The effects of a type 4 phosphodiesterase inhibitor and the muscarinic cholinergic antagonist tolterodine tartrate on detrusor overactivity in female rats with bladder outlet obstruction.

OBJECTIVE: To investigate the effects of the selective phosphodiesterase (PDE) type 4 inhibitor IC485 and the widely used antimuscarinic drug tolterodine tartrate on bladder activity in rats with bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle. MATERIALS AND METHODS: BOO was induced in female Sprague-Dawley rats by tying a silk ligature around the urethra. Six weeks after inducing BOO, conscious rats were assessed by cystometry with the urethral ligature intact. The effects of IC485 (5, 10 and 50 mg/kg intravenous, i.v.) were examined and compared with those of tolterodine (0.01, 0.1 and 1 mg/kg i.v.). RESULTS: IC485 (5-50 mg/kg i.v.) decreased the number and amplitude of non-voiding contractions during the storage phase by 63-88% and 49-83%, respectively; IC485 also increased bladder capacity by 28-37%. There was no change in blood pressure after applying IC485. Tolterodine tartrate (0.1 and 1.0 mg/kg) significantly decreased the number and amplitude of non-voiding contractions by 38-74% and 29-44%, respectively, and increased bladder capacity by 19-51%. Whereas voiding efficiency and maximum voiding pressure were not altered by IC485 at any dose, tolterodine significantly reduced both, by 35-67% and 19-34%, respectively. CONCLUSION: Both IC485 and tolterodine tartrate reduced detrusor overactivity in rats with BOO. In addition, doses of IC485 that suppressed non-voiding contractions had no effect on voiding function. Therefore, selective PDE4 inhibitors deserve further study as potential agents for treating detrusor overactivity in patients with BOO.

Suppression of detrusor overactivity in rats with bladder outlet obstruction by a type 4 phosphodiesterase inhibitor.

OBJECTIVE: To investigate the effects of a selective type 4 cyclic nucleotide phosphodiesterase (PDE4) inhibitor, IC486051, on bladder activity in normal rats and those with and bladder outlet obstruction (BOO), as inhibition of PDE4 leads to elevation of intracellular cAMP levels and relaxation of smooth muscle. MATERIALS AND METHODS: BOO was induced in female Sprague-Dawley rats by tying a silk ligature around the urethra. At 4 or 6 weeks after inducing BOO, conscious rats were assessed by cystometry with the urethral ligature intact. In unobstructed rats, blood pressure was also measured. RESULTS: In unobstructed rats, IC486051 (0.1 mg/kg intravenously) produced no significant changes in cystometric variables, while at a dose of 0.5 mg/kg maximum voiding pressure was reduced by 34%. At both doses, there was a small, transient increase in blood pressure. In both 4- and 6-week BOO rats IC486051 dose-dependently decreased the number and amplitude of non-voiding bladder contractions by up to 80%, relative to pre-treatment values. At doses of 0.1 and 0.5 mg/kg IC486051 had no significant effect on voiding variables. In the 4-week BOO rats, a dose of 1.0 mg/kg decreased bladder capacity, voided volume and residual volume by 21%, 32% and 18%, respectively. In 6-week BOO rats, a dose of 1.0 mg/kg decreased maximal voiding pressure by 17% and pressure threshold for voiding by 28%. In both groups of rats with BOO, voiding efficiency was unchanged. CONCLUSIONS: A selective PDE4 inhibitor can effectively suppress detrusor overactivity in rats with BOO, at doses that have no effect on voiding bladder contractions. Thus, selective PDE4 inhibitors should be considered for the treatment of overactive bladder in patients with BOO.

Detrusor overactivity induced by intravesical application of adenosine 5'-triphosphate under different delivery conditions in rats.

OBJECTIVES: To investigate the effects of intravesical application of adenosine 5'-triphosphate (ATP) on bladder activity to elucidate the role of urothelial barrier function and ecto-ATPase activity in the ATP-mediated mechanism inducing detrusor overactivity. METHODS: Continuous cystometry by an intravesical catheter inserted from the bladder dome was performed in conscious female rats. RESULTS: ATP solutions adjusted to pH 6.0 did not elicit significant detrusor overactivity at a concentration of 60 mM. However, in bladders pretreated with protamine sulfate (10 mg/mL) to increase urothelial permeability, ATP solution (pH 6.0) induced detrusor overactivity by decreasing the intercontraction intervals. These irritant effects of ATP after protamine treatment were antagonized by P2X receptor antagonists, such as pyridoxal-5-phosphate-6-azophenyl-2',4'-disulfonic acid (70 micromol/kg) and 2',3'-O-(2,4,6, trinitrophenyl) ATP (30 micromol/kg). These were also suppressed in rats pretreated with systemic capsaicin (125 mg/kg subcutaneously). Alpha,beta-methylene ATP (5 mM, pH 6.0) or ATP (60 mM, pH6) after intravesical infusion of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (5 mM, pH 6.0), an ecto-ATPase inhibitor, induced detrusor overactivity without protamine pretreatment, but the reduction in intercontraction intervals was smaller compared with that with ATP after protamine treatment. CONCLUSIONS: Low permeability of bladder epithelium and ecto-ATPase activity can prevent ATP activation of subepithelial P2X receptors to induce bladder overactivity. Thus, enhanced penetration of endogenous ATP owing to urothelial damage may contribute to urinary frequency and bladder pain in hypersensitive bladder disorders such as interstitial cystitis.

Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra.

OBJECTIVES: To detail, in a review, one institution's 6-year experience using botulinum toxin A (BTX-A) in the bladder and urethra in 110 patients for a variety of lower urinary tract disorders. METHODS: A total of 110 patients (35 men and 75 women, age range 19 to 82 years) received injections of BTX-A into the bladder (n = 42) or urethra (n = 68). Voiding dysfunction included neurogenic detrusor overactivity and/or detrusor sphincter dyssynergia, overactive bladder, bladder neck obstruction, and interstitial cystitis. Under light sedation in most cases, patients were treated with either 100 to 200 U of BTX-A in 4 mL divided in equal doses into the four quadrants of the external sphincter or by injection into the bladder base using 100 to 300 U of BTX-A diluted in approximately 10 to 30 mL of sterile saline. At last follow-up, 27 patients had received additional injections (up to six) at intervals of 6 months or longer. RESULTS: All patients who underwent bladder BTX-A injection had preoperative evidence of involuntary detrusor contractions during urodynamic testing. Analysis of the 110 patients indicated that 67.3% reported a decrease or absence of incontinence. Diaries indicated a decrease in both daytime and nighttime voiding symptoms. Maximal efficacy occurred between 7 and 30 days and lasted for at least 6 months. Condition-specific quality-of-life symptom scores also demonstrated improvement. No long-term complications had occurred at last follow-up. Two women with multiple sclerosis and mild baseline stress urinary incontinence reported increased leakage with stress after BTX-A external sphincter injection, and one woman with multiple sclerosis noted new onset stress urinary incontinence after external sphincter injection. However, they all reported significant improvement in their detrusor sphincter dyssynergia with decreased postvoid residual urine volume, improved uroflow, decreased urge incontinence, and decreased daytime and nighttime frequency. One woman with multiple sclerosis who underwent bladder injection had increased postvoid residual urine volume from 78 to 155 mL. She did not have to perform intermittent catheterization. CONCLUSIONS: BTX-A injection is a safe and promising treatment modality for a variety of lower urinary tract dysfunctions for both skeletal and smooth muscle dysfunction. In our series, BTX-A is equally effective in women as it is in men. When injected into the sphincter, the risk of stress incontinence is low. Bladder injections with BTX-A are effective for not only neurogenic detrusor overactivity, but also overactive bladder. BTX-A can even be considered for interstitial cystitis.

Change in parameters before and after alpha-1-blocker therapy for men with lower urinary tract symptoms using color doppler ultrasound urodynamics: possible application for prediction of clinical outcome.

INTRODUCTION: We previously developed a noninvasive video urodynamic study using color Doppler ultrasonography. We sought the best flow velocity-related parameter which would allow prediction of an improvement in lower urinary tract symptoms (LUTS) after alpha 1-blocker treatment. METHODS: Twenty-two men with benign prostatic hyperplasia who were treated with a nonselective alpha 1-blocker (urapidil) were included. Subjective symptoms were evaluated using the International Prostate Symptom Score (IPSS) before and after alpha 1-blocker treatment. We measured the flow velocities using a transperineal ultrasound technique in the distal prostatic urethra just proximal to the external urethral sphincter (V1) and in the sphincteric urethra (V2), and used them to obtain the velocity ratio (VR=V1/V2). The corresponding functional cross-sectional areas of the urethra at these two sites (A1 and A2) were calculated as Q(max)/V. All these parameters obtained by the velocity-flow urodynamics were compared before treatment and after 4 weeks. RESULTS: After treatment, V1 and VR were decreased, and A1 was increased. V2 correlated best with the change in IPSS before and after alpha 1-blocker therapy, with Spearman's rho of 0.584. All men with V2 exceeding 50 cm/s did not show an improvement in the LUTS. CONCLUSIONS: The maximum flow velocity at the sphincteric urethra (V2) can predict the subjective outcome of alpha 1-blocker treatment. The velocity-flow parameters changed after alpha 1-blocker treatment. We confirmed that the transperineal ultrasound urodynamic study is not only noninvasive but also informative.

Extracorporeal magnetic innervation treatment for urinary incontinence.

BACKGROUND: Extracorporeal magnetic innervation (ExMI) is a new technology used for pelvic muscle strengthening for the treatment of stress urinary incontinence. We explored whether this new technology is effective for patients with urge incontinence, as well as those with stress urinary incontinence. METHODS: We studied 20 patients with urge incontinence and 17 patients with stress urinary incontinence. The Neocontrol system (Neotonus Inc., Marietta, GA) was used. Treatment sessions were for 20 min, twice a week for 8 weeks. Evaluations were performed by bladder diaries, one-hour pad weight testing, quality-of-life surveys and urodynamic studies. RESULTS: Of the urge incontinence cases, five patients were cured (25.0%), 12 patients improved (60.0%) and three patients did not show any improvement (15.0%). Leak episodes per day reduced from 5.6 times to 1.9 times at 8 weeks (P < 0.05). Eight patients with urge incontinence recurred within 24 weeks after the last treatment (47.1%). Of the stress incontinence cases, nine patients were cured (52.9%), seven patients improved (41.1%) and one patient did not show any improvement (6%). In one-hour pad weight testing, the mean pad weight reduced from 7.9 g to 1.9 g at 8 weeks (P < 0.05). Three patients returned to the baseline values within 24 weeks after the last treatment (17.6%). No side-effects were experienced by any of the patients. CONCLUSION: Although the results for urge incontinence were less effective than for stress urinary incontinence, ExMI therapy offers a new option for urge incontinence as well as stress urinary incontinence.

Effects of isolectin B4-conjugated saporin, a targeting cytotoxin, on bladder overactivity induced by bladder irritation.

In order to clarify the functional role of the isolectin B4 (IB4)-binding afferent pathway in the micturition reflex, we investigated the effects on bladder activity of intrathecal application of the IB4-saporin conjugate, a targeting cytotoxin that destroys neurons binding IB4. In rats, IB4-saporin (2.5 micro m) or vehicle was administered through an intrathecal catheter implanted at the level of the L6-S1 spinal cord. Three weeks after IB4-saporin administration, cystometry in conscious animals revealed a reduction in bladder overactive responses induced by intravesical capsaicin or ATP infusion without affecting normal voiding function. In histochemical studies, double staining for IB4 and saporin was detected in L6 dorsal root ganglia (DRG) neurons 2 days after the treatment. Three weeks after the treatment, the area in lamina II of the L6 spinal cord stained with IB4 was significantly reduced compared with the area stained in control rats. The staining in the L1 spinal cord was not affected. The percentage of neurons in the L6 DRG intensely labeled with IB4 was also reduced in IB4-saporin-treated rats. These results indicate that intrathecal treatment with the IB4-saporin conjugate at the level of L6-S1 spinal cord, which reduces IB4 afferent nerve terminal staining in lamina II of the L6 spinal cord as well as the number of IB4-binding neurons in L6 DRG, suppressed bladder overactivity induced by bladder irritation without affecting normal micturition. Thus targeting IB4-binding, non-peptidergic afferent pathways sensitive to capsaicin and adenosine 5'-triphosphate may be an effective treatment for overactivity and/or pain responses in the bladder.

Comparative study of ureteral stripping versus open ureterectomy for nephroureterectomy in patients with transitional carcinoma of the renal pelvis.

OBJECTIVES: To evaluate the clinical outcome of nephroureterectomy with endoscopically assisted transurethral ureteral stripping for transitional cell carcinoma of the renal pelvis in a comparative study. METHODS: Sixty patients with localized renal pelvic cancer were enrolled in a prospective comparative nonrandomized study. Of these, 28 patients underwent nephroureterectomy with endoscopically assisted transurethral ureteral stripping and 32 underwent conventional nephroureterectomy with a bladder cuff. Both short-term and long-term results were analyzed in this series. RESULTS: The operating time for patients with ureteral stripping was significantly shorter than for those with a standard two-incision nephroureterectomy (median 183 versus 250 minutes, P = 0.0231), and the amount of blood loss was significantly less (median 150 versus 390 mL, P = 0.0002). Intravesical recurrence was detected in 10 (35.7%) of the 28 patients with ureteral stripping, and the 1-year and 3-year recurrence-free rate was 68.0% and 57.7%, respectively. Seven patients treated by the standard two-incision nephroureterectomy (21.9%) experienced intravesical recurrence, with a 1-year and 3-year recurrence-free rate of 96.8% and 75.0%, respectively. The recurrence rate was significantly greater in the group with ureteral stripping (P = 0.0287). CONCLUSIONS: Compared with conventional nephroureterectomy with a bladder cuff, nephroureterectomy with transurethral stripping is a minimally invasive procedure with a shorter operating time and less blood loss, but a statistically significantly greater intravesical recurrence rate. Greater consideration should be taken before selecting this procedure.

Comparative study of effects of extracorporeal magnetic innervation versus electrical stimulation for urinary incontinence after radical prostatectomy.

OBJECTIVES: To perform a randomized comparative study to investigate the clinical effects of extracorporeal magnetic innervation (ExMI) and functional electrical stimulation (FES) on urinary incontinence after retropubic radical prostatectomy. METHODS: Thirty-six patients with urinary incontinence after radical prostatectomy were randomly assigned to three groups (12 patients each in the FES, ExMI, and control groups). For FES, an anal electrode was used. Pulses of 20-Hz square waves at a 300-micros pulse duration were used for 15 minutes twice daily for 1 month. For ExMI, the Neocontrol system was used. The treatment sessions were for 20 minutes, twice a week for 2 months. The frequency of the pulse field was 10 Hz for 10 minutes, followed by a second treatment at 50 Hz for 10 minutes. For the control group, only pelvic floor muscle exercises were performed. Objective measures included bladder diaries, 24-hour pad weight testing, and a quality-of-life survey, at 1, 2, and 4 weeks and 2, 3, 4, 5, and 6 months after removing the catheter. RESULTS: The leakage weight during the 24 hours after removing the catheter was 684, 698, and 664 g for the FES, ExMI, and control groups, respectively. At 1 month, it was 72, 83, and 175 g (FES versus control, P <0.05) and at 2 months was 54, 18, and 92 g (ExMI versus control, P <0.05) in the FES, ExMI, and control groups, respectively. Finally, 6 months later, the average 24-hour leakage weight was less than 10 g in all groups. Quality-of-life measures decreased after surgery, but gradually improved over time in all groups. No complications were noted in any of the groups. CONCLUSIONS: ExMI and FES therapies offered earlier continence compared with the control group after radical prostatectomy. We consider ExMI and FES to be recommendable options for patients who want quick improvement of postoperative urinary incontinence.