders treated with 30% ethanol alone. CONCLUSIONS: In comparison with 30% ethanol liposomes are a superior vehicle for the intravesical administration of capsaicin, producing comparable efficacy with less tissue damage. Hydrogel can also serve as safe alternative option for capsaicin delivery.

Administration, Intravesical↗

PubMed2004

Urethral dysfunction in diabetic rats.

PURPOSE: We investigated the effects of diabetes mellitus (DM) on urethral relaxation mechanisms during reflex bladder contractions in rats. MATERIALS AND METHODS: Five weeks after streptozotocin injection (65 mg/kg intraperitoneally) the effects of DM on urethral relaxation mechanisms were evaluated by simultaneous recordings of intravesical pressure under isovolumetric conditions and urethral perfusion pressure (UPP) using urethane anesthesia. RESULTS: In diabetic rats the UPP nadir during urethral relaxation and intravesical pressure thresholds for inducing urethral relaxation were significantly higher (199% and 92%, respectively) than in normal rats, while baseline UPPs were not significantly different. The mean rate and amplitude of high frequency oscillations of urethral striated muscle in diabetic rats were also significantly lower (17% and 64%, respectively) compared with normal rats. Following alpha-bungarotoxin treatment to eliminate striated muscle sphincter contractions intravenous administration of L-arginine (200 mg/kg) [corrected] , the substrate of nitric oxide (NO) synthase, decreased the UPP nadir (36% and 22%, in diabetic and normal rats) as well as intravesical pressure thresholds (49% and 22%, respectively). The effect was greater (61% to 126%) in diabetic rats than in normal rats. In each group of rats the effect of L-arginine was inhibited by Nomega-nitro-L-arginine (100 mg/kg intravenously) [corrected], a NO synthase inhibitor. CONCLUSIONS: During reflex bladder contractions streptozotocin induced diabetic rats exhibited smooth and striated muscle dysfunctions of the urethral outlet. L-arginine therapy, which could augment urethral smooth muscle relaxation by increasing NO production, may be useful for partially restoring the urethral relaxation mechanism in DM.

Animals↗

PubMed2003

Development of an experimental system for the study of urethral biomechanical function.

Despite its principal mechanical function in the storage and release of urine, the biomechanical properties of the urethra have remained largely unexplored. The purpose of this study was to develop and validate an experimental model that can be used for evaluating whole urethral tissue in such a manner. Bladder-urethral specimens were excised from halothane-anesthetized female rats and mounted at in vivo length within the experimental apparatus consisting of a tissue perfusion chamber, an adjustable fluid column, and a laser micrometer. Outer diameter measurements were made at proximal, mid, and distal axial locations in response to increases in intraluminal pressure and after addition of various muscle-responsive agents. Basal smooth muscle tone and regional variations in compliance were detected through pressure-diameter responses. Chemically evoked contractile responses were measured and correspond to regional compositions of intrinsic smooth and striated muscle components. The results presented illustrate the utility of this system, which should permit a more thorough characterization of structure-function relationships and urethral biomechanical function in relation to normal and dysfunctional tissue states.

Acetylcholine↗

PubMed2003

Identification of c-kit-positive cells in the mouse ureter: the interstitial cells of Cajal of the urinary tract.

The existence of a pacemaker system in the urinary tract capable of orchestrating the movement of filtrated urine from the ureteral pelvis to the distal ureter and lower urinary tract seems intuitive. The coordinated activity necessary for such movement or "peristalsis" would likely require an intricate network of cells with pacemaker-like activity, as is the case with the interstitial cells of Cajal (ICC) of the gut. We investigated whether these putative pacemaker cells of the urinary tract are antigenically similar to ICC of the gut by using immunofluorescence staining for c-kit, a cell-surface marker specific for ICC. Ureteral, urinary bladder, and urethral tissues were harvested from female mice of the WBB6F1 strain, and fixed sections were prepared and stained for c-kit. Cell networks composed of stellate-appearing, c-kit-positive, ICC-like cells were found in the lamina propria and at the interface of the inner longitudinal and outer circular muscle layers of the ureteral pelvis but not in the urinary bladder or urethra. Thus, like in the gut, c-kit-positive, ICC-like cells are present in the urinary tract but appear to be restricted to the proximal ureter of this murine species.

Animals↗

PubMed2003

Intravesical protamine sulfate and potassium chloride as a model for bladder hyperactivity.

OBJECTIVES: An acute animal model for hyperactive bladder in rats was developed using intravesical infusion of protamine sulfate (PS), an agent thought to break down urothelial barrier function, and physiologic concentrations of potassium chloride (KCl). METHODS: Continuous cystometrograms (CMGs) were performed in urethane-anesthetized female rats by filling the bladder (0.04 mL/min) with normal saline followed by intravesical infusion of a test solution consisting of either KCl (100 or 500 mM) or PS (10 or 30 mg/mL) for 60 minutes. Subsequently, the 10 mg/mL PS-treated animals were infused intravesically with 100, 300, or 500 mM KCl. Some animals were pretreated with capsaicin (125 mg/kg subcutaneously) 4 days before the experiments. RESULTS: Unlike KCl (100 or 500 mM) or a low concentration of PS (10 mg/mL) alone, the intravesical administration of a high concentration of PS (30 mg/mL) produced irritative effects with a decreased intercontraction interval (by 80.6%). After infusion of a low concentration of PS, infusion of 300 or 500 mM KCl produced irritative effects (intercontraction interval decreased by 76.9% or 82.9%, respectively). The onset of irritation occurred more rapidly after 500 mM KCl (10 to 15 minutes) than after 300 mM KCl (20 to 30 minutes). Capsaicin pretreatment delayed the onset (approximately 60 minutes) and reduced the magnitude (intercontraction interval decreased by 35.5%) of irritative effects. CONCLUSIONS: Intravesical administration of KCl after PS treatment activates capsaicin-sensitive afferents and detrusor muscle and presumably capsaicin-resistant afferents. Modest, noncytotoxic affronts to urothelial barrier function can result in dramatic irritative responses. This model may be useful in the study of bladder irritation and hyperactivity.

Administration, Intravesical↗

PubMed2003

Intravesical liposome administration--a novel treatment for hyperactive bladder in the rat.

OBJECTIVES: To examine the effect of intravesical administration of liposomes (LPs) on chemically induced bladder hyperactivity in the rat. It has been suggested that interstitial cystitis (IC) is associated with a dysfunctional or leaky epithelium. Thus, enhancement of epithelial barrier function might be useful in the treatment of IC. LPs are vesicles that are concentric phospholipid bilayers separated by an aqueous compartment and can fuse with cells to provide a molecular film that can promote wound healing. METHODS: The intravesical pressure was recorded using a transurethral catheter in adult female Sprague-Dawley rats anesthetized with urethane (1.2 g/kg subcutaneously). Some animals were pretreated with capsaicin (125 mg/kg subcutaneously) 4 days before the experiments. Continuous cystometrograms were performed by slowly filling the bladder (0.04 mL/min) with solutions of varying compositions, including saline, acetic acid (AA, 0.1%), potassium chloride (KCl, 500 mM), protamine sulfate (PS, 10 mg/mL), LPs, PS/KCl, or LPs/KCl. The parameters measured included the intercontraction interval (ICI), amplitude of bladder contractions, compliance, and micturition pressure threshold. RESULTS: The ICI was decreased after exposure to AA (79.8% decrease) or PS/KCl (81% decrease); however, the ICI was not changed after LPs, PS, or KCl alone. The decreased ICI was partially reversed after infusion of LPs (172.8% increase) or LPs/KCl (63% increase), but was not significantly changed after switching to saline or KCl administration. Pretreatment with capsaicin delayed the onset of the irritative effects of AA by approximately 30 to 60 minutes, but had not changed the magnitude after 2 hours of infusion. CONCLUSIONS: Intravesical administration of PS/KCl or AA activates capsaicin-sensitive and capsaicin-resistant afferents in a time-dependent sequence that is partially reversed by LP infusion. We hypothesize that LPs might enhance the barrier properties of a dysfunctional uroepithelium and increase resistance to irritant penetration. Thus, intravesical LP administration could be a novel treatment of patients with IC.

Administration, Intravesical↗

PubMed2002

Immunoneutralization of nerve growth factor in lumbosacral spinal cord reduces bladder hyperreflexia in spinal cord injured rats.

PURPOSE: We investigated the effects of intrathecal application of nerve growth factor (NGF) antibodies (Ab) on bladder hyperreflexia in chronic spinalized rats. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Afferent Pathways↗

PubMed2002

Diabetic cystopathy correlates with a long-term decrease in nerve growth factor levels in the bladder and lumbosacral dorsal root Ganglia.

PURPOSE It has been proposed that a deficiency in the axonal transport of nerve growth factor (NGF) may have an important role in inducing diabetic neuropathy, which contributes to diabetic cystopathy. Therefore, in streptozotocin (Sigma Chemical Co., St. Louis, Missouri) induced diabetic rats we investigated the relationship of bladder function with NGF levels in the bladder and lumbosacral dorsal root ganglia, which contain afferent neurons innervating the bladder. MATERIALS AND METHODS At 6 and 12 weeks after the induction of diabetes with streptozotocin (65 mg./kg. intraperitoneally) the effects of diabetes on Adelta afferent fiber dependent, conscious voiding were evaluated by metabolic cage measurements and awake cystometry. The effects of diabetes on C-fiber mediated bladder nociceptive responses were also investigated by cystometry with intravesical instillation of 0.25% acetic acid in the rats under urethane anesthesia. NGF levels in the bladder and L6 to S1 dorsal root ganglia were measured by enzyme-linked immunosorbent assay 3, 6, 9 and 12 weeks after streptozotocin injection. RESULTS In diabetic rats NGF levels in the bladder and L6 to S1 dorsal root ganglia were significantly decreased 12 weeks after streptozotocin injection (p <0.01). In cystometry and metabolic cage studies bladder capacity and post-void residual volume were significantly increased 12 weeks after streptozotocin injection (p <0.01). Bladder nociceptive responses revealed by a reduction in inter-contraction intervals after acetic acid infusion were significantly decreased in a time dependent manner 12 weeks after streptozotocin injection.CONCLUSIONS Rats with streptozotocin induced diabetes mellitus showed a significant time dependent decrease in NGF levels in the bladder and L6 to S1 dorsal root ganglia that was associated with voiding dysfunction attributable to defects in Adelta and C-fiber bladder afferents. Therefore, reduced production of NGF in the bladder and/or impaired transport of NGF to L6 to S1 dorsal root ganglia, which contain bladder afferent neurons, may be an important mechanism inducing diabetic cystopathy.

Animals↗

PubMed2002

Passive biaxial mechanical properties of the rat bladder wall after spinal cord injury.

PURPOSE: Changes in the mechanical properties of the bladder wall after spinal cord injury can alter bladder compliance and wall tension, leading to changes in afferent nerve activity and to abnormal reflex mechanisms. To our knowledge we report the first application of biaxial mechanical testing to the normal bladder wall and demonstrate how these properties change after spinal cord injury. MATERIALS AND METHODS: Whole bladders were harvested from mature female Sprague-Dawley rats weighing 250 to 300 gm. Test group animals underwent complete spinal cord transection at the T9 to T10 level and normal animals comprised the control group. The bladders were cut open longitudinally, the trigone and apex were removed and the remaining tissue was trimmed to a square of 9 to 13 mm. per side. Mechanical properties of the tissue sample were tested using planar biaxial testing, in which a stress was applied in the circumferential and longitudinal (base-apex) directions, and resulting axial strains were measured. RESULTS: In normal and spinal cord injured rats bladder wall tissue demonstrated isotropic mechanical behavior when equal stress levels were applied in anatomical directions. However, under nonequi-biaxial loading bladder specimens were not truly isotropic but displayed anisotropic-like behavior. Spinal cord injured tissues were consistently more compliant than normal controls. CONCLUSIONS: Biaxial mechanical testing can detect differences in normal control and hypertrophied rat bladders 10 and 14 days after spinal cord injury. These changes represent an important component of the bladder response to spinal cord injury.

Animals↗

PubMed2002

The future of bladder control-intravesical drug delivery, a pinch of pepper, and gene therapy.

The incidence of urinary incontinence and overactive bladder problems will continue to grow as the population ages. Future treatments are likely to include an implantable drug delivery system, gene therapy, and the intravesical use of the vallinoids capsaicin and resiniferatoxin (RTX). An understanding of the urothelium is essential for effective design of these therapies. Intravesical anticholinergic drug treatment is currently not widely used, but intravesical pumps are under development to provide less cumbersome treatment methods and will provide nonsurgical options for patients who cannot tolerate oral anticholinergic agents. Research on the use of capsaicin as an intravesicular drug has had limited success, but trials have confirmed the efficacy of intravesical capsaicin for detrusor hyperreflexia. RTX is as effective as capsaicin but without side effects, such as pain and inflammatory neuropeptide release. RTX treatment may eliminate the need for surgical and other drug treatments of lower urinary tract dysfunction in patients with spinal cord injuries. Gene therapy will change the practice of urology by addressing the deficiencies that cause symptoms rather than attacking the symptoms themselves.

Journal Article↗