Bladder Hyperreflexia Research Articles

Enterocistoplastia de ampliación laparoscópica: experiencia inicial

ObjectiveTo analyze the initial experience of our group in the realization of the augmentation enterocystoplasty by laparoscopyc approach. Methods and patientsWe describe the augmentation enterocystoplasty technique with ileal segment completely achieved by laparoscopyc approach. We present the cases of two patients suffering from hyperreflexic bladder refractory to medical treatment who underwent this surgery. In both cases the technique was realized without intraoperative complications although it was needed a surgical time of 6 and 4,5 hours respectively. The results after 12 and 5 months were satisfactory in both patients, obtaining a low pressure bladder with a good continence. ConclusionsLaparoscopyc augmentation enterocystoplasty is a complicated technique that requires a great experience, mainly in laparoscopyc suture. It reproduces completely the open surgery and it offers all the advantages inherent to the laparoscopyc surgery.

Migration of a bullet in the spinal canal

Migration of a bullet within the spinal canal after gunshot injury is rare. We report here the case of a penetrating gunshot injury of the lumbar spine at L3 with migration of the bullet within the spinal canal S2. The patient had marked paraparesis (proximal 1/5, distal 0/5 muscle strength) and anaesthesia at L3 and below, and had a hypocompliant, hyper-reflexive bladder with decreased capacity, and absent anal tonus. We removed osseous fragments in the canal with an L3 laminectomy and extracted the bullet by S2 laminectomy. After surgery, we observed an improvement in paraparesis, an increase in bladder capacity and urinary compliance, and improvement in anal tonus. The appropriate course of action in this type of injury remains unclear, because the number of cases described in the literature is not sufficient to provide a basis on which to make a definitive therapeutic decision. We herein review the literature describing cases in which a bullet in the spinal canal has migrated; we describe the treatment used and the outcomes in these cases.

Closed Loop Electrical Control of Urinary Continence

Individuals with spinal cord injury or neurological disorders may have neurogenic detrusor contractions at low volumes (bladder hyperreflexia), which cause incontinence and can lead to significant health problems. Bladder contractions can be suppressed by electrical stimulation of inhibitory pathways but continuous activation may lead to habituation of the inhibitory reflex and loss of continence. We determined whether conditional stimulation with electrical stimulation of inhibitory pathways applied only at the onset of nascent bladder contractions allows the bladder to fill to a greater volume before continence is lost compared with continuous stimulation. In 6 alpha-chloralose anesthetized cats cystometry was performed to compare the volume at which continence was lost under the conditions of no stimulation, continuous stimulation and conditional electrical stimulation of inhibitory pathways. PNT ENG was used to detect the onset of bladder contractions and it served as the input to an event triggered control system that regulated conditional stimulation to maintain continence. Conditional stimulation controlled by PNT ENG increased bladder capacity by 36% over no stimulation and by 15% over continuous stimulation (p <0.001 and 0.027, respectively). The event triggered control system decreased stimulation time by 67% compared to continuous stimulation. Conditional electrical stimulation of inhibitory pathways is more effective than continuous stimulation. A control system triggered by PNT ENG can maintain urinary continence.

Micturition syncope following intermittent catheterisation in a tetraplegic patient

Case report. To describe a case of severe hypotension and occasional syncope following intermittent catheterisations in a tetraplegic patient. Department of Spinal Injuries, Berck, France. A 47-year-old man presenting with C7 ASIA B tetraplegia for 9 months, developed episodes of severe hypotension and occasional syncope following intermittent catheterisations. These episodes were observed in the minutes following the catheterisations performed in the sitting position, associating hypotension and bradycardia. He was on intermittent catheterisation, had a history of bladder hyper-reflexia with some episodes of symptomatic urinary tract infections, of mild autonomic dysreflexia (headache, sweating) on high bladder distension, of mild orthostatic hypotension, and of reactional depression to the trauma, treated with fluoxetine hydrochloride (Prozac). The progressive removal of the fluoxetine hydrochloride (Prozac) led to disappearance of the syncope 1 week later. Mild hypotension after catheterisations still persisted though, but completely disappeared a few months later after further management of bladder hyper-reflexia with botulinum-A toxin injections into the detrusor. In spinal cord injury patients at risk of micturition syncope, care should be taken to achieve a gradual decrease in bladder volume, to control bladder hyper-reflexia and to avoid any medications with orthostatic hypotension's side effects.

The Effect and Mechanism of Intravesical Electrical Stimulation in Spinal Cord Injured Rats

Purpose: The objective of this study was to evaluate whether the effect on afferent c-fiber activity is the underlying mechanism of intravesical electrical stimulation (IVES) in spinal cord injured rats. Materials and Methods: Thirty five female Sprague-Dawley rats weighting 200-300g each were divided into the normal and spinalized groups. For the spinalized rats, we observed the c-fos expression, and we compared this in the non-IVES group with that in the IVES group. Cystometrograms were performed for all the groups via a suprapubic catheter. Results: After performing IVES in the normal and spinalized rats, the abnormal increases of the intercontraction interval (ICI) and the voiding pressure (VP) were reduced close to the normal range. In the spinalized rats, the number of c-fos positive cells in the dorsal commissure (DCM) decreased in the group that had IVES performed when compared with the non-IVES group. Conclusions: The IVES reduced the c-fos gene expression in the L6-S1 spinal cord segment and also the bladder hyperreflexia in the spinalized rats through the inhibition of afferent c-fiber activity, in addition to affecting the Aδ mechanoreceptors. (Korean J Urol 2006;47:303-309) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Structural basis of neurogenic bladder dysfunction. III. Intrinsic detrusor innervation.

We studied the ultrastructure of intrinsic detrusor innervation in long-standing neurogenic bladder dysfunction in the human. Endoscopic or open detrusor biopsies were obtained from 15 female and 31 male patients 7 to 96 years old who had hyperreflexic neurogenic bladder dysfunction for less than 1 to 43 years. Of the patients 9 had meningomyelocele, 25 had spinal cord injury and 12 had a brain disorder. Changes in intrinsic detrusor nerves were evaluated by electron microscopy qualitatively and quantitatively according to predefined criteria. Axonal degeneration was observed in 44 of the 45 biopsies with discernible intrinsic nerves. Structurally normal axons were 5(1/2) or 4 times more common in brain disorder than meningomyelocele or spinal cord injury group biopsies (median 33%, 6%, 8%, respectively). Axonal regeneration, not encountered in nonneuropathic dysfunctional detrusors, was observed in restricted distribution in most biopsies (76%) and was independent of the duration of neurogenic bladder dysfunction. Axon sprouts were observed in 17 biopsies (38%), and copeptidergic axons formed 20% (median per biopsy) of discernible axon profiles in contrast to less than 1% in normal detrusor. Activated Schwann cells were observed in all but 1 biopsy. The axonal changes were not associated with the level or degree of spinal cord lesion in patients with meningomyelocele or spinal cord injury. Combined degeneration and regeneration is the characteristic change in intrinsic nerves of detrusor in upper motoneuron neurogenic bladder dysfunction. The observed changes offer the possibility of clinically recognizing neuropathic contribution to a dysfunctional detrusor, as well as the potential to distinguish its spinal versus supraspinal etiology.

Detecting the onset of hyper-reflexive bladder contractions from the electrical activity of the pudendal nerve

Individuals with a spinal cord injury or neurological disorders may develop involuntary bladder contractions at low volumes (bladder hyper-reflexia), which can lead to significant health problems. Present devices can inhibit unwanted contractions through continuous stimulation, but do not enable conditional stimulation only at the onset of bladder contractions. The objectives of this study were to determine the relationship between the electrical activity of the pudendal nerve trunk (PNT) and bladder pressure during hyper-reflexive bladder contractions and to determine whether PNT activity could be used to detect the contractions. Bladder pressure and PNT electroneurogram (ENG) were recorded in eight adult male cats. The PNT ENG activity increased at the onset of a bladder contraction and the activity during bladder contractions was greater than during the intercontraction interval (p < 0.001). Three algorithms were developed to detect the onset of a bladder contraction from the PNT ENG activity. A cumulative sum (CUSUM) algorithm performed better than either a constant threshold or a dynamic threshold algorithm, and enabled detection of reflex bladder contractions from the PNT ENG an average of 1.2 s after the contraction started with an average increase in pressure 7.1 cm H2 x O when evaluated on data not used to set detection parameters. These data demonstrated that recordings from the PNT could be used to detect hyper-reflexive bladder contractions and provide a signal to control closed-loop inhibitory stimulation.

Inyección de toxina botulínica en disfunción vesical neurogénica y no neurogénica

Botulinum toxin A (BT A) has gained popularity among urologists in the treatment of detrusor muscle dysfunctions. The aim of this article is to review our experience with this therapy From 2001 we used BT A in 28 patients. It was injected in the bladder wall under cystoscopical vision. We analyze the indication of treatment, clinical data and urodynamics before and after treatment. We treated 28 patients. 71 percent had neurogenic hyperreflexic bladder, 18% idiopathic unstable bladder and 11% other diseases. No direct complications were observed. Neurogenic hyperreflexic bladder (n = 20): Mean preoperative bladder capacity was 220 cc, improving to 430 cc after treatment. Non inhibited contractions disappeared. All patients except one with multiple sclerosis, who had spontaneous voiding, required self catheterization after injection. Average time interval between injections was 8.6 months. Idiopathic unstable bladder (n = 5): a lower dose was used, with an average of 100 U. Non inhibited contractions disappeared and all patients were able to maintain spontaneous voiding with post void residuals under 50 ml. No patients required self catheterization. Bladder capacity improved from 128 ml to 370 ml. Average number of voidings per day diminished from 16 to 7 times. Other diseases (n = 3): results were poor in these patients. There were no changes in either bladder function studies or average voiding frequency (15 times per day). These patients required surgery for bladder augmentation in 2 cases and continent diversion in 1 case. BT A has a role in the treatment of neurogenic hyperreflexic bladder diminishing incontinence and improving bladder capacity. In cases of idiopathic unstable bladder without anatomical changes its results are promising, but a limited number of patients does not allow a definitive conclusion. In other bladder diseases with anatomical changes results are poor and its use should not be routinely recommended.

Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin

Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+) permeable non-selective cation channel activated by physical and chemical stimuli. Resiniferatoxin (RTX), an ultrapotent agonist of TRPV1, is under investigation for treatment of urinary bladder hyper-reflexia and chronic pain conditions. Here, we have determined the characteristics of RTX-induced responses in cells expressing native and cloned rat TRPV1. Whole-cell currents increase with repeated application of submaximal concentrations of RTX until a maximal response is attained and do not deactivate even after prolonged washout. Interestingly, the rate of activation and block by capsazepine of RTX-induced currents are significantly slower than for capsaicin-induced currents. RTX-induced whole-cell currents are outwardly rectifying, but to a lesser extent than capsaicin-induced currents. RTX-induced single channel currents exhibit multiple conductance states and outward rectification. The open probability (P(o)) of RTX-induced currents is higher at all potentials as compared to capsaicin-induced currents, which showed a strong voltage-dependent decrease at negative potentials. Single-channel kinetic analyses reveal that open-time distribution of RTX-induced currents can be fitted with three exponential components at negative and positive potentials. The areas of distribution of the longer open time constants are significantly larger than capsaicin-induced currents. The closed-time distribution of RTX-induced currents can be fitted with three exponential components as compared to capsaicin-induced currents, which require four exponential components. Current-clamp experiments reveal that low concentrations of RTX caused a slow and sustained depolarization beyond threshold while generating few action potentials. Concentrations of capsaicin required for the same extent of depolarization generated a significantly greater number of action potentials. These properties of RTX may play a role in its clinical usefulness.

Influence of estradiol on micturition thresholds in the rat: involvement of the hypogastric nerve

Studies have shown that the severity of bladder hyperreflexia induced by acute bladder inflammation varies with the ovarian cycle. These results suggest that the hyperreflexia is modulated by ovarian hormones. Other studies have suggested that such modulation involves the bladder's sympathetic innervation. These hypotheses were tested by assessing the development of bladder hyperreflexia in urethane-anesthetized rats subjected to different hormonal manipulations with or without bilateral hypogastric neurectomy (HYPX). The groups included sham ovariectomy (sham OVX), ovariectomy (OVX), OVX with estradiol replacement (OVX+E), OVX+HYPX, and OVX+HYPX+E. Assessments were performed using repeated cystometrograms (CMGs) to measure micturition thresholds (MT) before and hourly for 3 h after intravesicular treatment with 50% turpentine oil (or olive oil in an OVX+E control group). In the uninflamed bladder, treatment with estradiol increased MTs in the OVX+E group compared with the OVX group. As expected, bladder inflammation induced bladder hyperreflexia in sham OVX rats (studied in estrus). This hyperreflexia was eliminated by OVX and restored by either estradiol replacement or HYPX. Combining estradiol replacement and HYPX (i.e., OVX+E+HYPX) did not increase the severity of bladder hyperreflexia compared with either manipulation alone. These results indicate that the bladder hyperreflexia that is induced by bladder inflammation requires the presence of estradiol and suggest that this hormonal modulation is exerted via the sympathetic control of the bladder, possibly via an increase of beta-adrenergic inhibitory actions on the detrusor muscle. Similar mechanisms may contribute to bladder disorders in postmenopausal women.

AN ARTIFICIAL SOMATIC-AUTONOMIC REFLEX PATHWAY PROCEDURE FOR BLADDER CONTROL IN CHILDREN WITH SPINA BIFIDA

Neurogenic bladder is a major problem for children with spina bifida. Despite rigorous pharmacological and surgical treatment, incontinence, urinary tract infections and upper tract deterioration remain problematic. We have previously demonstrated the ability to establish surgically a skin-central nervous system-bladder reflex pathway in patients with spinal cord injury with restoration of bladder storage and emptying. We report our experience with this procedure in 20 children with spina bifida. All children with spina bifida and neurogenic bladder underwent limited laminectomy and a lumbar ventral root (VR) to S3 VR microanastomosis. The L5 dorsal root was left intact as the afferent branch of the somatic-autonomic reflex pathway after axonal regeneration. All patients underwent urodynamic evaluation before and after surgery. Preoperative urodynamic studies revealed 2 types of bladder dysfunction- areflexic bladder (14 patients) and hyperreflexic bladder with detrusor external sphincter dyssynergia (6). All children were incontinent. Of the 20 patients 17 gained satisfactory bladder control and continence within 8 to 12 months after VR microanastomosis. Of the 14 patients with areflexic bladder 12 (86%) showed improvement. In these cases bladder capacity increased from 117.28 to 208.71 ml, and mean maximum detrusor pressure increased from 18.35 to 32.57 cm H2O. Five of the 6 patients with hyperreflexic bladder demonstrated improvement, with resolution of incontinence. Urodynamic studies in these cases revealed a change from detrusor hyperreflexia with detrusor external sphincter dyssynergia and high detrusor pressure to nearly normal storage and synergic voiding. In these cases mean bladder capacity increased from 94.33 to 177.83 ml, and post-void residual urine decreased from 70.17 to 23.67 ml. Overall, 3 patients failed to exhibit any improvement. The artificial somatic-autonomic reflex arc procedure is an effective and safe treatment to restore bladder continence and reverse bladder dysfunction for patients with spina bifida.

Percutaneous electrical stimulation of sensory nerve fibers to improve motor function: applications in voiding dysfunction

Abstract The aim of this study was to describe the clinical applications of percutaneous electrical stimulation to sensory nerve fibers to improve motor function and its limitation. Semi-conditional dorsal penile nerve stimulation was used in this study to improve the storage function of the bladder in patient with spinal cord injury. The result of percutaneous electrical stimulation was compared with that of transcutaneous electrical stimulation. Seven subjects, who showed favourable results in suppression of bladder hyper-reflexia by transcutaneous, were tested using percutaneous electrical stimulation to compare the effect. For the transcutaneous stimulation surface electrodes with 1 cm diameters were used. The cathode and anode were placed, proximally and distally, respectively, on the dorsum of the penile shaft. For the percutaneous stimulation two sets of paired wire electrodes were placed in subcutaneous layer of dorsum of penile shaft, using guide needle. We applied dorsal penile nerve (DPN) stimulation using portable stimulator during the continuous bladder filling. Stimulation parameters were biphasic rectangular pulses of 25 Hz frequency, 250 μs pulse width. The 1 min stimulation was repeated to every reflex contraction during the cystometry. Immediate suppressive effect of DPN was analyzed. The infused volume of saline at the first and last reflex contraction during the percutaneous stimulation was not significantly different from that during the transcutaneous stimulation. The duration of suppression at the first and the last reflex contraction was not significantly different between two method of current delivery. The peak detrusor pressure ( P max ) were effectively suppressed by transcutaneous and percutaneous DPN stimulation. There were no statistically significant differences in baseline detrusor pressure ( P ini ), P max and suppressed pressure ( P sup ), between two stimulation techniques. Percutaneous electrical stimulation of neural pathway has definitive advantage compared with transcutaneous method. To get percutaneous stimulation into clinical practice, however, current limitation, such as, risk of infection, difficulties in placement to proper position, durability and affinity should be improved.

INFLAMMATION OF THE RAT PROSTATE EVOKES RELEASE OF MACROPHAGE MIGRATION INHIBITORY FACTOR IN THE BLADDER: EVIDENCE FOR A VISCEROVISCERAL REFLEX

Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, is found in preformed stores in bladder epithelium. We examined the effects of prostatic inflammation on micturition frequency, bladder histology and bladder MIF content as a model in which to study viscerovisceral reflexes mediating pelvic visceral inflammation. Cystometry was performed in urethane anesthetized male rats. Formalin or saline was injected into the ventral lobe of the prostate to induce inflammation. Cystometry continued 1 hour after injection. The bladder, ventral lobes of the prostates and lumbosacral spinal cord were then removed, and protein levels and gene expression of MIF, cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) were examined. Edema was verified histologically in the bladder and prostate. Intraprostatic formalin produced almost immediate bladder hyperreflexia, which was maintained during the observation period. Bladder edema was noted during histological examination. Bladder MIF protein amounts decreased, while COX-2 and NGF increased after prostatic injection. Bladder MIF, COX-2 and NGF mRNA increased. In the lumbosacral spinal cord protein and mRNA amounts increased for all factors examined in animals that received intraprostatic formalin. No changes were observed in the cervical cord. Rats injected with formalin mixed with dye showed restriction of the dye to the prostate. A viscerovisceral reflex in the rat, probably mediated by the lumbosacral spinal cord, produced bladder hyperreflexia and bladder edema, and evoked MIF release from the bladder and the induction of other inflammatory mediators. This supports our hypothesis that MIF is involved in neurogenic inflammation in the pelvic viscera and it may represent an interesting therapeutic target.

Les troubles vésicosphinctériens de la maladie de Parkinson

Parkinson's disease related to degeneration of the extrapyramidal structures is characterized in its typical form by the classic triad of tremors, rigidity and akinesia, constituting Parkinson's syndrome. These are combined with neurovegetative disorders, responsible for sexual and bladder sphincter dysfunction. The latter occurs in from 30 to 90 % of cases, depending on the stage of progression of the disease. The dopamine deficiency in the nigrostriatal tract leads to a lifting of the inhibition which is probably the cause of the bladder hyperreflexia. Irritative signs are most frequently observed. The flowmetry data are contradictory, depending on the publication whereas the bladder overactivity, objectified by cystomanometry, is described in most of the studies although certain authors report, on the contrary, bladder hypoactivity. Conflicting data have also been published on bladder sphincter dyssynergia although in most studies, micturition was described as synergic in Parkinson's disease patients. L-dopa, the main drug for Parkinson's disease, has, according to the publication, either no action, or contradictory effects with bladder hypoactivity or hyperactivity. Anticholinergics are effective on overactive bladder, the alphablockers on the urethral hypertonia at the price of a higher risk of arterial hypotension in this diathesis. The indication for prostatic surgery must be carefully considered and preceded by precise clinical, urodynamic and sometimes electromyography evaluation. There is a high risk of post surgical incontinence. Endourethral prostheses provide an attractive alternative in the case of prostatic obstruction.

Acute renal failure associated with dysfunctioning detrusor muscle in multiple sclerosis

Patients with multiple sclerosis (MS) typically have neurogenic lower urinary tract dysfunction. Most patients present with bladder hyperreflexia and failure to empty the bladder secondary to detrusor-distal sphincter dyssynergia. This case study is unique in the literature in reporting on a patient presenting with acute renal failure (ARF) due to vesico-sphincter dysfunction associated with MS. A 64-year-old man with MS presented in the emergency department with the chief complaint of a marked decrease in urinary output for 2 days and weakness. He had been treated for MS for 7 years. A mass compatible with a full bladder was palpated in the suprapubic region on examination. Digital rectal examination disclosed grade I-Il prostate hypertrophy. Urinary catheters were inserted and urinary output was monitored. The residual urine was drained and recorded as 1100 mL. Initial laboratory findings, such as the BUN/creatinine ratio, urinary sodium concentration, and urine gravity, were compatible with ARF. The patient recovered rapidly in 24 hours following urinary catheterization and prompt medication in the emergency department. He was admitted to the neurology ward with a diagnosis of acute urinary outflow obstruction resulting in ARF due to detrusor dysfunction complicating an MS attack. ARF may complicate the course of patients with MS and associated detrusor-external sphincter dyssynergia. Renal recovery of these patients may be facilitated by urinary catheterization and supportive treatment.

Bladder and urethral sphincter responses evoked by microstimulation of S2 sacral spinal cord in spinal cord intact and chronic spinal cord injured cats

Urinary bladder and urethral sphincter responses evoked by bladder distention, ventral root stimulation, or microstimulation of S2 segment of the sacral spinal cord were investigated under α-chloralose anesthesia in cats with an intact spinal cord and in chronic spinal cord injured (SCI) cats 6–8 weeks after spinal cord transection at T9–T10 spinal segment. Both SCI and normal cats exhibited large amplitude reflex bladder contractions when the bladder was fully distended. SCI cats also exhibited hyperreflexic bladder contractions during filling and detrusor–sphincter dyssynergia during voiding, neither was observed in normal cats. Electrical stimulation of the ventral roots revealed that the S2 sacral spinal cord was the most effective segment for evoking large amplitude bladder contractions or voiding in both types of cats. Microstimulation with a stimulus intensity of 100 μA and duration of 30–60 s via a single microelectrode in the S2 lateral ventral horn or ventral funiculus evoked large amplitude bladder contractions with small urethral contractions in both normal and SCI cats. However, this stimulation evoked incomplete voiding due to either co-activation of the urethral sphincter or detrusor–sphincter dyssynergia. Stimulation in the S2 dorsal horn evoked large amplitude sphincter responses. The effectiveness of spinal cord microstimulation with a single electrode to induce prominent bladder and urethral sphincter responses in SCI animals demonstrates the potential for using microstimulation techniques to modulate lower urinary tract function in patients with neurogenic voiding dysfunctions.

Drug stability testing to support clinical feasibility investigations for intrathecal baclofen-clonidine admixture

For a spinal cord injury patient, control of spasticity and bladder hyperreflexia can be obtained with the use of an intrathecal baclofen-clonidine admixture. The purpose of this study was to evaluate stability and compatibility of baclofen-clonidine admixtures in an implantable infusion system that could be used to treat patients. Implantable infusion systems and glass vials were filled with three different concentrations of admixture and maintained at 37°C for 16 weeks. Samples were collected every two weeks. Drug concentrations were determined using a validated high-performance liquid chromatography method. No modification of the physical appearance of the admixture was observed during the 16-week follow-up and the pH value variations were less than 0.5 units from those of initial samples. Until Week 14, both clonidine and baclofen concentrations were above 90% of the initial values. At Week 16, the drug concentrations had declined by more than 10% only in the implantable pump reservoir, but remained greater than 90% of the original concentration in all other vials. This study showed a good stability for both compounds until at least Week 14 and supports clinical feasibility investigations for intrathecal baclofen-clonidine admixture using implantable pump with refills every 12 or 14 weeks. This study also supports the idea that long-term studies of drug stability may be more accurate if performed in the pump rather than in glass vials.

KW-7158 [(2S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] enhances A-type K+ currents in neurons of the dorsal root ganglion of the adult rat.

Recent studies revealed that a new compound, KW-7158 [(2S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide], can depress the excitability of afferent pathways from the urinary bladder and reduce bladder overactivity induced by chemical irritation of the urinary tract with xylene, an agent that sensitizes capsaicin-sensitive, C-fiber afferent nerves. In the present experiments, we examined the mechanisms that might underlie the depressant effect of KW-7158 on primary afferent neurons by studying the actions of the compound on ion channels and firing in dissociated dorsal root ganglion (DRG) cells from adult rats using whole cell patch-clamp techniques. KW-7158 increased transient, A-type K+ currents at concentrations ranging from 50 nM to 1 microM (20-50% increases). Similar effects were seen in fast blue identified bladder afferent neurons. Low concentrations of KW-7158 shortened the action potential duration, produced a 5- to 10-mV hyperpolarization, and inhibited repetitive firing induced by either 4-AP (50 microM) or substance P (0.5 microM) in phasic firing DRG neurons. Above 1 microM, KW-7158 elicited a smaller enhancement of A-type K+currents and in high concentrations inhibited the currents. Tetraethylammonium (5-60 mM) and verapamil (50 microM), which block noninactivating K+ currents, did not prevent the facilitatory effects of KW-7158. High concentrations of 4-AP (5 mM) inhibited A-type K+ currents and prevented the facilitatory effect of KW-7158 on the remaining currents. These data suggest that KW-7158 enhances A-type K+ currents in DRG neurons. Because A-type K+ channels regulate afferent neuron excitability and firing properties, KW-7158 is a promising new compound for treatment of hyper-reflexic bladder conditions.

Urine 8-isoprostane F 2α concentrations in patients with neurogenic bladder due to spinal cord injury

Background: Isoprostanes are prostaglandin-like end products of arachidonic acid peroxidation that are produced by a free radical-catalyzed mechanism. Considering its free radical-dependent formation and potent contractor effect, it is postulated that isoprostane 8-iso PGF 2α may play an important role in oxidative stress-related smooth muscle dysfunction. These substances may also influence bladder activity directly by effects on the smooth muscle. The present study was designed to measure traditional biochemical parameters (MDA, TAS, vitamin E) in plasma and 8-iso PGF 2α concentrations in urine of patients with spinal cord injury and to evaluate the relation of urinary isoprostane concentrations to the bladder function. Methods: All spinal cord patients underwent urodynamic evaluations. The biochemical tests were performed in both hyperreflexic bladder group ( n=23) and areflexic bladder group ( n=10), and the findings were compared to those of the patients with normally functioning bladder (controls, n=19). Results: Urine 8-iso PGF 2α concentrations were significantly increased in hyperreflexic group (median value 0.89 pg/mg creatinine) compared to both control (0.52 pg/mg creatinine) and areflexic groups ( p<0.001). The lowest concentrations of urinary 8-iso PGF 2α were observed in the areflexic group (0.22 pg/mg creatinine), and these were positively correlated to the plasma MDA concentrations in areflexic patients ( p=0.05; r=0.684). Conclusion: Isoprostanes may be involved in the pathogenesis of neurogenic bladder dysfunction. It may be of value to determine the urinary concentrations of 8-iso PGF 2α in order to distinguish areflexic bladders from the hyperreflectics.

VR1 receptor modulators as potential drugs for neuropathic pain.

The involvement of VR(1) in the endogenous pain signalling has converted this receptor into a promising therapeutic target for the development of a new family of potent analgesics devoid of the shortcomings of other analgesics commonly used. The desensitisation induced after VR(1) activation points to the utility of VR(1) agonists for the treatment of various nociceptive disorders including mitigation of neuropathic pain, inhibition of neurogenic inflammation and suppression of urinary bladder hyperreflexia, whereas VR(1) antagonists have been described as valuable agents for the treatment of inflammatory hyperalgesia and pain. Structure of the main classes of VR(1) ligands developed to date, their molecular mechanisms of action and their promising utility for the management of diverse nociceptive alterations, specially neuropathic pain, are discussed in this review.