Biomedical subjects

Michael B Chancellor

Publications and source records attributed to Michael B Chancellor.

At least 19 recordsLinked to original sources

PubMed2003

Effect of stimulation intensity and botulinum toxin isoform on rat bladder strip contractions.

The present experiments compared the inhibitory effects of botulinum toxin A (BoNT-A) and botulinum toxin D (BoNT-D) on neurally evoked contractions of rat bladder strips. We examined the effect of fatigue (trains of 100 shocks at 20Hz every 20s for 10min) followed by non-fatigue stimulation (trains of 100 shocks at 20Hz every 100s for 20min) on the onset of effect and potency of the two toxins. For non-fatigue experiments, strips were untreated (n=4); or incubated with 1.36nM BoNT-A (n=4). During fatigue experiments, strips were untreated (n=5); or treated with either 1.36nM BoNT-A (n=6) or 0.8nM BoNT-D (n=6). In non-fatigue experiments, BoNT-A produced significant decreases in contractile area after 1h of stimulation compared to untreated strips (P<0.05). After three series of fatigue stimulation, differences in recovery amplitude and area between untreated versus BoNT-A, and untreated versus BoNT-D bladder strips, were statistically significant (P<0.05). The onset of inhibitory effect was quicker in BoNT-D-treated strips, as a significant reduction (P<0.05) in recovery of contractile area was observed after 1h of stimulation compared to both untreated and BoNT-A-treated preparations. In addition, treated (BoNT-A and BoNT-D) and untreated bladder strips responded similarly to atropine, suggesting that the effects of BoNT result from inhibition of both acetylcholine and ATP release. Our results demonstrate that BoNT-D may be a more effective agent to inhibit transmitter release from autonomic nerves of the rat lower urinary tract. Moreover, in our hands, non-fatigue stimulation is as effective as fatigue stimulation in inhibiting bladder strip contractions.

Animals↗

PubMed2003

Urethral closure mechanisms under sneeze-induced stress condition in rats: a new animal model for evaluation of stress urinary incontinence.

The urethral closure mechanism under a stress condition induced by sneezing was investigated in urethane-anesthetized female rats. During sneezing, while the responses measured by microtip transducer catheters in the proximal and middle parts of the urethra increased, the response in the proximal urethra was almost negligible when the bladder response was subtracted from the urethral response or when the abdomen was opened. In contrast, the response in the middle urethra during sneezing was still observed after subtracting the bladder response or after opening the abdomen. These responses in the middle urethra during sneezing were significantly reduced approximately 80% by bilateral transection of the pudendal nerves and the nerves to the iliococcygeous and pubococcygeous muscles but not by transection of the visceral branches of the pelvic nerves and hypogastric nerves. The sneeze leak point pressure was also measured to investigate the role of active urethral closure mechanisms in maintaining total urethral resistance against sneeze-induced urinary incontinence. In sham-operated rats, no urinary leakage was observed during sneeze, which produced an increase of intravesical pressure up to 37 +/- 2.2 cmH2O. However, in nerve-transected rats urinary leakage was observed when the intravesical pressure during sneezing exceeded 16.3 +/- 2.1 cmH2O. These results indicate that during sneezing, pressure increases elicited by reflex contractions of external urethral sphincter and pelvic floor muscles occur in the middle portion of the urethra. These reflexes in addition to passive transmission of increased abdominal pressure significantly contribute to urinary continence mechanisms under a sneeze-induced stress condition.

Animals↗

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↗

PubMed2003

Muscle-derived stem cells seeded into acellular scaffolds develop calcium-dependent contractile activity that is modulated by nicotinic receptors.

OBJECTIVES: To explore the contractile activity and physiologic properties of muscle-derived stem cells (MDSCs) incorporated into small intestinal submucosa (SIS) scaffolds. METHODS: MDSCs were harvested from mice hind leg muscles using the preplate technique and stably transfected with a plasmid to express the LacZ reporter gene. Fifty different preparations of SIS cultured with MDSCs (MDSC/SIS) or SIS alone were incubated at 37 degrees C for 1, 4, and 8 weeks and also were mounted in a bath to measure the isometric contractions. RESULTS: LacZ and Masson-trichrome staining revealed MDSCs could migrate into and distribute throughout the SIS and form myotubes. In MDSC/SIS, spontaneous contractile activities were noted in the 4-week (five of six specimens) and 8-week (eight of eight specimens) cultures, but not in 1-week cultures (n = 11). All SIS control groups after 1 (n = 11), 4 (n = 6), and 8 (n = 8) weeks of incubation did not show any activity. In most of the 4-week, and all of the 8-week, MDSC/SIS cultures, the frequency and amplitude of spontaneous contractile activities were decreased by succinylcholine 10 microM and 20 microM. Electrical field stimulation, carbachol, and KCl did not alter the frequency, amplitude, or pattern of spontaneous contractile activities in MDSC/SIS. Spontaneous contractile activities were blocked by Ca(32+)-free Krebs solution with ethyleneglycoltetraacetic acid 200 microM and distilled water. CONCLUSIONS: MDSCs could be incorporated into SIS-forming myotubes capable of contracting. The contractile activity of this three-dimensional construct is Ca(2+) dependent and is modulated by nicotinic receptors. MDSC seeding of an acellular matrix may become a functional sling to reengineer the deficient sphincter or as contractile bladder augmentation.

Animals↗

PubMed2003

Implications of diabetes mellitus in urology.

The incidence of DM is rapidly growing among Americans. DM will rival cancer and heart disease in terms of cost and suffering. The National Institute of Health is tripling the research dollars that are spent on diabetic-related research in an attempt to combat this disease. Urologists are on the front line in the diagnosis and treatment of the complications of DM. The complications of DM that we reviewed in this article, diabetic cystopathy and diabetic ED, can occur in the early stage of DM and often progress in a silent fashion. More awareness and interest are needed to improve our understanding of diabetic complications in urology. Exciting new approaches in the treatment of diabetic cystopathy and ED are being investigated.

Clinical Trials as Topic↗

PubMed2003

Dopaminergic mechanisms underlying bladder hyperactivity in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway.

1. This study was undertaken to elucidate dopaminergic mechanisms underlying bladder hyperactivity in a rat model of Parkinson's disease (PD) induced by a unilateral 6-OHDA injection into the substantia nigra pars compacta. 2. In 6-OHDA-lesioned rats, voided volume per micturition (0.41+/-0.04 ml, mean+/-s.e.m.) measured during 24 h in a metabolic cage was significantly smaller than in sham-operated rats (0.67+/-0.07 ml). 3. Cystrometrograms (CMG) in conscious animals revealed significantly smaller bladder capacity (BC) (0.46+/-0.03 ml) in 6-OHDA-lesioned rats than in sham rats (0.72+/-0.06 ml). 4. SKF38393 (D1/D5 receptor agonist, i.v.) significantly increased BC in 6-OHDA rats without apparent effects in sham rats. SKF38393 applied intracerebroventricularly (i.c.v.) under urethane anesthesia also increased BC in 6-OHDA-lesioned rats and by a smaller increment in sham rats. 5. In contrast, quinpirole (D2/D3/D4 receptor agonist, i.v.) significantly reduced BC in sham and 6-OHDA-lesioned rats. Intrathecal injection of quinpirole similarly reduced BC in sham and 6-OHDA-lesioned rats. 6. PD128907 (D(3)-receptor agonist) did not have significant effects on BC in 6-OHDA-lesioned rats. 7. These results indicate that a rat model of PD exhibited bladder hyperactivity as observed in patients with PD, and that stimulation of D1/D5 dopamine receptors at a supraspinal site can suppress bladder hyperactivity in PD, whereas stimulation of D2/D4, but not D3, dopamine receptors had the opposite effect to reduce bladder capacity. Thus, D1/D5 dopamine receptor agonists might be effective in treating neurogenic bladder hyperactivity in PD.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2003

Effect of controlled-release oxybutynin on neurogenic bladder function in spinal cord injury.

OBJECTIVE: This study evaluated the effects and tolerability of extended-release oxybutynin chloride on the frequency of voiding and catheterization and urodynamic capacity in spinal cord injury (SCI) patients with defined detrusor hyperreflexia. METHODS: This was a 12-week, prospective, dose-titration study of extended-release oxybutynin (oxybutynin XL). SCI patients with urodynamically defined detrusor hyperreflexia were recruited for this study. Following a 7-day washout period, patients were evaluated via video-urodynamic study and then treatment was initiated at a dosage of 10 mg per day. Dosage was increased in weekly intervals to a maximum of 30 mg per day. Micturation frequency diaries and urodynamics were completed at baseline and repeated at week 12. Tolerability information was collected at each follow-up visit. RESULTS: Ten patients (mean age = 49 years) with complete or incomplete SCI were enrolled. Participants reported clinical improvement (decreased urinary frequency and fewer incontinence episodes) with oxybutynin therapy following titration to 30 mg per day. All patients chose a final effective dosage of greater than 10 mg, with 4 patients taking the maximum of 30 mg per day. Mean cystometric bladder capacity increased from 274 mL to 380 mL (P = 0.008). No patient experienced serious adverse events during the 12-week study. CONCLUSION: Oxybutynin XL is safe and effective in patients with detrusor hyperreflexia secondary to SCI. The onset of clinical efficacy occurs within 1 week, and daily dosages up to 30 mg are well tolerated.

Adult↗

PubMed2003

Effect of botulinum toxin A on the autonomic nervous system of the rat lower urinary tract.

PURPOSE: The magnitude and duration of the effects of botulinum toxin A on acetylcholine (ACh) and norepinephrine release from the bladder and urethra of rats were measured using a radiochemical method. MATERIALS AND METHODS: Saline (sham treatment) or botulinum toxin A was injected into the bladder (50 microl.) or urethra (30 microl.) in separate groups of animals. The release of 3H-norepinephrine or 14C-choline was measured at 2 time points after injection (5 or 30 days). RESULTS: The fractional release of ACh in botulinum toxin A treated animals was significantly inhibited at higher frequencies of electrical field stimulation (20 Hz.) but not at lower frequencies (2 Hz.) 5 days after injection. However, ACh release recovered to sham injected values 30 days after toxin injection. No significant differences in the fractional release of norepinephrine from sham injected or botulinum toxin A bladders were observed. In contrast, norepinephrine release from the urethra was inhibited by botulinum toxin A for at least 30 days after injection. Similar to its effect on transmitter release in the bladder, botulinum toxin A inhibited norepinephrine release in the urethra at high (20 Hz.) but not at low (4 Hz.) electrical stimulation frequencies. CONCLUSIONS: These data indicate that the clinical effects of botulinum toxin A on the lower urinary tract may vary depending on the site of injection and level of nerve activity.

Acetylcholine↗

PubMed2003

Pharmacokinetics, metabolism, and saliva output during transdermal and extended-release oral oxybutynin administration in healthy subjects.

OBJECTIVE: To compare the pharmacokinetics and adverse effect dynamics of 2 modified-release oxybutynin treatments. SUBJECTS AND METHODS: Between October 15 and November 6, 2001, 13 healthy subjects (7 men and 6 women) participated in a randomized, 2-way crossover study of transdermal (Oxytrol, 3.9 mg/d) and extended-release oral (Ditropan XL, 10 mg) oxybutynin. Multiple blood and saliva samples were collected. Pharmacokinetic parameters and total salivary output were assessed. Statistical analyses included 95% confidence intervals, paired t test, analysis of variance, and linear regression. RESULTS: Steady-state plasma concentrations were achieved after the first transdermal application and after the second extended-release oral dose. Mean +/- SD 24-hour oxybutynin areas under the concentration-time curve were comparable during transdermal and oral extended-release treatments, 10.8 +/- 24 vs 9.2 +/- 33 ng x h(-1) x mL(-1), respectively. However, the ratio of area under the curve (N-desethyloxybutynin/oxybutynin) after transdermal administration (1.2 +/- 03) was significantly lower (P < .001) than after extended-release oral administration (4.1 +/- 0.9). Mean plasma concentrations were less variable during transdermal compared with extended-release oral administration. Mean +/- SD saliva output was greater during transdermal than extended-release oral treatment (15.7 +/- 93 vs 12.2 +/- 6.8 g, respectively; P = .02). Lower N-desethyloxybutynin during transdermal application was associated with greater saliva output (r = -059, P = .04). No clinically important treatment-related adverse effects were observed. CONCLUSIONS: Transdermal oxybutynin administration results in greater systemic availability and minimizes metabolism to N-desethyloxybutynin compared with extended-release oral administration. Lower N-desethyloxybutynin plasma concentration and greater saliva output during transdermal treatment correspond to the reported low incidence of dry mouth in patients with overactive bladder.

Administration, Cutaneous↗

PubMed2003

Botulinum toxin treatment of urethral and bladder dysfunction.

Botulinum toxin (BTX) is the most lethal naturally occurring toxin known to mankind. Injection of BTX into the urethral sphincter or bladder is an effective treatment for lower urinary tract dysfunction. We reviewed the literature on the mechanisms of action and clinical efficacy of BTX treatment in urologic diseases, with a focus on lower urinary tract dysfunction. Injection of BTX is safe and effective in the treatment of detrusor-sphincter dyssynergia, non-neurogenic pelvic floor spasticity, and refractory overactive bladder. Urodynamic assessment after sphincter injection with BTX reveals a decrease of bladder voiding pressure, urethral pressure profile, and post-void residual urine. An increase of the functional bladder capacity and a decrease of the bladder voiding pressure can be seen after bladder injection with BTX. Clinical improvement was found in a moderate percentage of treated patients in most reported series and lasted for 3 to 14 months without significant adverse effects. In addition, BTX-A treatment inhibits afferent-nerve-mediated bladder contraction. This analgesic effect may expand the application of BTX in the localized genitourinary tract pain syndrome, such as interstitial cystitis and prostatodynia. In conclusion, application of BTX is a promising treatment for lower urinary tract dysfunction with profound basic and clinical implications.

Anti-Dyskinesia Agents↗

PubMed2002

Effect of cryoinjury on the contractile parameters of bladder strips: a model of impaired detrusor contractility.

In anesthetized Sprague-Dawley rats, the bladder was exposed and cryoinjury was induced by abruptly freezing the serosal side of the bladder wall with a chilled aluminum rod previously placed on dry ice (-40 degrees C). Five days later, the rats were euthanized, and strips were prepared from the area adjacent to the injury. Neurally and alpha,beta methylene-ATP (alpha,beta m-ATP; 50 microM)-evoked contractions were measured in bladder strips from cryoinjured or intact bladders prepared from sham-operated rats. Cryoinjured bladder strips produced significantly lower contractile forces than intact strips to electrical stimulation at higher (10-40 Hz) frequencies. The maximal rate of the neurally evoked contractions was slower in the cryoinjured bladders. The contractile response to alpha,beta m-ATP was smaller in the cryoinjured preparations indicating that the changes may have also occurred at the postjunctional site. In addition, atropine was more effective at inhibiting the neurally evoked contractions in the cryoinjured bladder strips suggesting that a cholinergic dominance occurs after cryoinjury. It is concluded that cryoinjury is a viable method of causing a defined, reproducible injury to the urinary bladder resulting in impaired function of both the cholinergic transmission and the smooth muscle. The bladder cryoinjury can be used as a model for studying impaired bladder compliance and detrusor contractility as well as treatments that may improve bladder function such as tissue engineering.

Adenosine Triphosphate↗

PubMed2002

Muscle derived cell mediated ex vivo gene transfer to the lower urinary tract: comparison of viral vectors.

Gene therapy is a novel form of molecular medicine that may have a major impact on the future of human health care. We explored the efficacy of skeletal muscle derived cells (MDC) transduced with four viruses for ex vivo gene transfer into the lower urinary tract. Primary MDC were isolated from normal neonatal rats and transduced with: (1). adenovirus, (2). herpes simplex virus type-1 (HSV-1), (3). retrovirus or (4). adeno-associated virus (AAV), all of which express the beta-galactosidase reporter gene. Adult Sprague Dawley rats ( n=4 each group-time) were used. The MDC were injected into the right and left lateral bladder walls. The number of injected MDC ranged from 1 to 1.5 x 10(6). The tissues were harvested after 1, 4, 7, and 15 days, sectioned and assayed for beta-galactosidase expression. In the bladder wall, we noted cells expressing beta-galactosidase for each viral group. Adenoviral and HSV-1 transduced cells showed strong expression at 1 and 4 days post-injection, but the expression decreased gradually and was not detectable at 15 days post-injection. Retroviral transduced cells were detected at each time point with a strong expression persisting for 15 days but decreasing gradually over time. Although expression of the AAV transduced cells was initially weak, the later time points exhibited a much stronger expression, especially at day 7 post-injection. This expression persisted for at least 15 days post-injection. In conclusion, successful MDC mediated ex vivo gene transfer into the lower urinary tract was achieved with all four viral vectors. Our results suggest that the ex vivo approach may lead to an efficient and persistent viral gene delivery to the lower urinary tract while minimizing exposure of the host to virus.

Adenoviridae↗

PubMed2002

Effect of KW-7158, a putative afferent nerve inhibitor, on bladder and vesico-vascular reflexes in rats.

The effects of KW-7158, a putative afferent nerve inhibitor, on reflex bladder activity and vesico-vascular reflexes were evaluated in urethane anesthetized SD rats with normal and xylene-irritated bladders. The bladder was filled with saline until the appearance of large amplitude spontaneous bladder contractions (LA-BC). Vesico-vascular reflexes were measured as increases in systolic arterial blood pressure during LA-BC or when the bladder was distended by a range of pressures. In normal rats, KW-7158 (10 and 100 microg/kg, i.v.) did not alter the amplitude or volume threshold for inducing LA-BC but increased the intercontraction interval. After xylene-irritation, which decreased volume threshold and intercontraction interval and induced small amplitude bladder contractions, KW-7158 increased volume threshold (65%) and intercontraction interval (150%) and decreased the number of small amplitude bladder contractions. Vesico-vascular reflexes induced during LA-BC or by bladder distension were suppressed (19.4-100%) by KW-7158. The effect of KW-7158 to depress vesico-vascular reflexes as well as xylene-induced bladder hyperactivity without altering the amplitude of contractions is consistent with the view that the drug affects reflex bladder activity at least in part by depressing afferent pathways.

Animals↗

PubMed2002

Emerging role of botulinum toxin in the treatment of neurogenic and non-neurogenic voiding dysfunction.

Botulinum toxin (BTX) is the most lethal naturally occurring toxin known to mankind. Why, then, would an urologist want to use this agent to poison the bladder or urethral sphincter? This article reviews the mechanisms underlying the effects of BTX treatment, summarizes the current usage of this agent within the urologic community, and provides perspectives on future targets of this therapy.

Anti-Dyskinesia Agents↗

PubMed2002

Current and future pharmacological treatment for overactive bladder.

PURPOSE: Urinary incontinence and overactive bladder are important and common conditions that have received little general medical attention. We reviewed the magnitude and impact of these conditions, and discuss pharmacotherapy as well as new drugs under investigation. MATERIALS AND METHODS: The main emphasis of this review is pharmacological therapy for the bladder. We discuss currently available agents, drugs under development and pharmacological targets that would be suitable targets for treating overactive bladder. Drugs such as duloxetine that target not bladder smooth muscle, but rather central nervous system control of the micturition reflex are undergoing clinical trials. We also discuss intravesical therapy and alternative drug delivery methods, such as intravesical capsaicin and botulinum toxin, with special emphasis on approaches to modulate bladder afferent nerve function for preventing overactive bladder. RESULTS: There are many advantages to advanced drug delivery systems, including long-term therapeutic efficacy, decreased side effects and improved patient compliance. Future speculation such as gene therapy holds great promise for overactive bladder because it is possible to access all genitourinary organs via endoscopy and other minimally invasive techniques that are ideally suited for gene therapy. CONCLUSIONS: Traditional anticholinergic therapies are limited in their effectiveness. There is great hope for future research regarding voiding dysfunction and urinary incontinence through a focus on afferent nerve intervention for preventing overactive bladder.

Adult↗

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↗