Conditional stimulation of the dorsal penile/clitoral nerve may increase cystometric capacity in patients with spinal cord injury

AIMS: To investigate the feasibility of conditional short duration electrical stimulation of the penile/clitoral nerve as treatment for detrusor hyperreflexia, the present study was initiated. METHODS: Ten patients with spinal cord injury, 4 women and 6 men, with lesions at different levels above the sacral micturition center had a standard cystometry performed. During a subsequent cystometry, conditional short duration electrical stimulation of the penile/clitoral nerve was performed as treatment for one or more detrusor hyperreflexic contractions. RESULTS: In all patients, at least one contraction (mean, 7.8; range, 1-16 contractions) was inhibited by the stimulations. The mean cystometric capacity was increased significantly by conditional electrical stimulation, from 210 mL in the control cystometries to 349 mL in the stimulation cystometries (P=0.016). The maximal detrusor pressure during the first contraction in the control cystometries was mean 51 cm H(2)O, whereas the maximal pressure of the first contraction in the stimulation cystometries was reduced to mean 33 cm H(2)O (P=0.045). CONCLUSIONS: The authors conclude that repeated conditional short duration electrical stimulation significantly increased cystometric capacity in patients with spinal cord injury. The increase was caused mainly by an inhibition of detrusor contractions. The need for a reliable technique for chronic bladder activity monitoring is emphasized, as it is a prerequisite for clinical application of this treatment modality.     

Detrusor hyperreflexia in neurogenic bladder disorders caused by localized partial lesions of the spinal cord and cauda equina

In 70 patients studied by cystometry, detrusor hyperreflexia seen with localized partial lesions of the spinal cord and cauda equina could be differentiated into two types. In one type, in which the hyperreflexia was of a reflex nature and bladder compliance was unchanged, the detrusor contractility was described as compliant hyperreflexic. In the other type, in which the contractions were of a rhythmic nature and accompanied by reduced compliance, the contractility of the detrusor was described as noncompliant hyperreflexic. The compliant hyperreflexic contractions correlated well with signs of upper motor neuron disturbance, the noncompliant hyperreflexic contractions with lower motor neuron disturbance.     

The effects of botulinum-A toxin on bladder function and histology in spinal cord injured rats: is there any difference between early and late application?

PURPOSE: We explored the effects of early and late application of botulinum-A toxin (BTX-A) on reservoir function and histological bladder changes in spinal cord injured rats. MATERIALS AND METHODS: The study was done in 30 Sprague-Dawley rats randomly allocated into 5 groups. Group 1 of 6 rats underwent sham operation only. Group 2 of 6 rats underwent spinal cord transection. Group 3 of 6 rats underwent spinal cord transection followed by BTX-A application into the detrusor muscle 7 days later. Group 4 of 6 rats underwent spinal cord transection, followed by BTX-A application into the detrusor muscle 28 days later. Group 5 of 6 rats underwent spinal cord transection followed by saline injection into the detrusor muscle after 28 days. Spinal cord injury was created by transecting the cord at the T9 to T10 level. All rats underwent cystometric examination initially and on day 42 before sacrifice. The bladders were removed and examined histologically for fibrosis and hyperplasia. RESULTS: On cystometric examination BTX-A caused an improvement in baseline pressure, and the frequency and amplitude of uninhibited detrusor contractions (p <0.001). No significant differences were observed in maximal bladder capacity or urethral opening pressure (p >0.05). Histologically BTX-A led to decreased fibrosis and hyperplasia (p <0.001). No significant differences were found between histological or cystometric among the groups with respect to receiving BTX-A in the early and late periods (p >0.05). CONCLUSIONS: BTX-A has a functional and histological healing effect on detrusor hyperreflexia subsequent to spinal cord injury in rats. Although administering BTX-A in the early period had better quantifiable functional and histological outcomes compared to the late period, the difference was not statistically significant.     

Cystometric subtypes of bladder overactivity: A retrospective analysis of 501 patients

Three subtypes of bladder overactivity were recognized in a retrospective study of 501 patients. The subdivision was based on cystometry and clinical findings and includes the following diagnostic groups: 1) Phasic detrusor instability, characterized by phasic bladder contractions during the filling phase, with normal or increased bladder sensation; 2) uninhibited overactive bladder, characterized by impaired perception of bladder fullness, an uninhibited micturition reflex and a positive ice-water test; 3) Spinal detrusor hyperreflexia in upper motor neuron lesion, complete or incomplete. The largest group of patients had signs and symptoms consistent with the diagnosis of uninhibited over active bladder (47%). Phasic detrusor instability was found in 15% of the patients and 28% had spinal detrusor hyperreflexia. The remaining 10% had an atypical or mixed pattern of symptoms. There were large, significant differences between the groups with respect to several cystometric parameters, such as the occurrence of phasic detrusor contractions, abnormal perception of bladder fullness, voluntary inhibition of micturition and the outcome of the ice-water test. The proposed subdivision of bladder overactivity is simple, clinically relevant and based on parameters readily available in standard cystometry.     

Role of supraspinal tachykinins for volume- and L-dopa-induced bladder activity in normal conscious rats

To clarify the roles of tachykinins in volume-induced micturition and in bladder hyperactivity, presumed to originate from supraspinal structures, normal, female Sprague-Dawley rats were investigated cystometrically before and after intracerebroventricular (i.c.v) administration of RP 67,580, a selective antagonist of NK-1 receptors, and/or SR 48,968, a selective antagonist of NK-2 receptors. The effects of RP 67,580 and SR 48,968 on intra-peritoneal (i.p.) L-dopa-induced bladder hyperactivity were also investigated. I.c.v. administration of RP 67,580 (20 nmol) SR 48,968 (20 nmol) suppressed micturition. Combination of i.c.v. RP 67, 580 (2 nmol) and SR 48,968 (2 nmol) significantly decreased micturition pressure (18%), and increased bladder capacity (26%), micturition volume (18%), and residual volume (223%). In rats pretreated with i.p. carbidopa 50 mg/kg, i.p. L-dopa 50 mg/kg caused bladder hyperactivity that was attenuated by the combination of i.c. v. RP 67,580 (2 nmol) and SR 48,968 (2 nmol). The results suggest that tachykinins, via stimulation of NK receptors in supraspinal structures, are involved in both volume and L-dopa-induced stimulation of bladder activity. This may imply that tachykinins can influence both the supraspinal and spinal control of the urinary bladder. It also implies that supraspinal NK receptors are a possible target for drugs aimed for elimination of bladder hyperactivity mediated via these pathways. Neurourol. Urodynam. 19:101-109, 2000.     

Modulation of insulin-like growth factor-I system of the bladder using a somatostatin analogue in chronic spinalized rats

PURPOSE: We have previously reported the possible role of the insulin-like growth factor-I (IGF-I) system of mitogens in the development of detrusor smooth muscle hyperplasia and hypertrophy after spinal cord injury. We evaluated the in vivo effects of the anti-growth factor somatostatin analogue octreotide on the IGF-I system as well as subsequent changes in bladder smooth muscle hypertrophy and function after spinal cord injury in rats. MATERIALS AND METHODS: Included in this study were 90 adult female Sprague-Dawley rats weighing 200 to 250 gm. Of the rats 18 served as sham operated controls, while the remaining 72 underwent were spinal cord transection at the level of the T10 vertebra. The spinalized animals were randomly divided into 4 equal groups of 18, of which 1 group served as paraplegic controls. The other 3 groups received octreotide (60 microgram. daily for 4 weeks) delivered via a subcutaneously implanted osmotic pump immediately, 2 and 4 weeks after spinal cord injury. At the end of the experiment (6 to 8 weeks) each group of animals was subdivided into 2 subgroups of 9. In the first group filling cystometrography was done, while in the second subgroup wet bladder weight was estimated and Northern blot analysis was performed. RESULTS: Mean wet bladder weight plus or minus standard deviation in sham operated and paraplegic controls was 0.11 +/- 0.01 and 0.64 +/- 0.33 gm., respectively (p <0.05). The increase in bladder weight in paraplegic controls was associated with over expression of the IGF-I gene and with marked suppression of IGF binding proteins-3 and 5 compared with sham operated controls. On the other hand, mean wet bladder weight in the animals that received octreotide immediately after spinal cord injury was 0.17 +/- 0.02 gm., which was associated with a dramatic decrease in IGF-I gene expression and increased expression of IGF binding proteins-3 and 5. Mean cystometric bladder capacity in paraplegic controls was 0.48 +/- 0.18 ml. with an associated voiding pressure of 71 +/- 13 cm. water. All paraplegic controls showed detrusor hyperreflexia. In animals that received octreotide immediately after spinal cord injury mean cystometric bladder capacity was 2.49 +/- 1.75 ml. with an associated voiding pressure of 32 +/- 7 cm. water. Detrusor hyperreflexia disappeared in 88.89% of the rats in this group. There were less marked changes in bladder weight (mean 0.24 and 0.29 +/- 0.3 gm.), IGF-I gene expression and its binding proteins and urodynamic parameters when the drug was given 2 and 4 weeks, respectively, after spinal cord injury. CONCLUSIONS: Modulating the IGF-I system of mitogens in detrusor smooth muscle with consequently decreased bladder hypertrophy and improved urodynamic behavior in spinal cord injured animals using somatostatin analogue could be a possible therapeutic modality in patients with spinal cord injury.     

An artificial somatic-autonomic reflex pathway procedure for bladder control in children with spina bifida

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Role of dopamine D1 and D2 receptors in the micturition reflex in conscious rats

To clarify the role of dopamine D1 and D2 receptors in the volume-induced micturition reflex, conscious, female rats were investigated cystometrically before and after intravenous administration of SKF 38393 (a selective D1 receptor agonist), SCH 23390 (a selective D1 receptor antagonist), quinpirole (a selective D2 receptor agonist), and remoxipride (a selective D2 receptor antagonist). The effect of quinpirole was also investigated in the presence of remoxipride. Intravenous administration of SKF 38393 (0.01-3.0 mg/kg) did not affect any cystometric parameters investigated. On the other hand, SCH 23390 (0.1-1.0 mg/kg i.v.) reduced bladder capacity and micturition volumes and increased the micturition pressure in a dose-dependent manner. Quinpirole (0.01-0.1 mg/kg) given intravenously, dose-dependently decreased bladder capacity and micturition volumes. Pre-treatment with remoxipride (1.0 mg/kg i.v.) significantly attenuated the effect of quinpirole (0.1 mg/kg i.v.). Remoxipride (0.1-1.0 mg i.v.) itself did not cause any significant changes in the cystometric parameters. These results suggest that in conscious rats, D1 receptors tonically inhibit the micturition reflex and that D2 receptors are involved in facilitation of the micturition reflex. It may be speculated that detrusor hyperreflexia associated with Parkinson's disease results from activation failure of D1 receptors and that administration of D2 receptor agonists might worsen the condition.     

Effects of a selective metabotropic glutamate receptor agonist on the micturition reflex pathway in urethane-anesthetized rats

AIMS: To determine a possible role of metabotropic glutamate receptors in the spinobulbospinal micturition reflex pathway in the rat. MATERIALS AND METHODS: A selective metabotropic glutamate receptor agonist, trans-(+/-)-1-amino1,3-cyclopentanedicarboxylic acid (trans-ACPD) was administered to the lumbosacral spinal cord via an intrathecal catheter in urethane anesthetized rats. Amplitude of reflex bladder contractions evoked by bladder distension under isovolumetric condition as well as amplitude of bladder contractions elicited by electrical stimulation of the pontine micturition center (PMC) were examined before and after administration of trans-ACPD. The effect of trans-ACPD on the urethral activity during isovolumetric bladder contractions was also examined by monitoring urethral perfusion pressure and electromyography of the external urethral sphincter (EUS-EMG). RESULTS: Trans-ACPD (3-10 microg) completely inhibited reflex bladder contractions evoked by bladder distension and the duration of inhibition was dose dependent (3 microg: 11.4 +/- 2.8 min, 5 microg: 13.2 +/- 1.3 min, 10 microg: 36.2 +/- 2.4 min). The mean amplitude of bladder contractions evoked by electrical stimulation of the PMC was reduced to 12.6 +/- 2.3% of control by 10 microg of trans-ACPD. In addition, bursting activity of EUS-EMG and corresponding high frequency oscillations of urethral pressure during isovolumetric bladder contractions were completely abolished by 10 microg of trans-ACPD. CONCLUSIONS: These results indicate that intrathecal administration of a selective metabotropic glutamate receptor agonist to the lumbosacral spinal cord has an inhibitory effect on the spinobulbospinal micturition reflex pathway in urethane-anesthetized rats. This pharmacological action is attributed at least to the inhibitory effect on the descending pathway from the PMC to the lumbosacral spinal cord.     

Effects of tiagabine, a gamma-aminobutyric acid re-uptake inhibitor, on normal rat bladder function

PURPOSE: Previous reports have demonstrated the inhibitory effect of exogenous gamma-aminobutyric acid (GABA) on micturition. In the current study we tested whether tiagabine (Sanofi Synthelab., Newcastle-upon Tyne, United Kingdom), a GABA re-uptake inhibitor increasing endogenous GABA concentrations, would affect micturition in awake rats or influence rat detrusor contraction in vitro. MATERIALS AND METHODS: Nonanesthetized female Sprague-Dawley rats underwent cystometric investigation in a metabolic cage. Micturition was stimulated by infusing saline intravesically. Micturition parameters were recorded and compared before and after drug administration. In vitro the effects of tiagabine on electrical and carbachol induced contractions in bladder strips were investigated. Furthermore, it was studied whether tiagabine interfered with electrically induced release of acetylcholine. RESULTS: Intravenous administration of 5 and 20 mg. kg.-1 tiagabine in 7 and 9 rats decreased micturition pressure a mean plus or minus standard error of mean of 21% +/- 11% and 42% +/- 9%, and decreased voided volume a mean of 31% +/- 9% and 33% +/- 9%, respectively. At 20 mg. kg.-1 tiagabine intravenously increased post-void residual volume a mean of 300% +/- 120% and decreased bladder capacity a mean of 14% +/- 3%. Tiagabine (100 microg.) intrathecally in 7 rats reduced micturition pressure a mean of 34% +/- 10% and increased bladder capacity a mean of 30% +/- 9% and post-void residual volume a mean of 250% +/- 75%. However, voided volume was not changed. In vitro studies demonstrated that tiagabine attenuated bladder contractions induced by electrical field stimulation to a mean of 69% +/- 6% of controls at 100 microM. but did not affect contractions induced by carbachol. Release studies revealed that tiagabine inhibited electrical induced acetylcholine release to a mean of 82% +/- 5% of controls at 100 microM. CONCLUSIONS: The current results show that tiagabine has an inhibitory action on rat micturition. The site of action may be central and peripheral.     

Intrathecal or dietary glycine inhibits bladder and urethral activity in rats with spinal cord injury

PURPOSE: We examined the influence of intrathecal or dietary glycine on bladder and urethral activity in rats with spinal cord injury. MATERIALS AND METHODS: A total of 20 female Sprague-Dawley rats were used 4 weeks after lower thoracic spinal cord injury. The rats were divided into standard and 1% glycine diet groups. In the standard diet group isovolumetric cystometry and urethral pressure measurement were performed before and after intrathecal injection of glycine. In the 1% glycine diet group bladder and urethral activity were compared with control recordings in the standard diet group. RESULTS: In the standard diet group intrathecal injection of glycine prolonged the interval and decreased the amplitude of bladder contractions, decreased baseline urethral pressure and altered urethral activity during bladder contraction from a pattern of detrusor-sphincter dyssynergia to detrusor-sphincter synergy at 100 mug glycine. In the 1% glycine diet group the interval and amplitude of bladder contractions were prolonged and decreased, respectively, compared with those in the standard diet group. Baseline urethral pressure was lower than in the standard diet group even after intrathecal injection of 100 mug glycine. Urethral pressure did not change during bladder contraction and it was the same as baseline pressure. Residual urine volume was lower than in the standard diet group. CONCLUSIONS: Intrathecal or dietary glycine inhibits bladder and urethral activity, and improves detrusor hyperreflexia and detrusor-sphincter dyssynergia.     

Urodynamic effects of a novel EP(1) receptor antagonist in normal rats and rats with bladder outlet obstruction

PURPOSE: Prostaglandin E(2) and its EP(1) receptor were suggested as endogenous modulators of bladder function in the normal physiological state and under pathophysiological conditions. We investigated if the new EP(1) receptor antagonist PF-2907617-02 would influence the regulation of normal micturition in rats, and if it affects bladder function in animals with partial bladder outlet obstruction. MATERIALS AND METHODS: The study was performed in normal female Sprague-Dawley rats and in rats with moderate, experimentally induced bladder outlet obstruction 2 weeks in duration. All animals underwent continuous cystometry in the awake state. PF-2907617-02 was given intravenously at doses of 0.1 and 1.0 mg/kg(-1) in normal rats, and at 1.0 mg/kg(-1) in bladder outlet obstructed animals. In a group of normal rats detrusor overactivity was produced by intravesical instillation of prostaglandin E(2). RESULTS: In normal rats PF-2907617-02 (1 mg/kg(-1)) significantly increased bladder capacity, micturition volume and the micturition interval but it had no effect on other urodynamic parameters. The lower dose of PF-2907617 (0.1 mg/kg(-1)) showed no effect. Intravesical prostaglandin E(2) (50 muM) induced detrusor overactivity. The antagonist significantly decreased the stimulatory effects of prostaglandin E(2) at 0.1 and 1.0 mg/kg(-1). In obstructed animals PF-2907617-02 significantly increased the micturition interval but not bladder capacity and residual volume. The drug also decreased the frequency and amplitude of nonvoiding contractions. CONCLUSIONS: EP(1) receptor is involved in initiation of the micturition reflex in normal rats and in animals with bladder outlet obstruction. It may also contribute to the generation of detrusor overactivity after bladder outlet obstruction. Thus, EP(1) receptor antagonists may have potential as treatment for detrusor overactivity in humans.     

Effects of selective beta2 and beta3-adrenoceptor agonists on detrusor hyperreflexia in conscious cerebral infarcted rats

PURPOSE: We evaluated the effects of beta-adrenoceptor agonists on detrusor hyperreflexia in cerebral infarcted rats. MATERIALS AND METHODS: To produce cerebral infarction in Sprague-Dawley rats the left middle cerebral artery was occluded by introducing a monofilament nylon thread into the artery. In sham operated rats the same artery was exposed but not occluded. After these operations cystometric and cardiovascular experiments were performed with no anesthesia or restraint. RESULTS: After the operation bladder capacity was significantly decreased and voiding pressure was significantly increased in cerebral infarcted but not in sham operated animals. The difference in cerebral infarcted and sham operated rats was significant for each parameter (p <0.01). Post-void residual urine volume was not affected in either group. In the cerebral infarction group intravenous administration of CL316243 ([R,R]-5-2-[[2-(3-chlorophenyl-2-hydroxyethyl]-amino]propyl] -1,3-benzodioxole-2,2-dicarboxylate) (Kissei Central Laboratories, Hotaka, Japan) a selective beta3-adrenoceptor agonist, significantly increased bladder capacity at 10 and 100 microgram./kg. without affecting voiding pressure or post-void residual urine volume. Procaterol, a selective beta2-adrenoceptor agonist, significantly increased bladder capacity and post-void residual urine volume at 10 microgram/kg. intravenously without affecting voiding pressure. In separate experiments procaterol (1 to 100 microgram./kg. intravenously) decreased mean blood pressure and increased heart rate in a dose dependent manner. In contrast, the effects of CL316243 (0.1 to 100 microgram./kg. intravenously) on mean blood pressure and heart rate were minimal. CONCLUSIONS: These results indicate that in cerebral infarcted rats detrusor hyperreflexia can be suppressed by the selective beta3-adrenoceptor agonist CL316243 without increasing post-void residual volume and without significant cardiovascular side effects. If the current results hold true in humans, selective beta3-adrenoceptor agonists may prove useful for treating detrusor hyperreflexia associated with cerebral infarction.     

EFFECT OF TACHYKININ NK2 RECEPTOR BLOCKADE ON DETRUSOR HYPERREFLEXIA INDUCED BY BACTERIAL TOXIN IN RATS

Purpose

To see whether a recently characterized model of bacterial toxin-induced urinary bladder inflammation (Stein et al., J. Urol., 155, 1133-1138, 1996). is associated with detrusor hyperreflexia, and whether endogenous tachykinins acting through NK₂ or NK₁ receptors were involved in this model.

Materials and Methods

The bladder or urethane-anesthetized male Wistar rats was cannulated through the dome. Intravesical administration of protamine sulfate (PS, 10 mg./ml./rat) or vehicle for 1 hour was followed by the intravesical administration of E. coli lipopolysaccharide (LPS 1 mg./ml./rat) or vehicle for 1 hour. Cystometries (50 micro l./min.) were performed 3.5 hours after the exposure to LPS. MEN 11,420, a peptide tachykinin NK₂ receptor antagonist, was administered before cystometries or, in a separate group of animals, during cystometries. The effect of SR 140,333, a non-peptide NK₁ receptor antagonist, was also assessed in the presence or absence of MEN 11,420. The urodynamic effects of PS + LPS were also tested in capsaicin-pretreated rats.

Results

Unlike PS or LPS alone, the intravesical administration of PS + LPS induced detrusor hyperreflexia. In PS + LPS treated animals during nonstop cystometries, the intermicturition interval was decreased by about 50% as compared to vehicle-pretreated rats. A quantitatively similar reduction in the bladder capacity was also observed. MEN 11,420 (100 nmol./kg., i.v.) restored the intermicturition interval in PS + LPS-pretreated rats at the level of controls by increasing the bladder capacity, whereas it had no effect in vehicle-pretreated rats. SR 140,333 (1 micro mol./kg., i.v.) neither modified urodynamic parameters in controls and in PS + LPS-treated rats nor altered the effect of MEN 11,420 in these groups. Capsaicin pretreatment (164 micro mol./kg., s.c., 4-5 days before) induced a two-fold increase of the bladder capacity in control rats and prevented PS + LPS-induced bladder hyperreflexia.

Conclusions

The intravesical administration of PS + LPS produces the activation of capsaicin-sensitive afferents. Endogenous tachykinins released from these fibers act through NK₂ receptors to induce detrusor hyperreflexia.     

Effects of ZD6169 and ZD0947, 2 potassium adenosine triphosphate channel openers,on bladder function of spinalized rats

PURPOSE: The use of K+ channel openers is emerging as an attractive possibility for treating bladder overactivity. We tested the efficacy of the 2 adenosine triphosphate dependent K channel openers ZD6169 and ZD0947 on detrusor hyperreflexia after spinal cord injury in rats. MATERIALS AND METHODS: Included in this study were 72 adult Sprague-Dawley rats. Six animals served as normal controls, while 66 underwent spinal cord transection at the 10th thoracic vertebra. Two weeks after spinal cord injury 6 animals underwent filling cystometrography to confirm detrusor hyperreflexia, while another 12 served as control paraplegics. For each drug 24 animals were used and divided into 2 equal groups of 12. Group 1 received the drug in a dose of 3 mg./kg. daily, while group 2 received a dose of 0.3 mg./kg. daily. Each control paraplegic and treatment group was further subdivided into 2 subgroups of 6 rats. In subgroup 1 filling cystometrography was done 3 weeks after spinal cord injury, while in subgroup 2 it was done 4 weeks after spinal cord injury. RESULTS: Three weeks after spinal cord injury detrusor hyperreflexia developed in all control paraplegic animals with a mean bladder capacity plus or minus standard deviation of 0.7 +/- 0.2 ml. and a mean voiding pressure of 59 +/- 14.2 cm. water. Detrusor hyperreflexia resolved in 66% of the animals that received ZD6169 for 1 week at either dose. For example, mean bladder capacity was 2.5 +/- 1.8 versus 1.8 +/- 1.2 ml. and mean voiding pressure was 42.1 +/- 15.9 versus 43.2 +/- 21.4 cm. water in animals that received 3 versus 0.3 mg./kg. daily, respectively. All animals that received a dose of 3 mg./kg. ZD0947 daily for 1 week showed no detrusor hyperreflexia with a mean bladder capacity of 2.7 +/- 1.8 ml. and mean voiding pressure of 34 +/- 8.5 cm. water, while at 0.3 mg./kg. daily 83% showed no detrusor hyperreflexia with a mean bladder capacity of 2.5 +/- 2.0 ml. and a mean voiding pressure of 41.5 +/- 13.8 cm. water. Each drug produced better urodynamic results when given for 2 weeks. CONCLUSIONS: ZD6169 and ZD0947 are effective treatment for detrusor hyperreflexia after spinal cord injury and they may provide alternative treatment options for overactive bladder. Each drug has time and dose dependent response effects that reflect their wide range of efficacy. However, ZD0947 shows an efficacy profile that is relatively superior to that of ZD6169.     

Dorsal rhizotomy with anterior sacral root stimulation for neurogenic bladder

A spinal cord lesion above the sacral micturition center results in a loss of voluntary control and development of bladder sphincter dysynergia with hyperreflexia of the detrusor and spasticity of the sphincter. Sacral rhizotomy and implantation of an anterior sacral root stimulator appears as an effective method for the treatment not only of voiding dysfunction but also of defecation and sexual disturbance. The surgical technique is described as are the clinical and electrophysiological controls. The results of our series of operated patients with intradural implantation and sacral deaffentation show a constant improvement. 90% have satisfactory continence and no longer require an incontinence appliance. Bladder capacity and compliance have increased to 120% and urethral closure pressure has decreased. 80% have complete voiding or a post-void residue of not more than 50 ml. So, urinary infection rate is dramatically decreased.     

Urinary incontinence in the female. The value of detrusor reflex activation procedures.

One hundred consecutive female patients with urinary incontinence were investigated with CO2 cystometry including detrusor reflex activation procedures such as postural change and ability to suppress self-induced detrusor contractions. Detrusor hyperreflexia was seen in 20 patients during bladder filling in the supine position, and in an additional 35 patients after detrusor reflex activation procedures. Four different types of detrusor hyperreflexia are described based on the cystometric findings. In 38 patients treated with parasympatholytics, 66% showed a good result independent of the type of detrusor hyperreflexia.     

Sympathetic inhibition of reflex activation of bladder motility during filling at a physiological-like rate in urethane anaesthetized rats

The mean volume of saline (infused at a physiological-like rate) required to elicit neurogenic rhythmic contractions of the detrusor muscle (micturition threshold) in urethane anaesthetized rats was reduced by reserpine pretreatment, as well as by chemical (6-hydroxydopamine) or surgical sympathectomy (bilateral section of the hypogastric nerves). Propranolol pretreatment had no significant effect on micturition threshold but increased the intraluminal pressure at which the rhythmic contractions occurred. In spinal rats (T12L1) a flat pressure volume curve was obtained with only a minor phasic contractile activity. Propranolol administration or bilateral section of the hypogastric nerves significantly increased the intraluminal pressure response to saline filling in spinal rats. Topical tetrodotoxin increased the intraluminal pressure response to saline filling in control spinal rats but not following propranolol administration or bilateral section of the hypogastric nerves. These findings provide evidence for a sympathetic inhibition of the reflex activation of the detrusor muscle in response to a physiological-like filling of the urinary bladder.     

Investigation of neurokinin-2 and -3 receptors in the human and pig bladder

OBJECTIVE: To investigate the role of neurokinin (NK)-2 and -3 receptors in mediating the contraction of detrusor muscle strips from human and pig, to determine whether the pig is a good model for the study of tachykinin receptors in the human bladder, as the biological actions of tachykinins, e.g. substance P and NKA are mediated via three distinct receptor subtypes, NK-1, -2 and -3. MATERIALS AND METHODS: Strips of detrusor muscle were obtained from the bladder dome and neck of female pigs and from patients undergoing cystectomy. Cumulative concentration-response curves to NKA were obtained in the absence and presence of either the NK-2 receptor-selective antagonist SR48968 or the NK-3 receptor-selective antagonist SB223412. RESULTS: NKA produced concentration-dependent contractions in the human and pig detrusor muscle; the curves were shifted to the right by SR48968, with high affinity (pKB 8.9, 8.3 and 8.0 in the human, pig dome and pig neck, respectively), whereas SB223412 had a minimal effect (pKB 5.8, 5.8 and 6.3, respectively). CONCLUSION: These data confirm that the NK-2 receptor subtype mediates NKA-induced contraction of the human and pig detrusor muscle. The NK-3 receptor appears to have no role in detrusor contraction of either species. The results also provide evidence that the NK-2 receptor in human and pig are the same, and the latter may be an appropriate species to study tachykinin-induced contractions in human bladder.     

Vardenafil improves urodynamic parameters in men with spinal cord injury: results from a single dose, pilot study

PURPOSE: We assessed urodynamic changes after vardenafil administration in spinal cord injured male patients on oxybutynin treatment. MATERIALS AND METHODS: We performed a single center, randomized, double-blind, placebo controlled trial in 25 patients with spinal cord injury who had erectile dysfunction and micturition disorders. A baseline urodynamic test was performed as well as a second urodynamic test 1 to 3 hours after the administration of 20 mg vardenafil and placebo in 15 and 10 cases, respectively. In all patients standard oral oxybutynin administration was not discontinued. Statistical assessment included the 3 urodynamic parameters maximum detrusor pressure during voiding, maximum cystometric capacity and detrusor overactivity volume. RESULTS: Placebo administration did not affect urodynamic parameters. After vardenafil administration maximum detrusor pressure was significantly decreased (59.3 vs 52.1 cm H(2)O, p <0.001) and maximum cystometric capacity considerably improved (233.5 vs 272 ml, p <0.001). The most dramatic variations were observed for detrusor overactivity volume (174 vs 218 ml, p <0.0001). In 7 patients with American Spinal Injury Association classification A and spinal cord injury above T6 we observed the most significant improvement in the evaluated urodynamic items, including maximum detrusor pressure 57 vs 52 cm H(2)O (p = 0.039), maximum cystometric capacity 253 vs 296 ml (p = 0.004) and detrusor overactivity volume 177 vs 229 ml (p = 0.003). CONCLUSIONS: This trial demonstrates that in spinal cord injured patients a single 20 mg vardenafil administration achieved a significant decrease in maximum detrusor pressure, an improvement in maximum cystometric capacity and a remarkable increase in detrusor overactivity volume value.